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The Asian Journal of

Diabetology

Volume 12, Number 4

Contents

An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor

From the Desk of Group Editor-in-Chief

CDC Study Predicts Increase in Diabetes Incidence in the US

5

KK Aggarwal

Anand Gopal Bhatnagar Editorial Anchor AJD Speciality Panel Editor Dr Vijay Viswanathan Joint Editor Dr G Vijaya Kumar Associate Editors Dr V Mohan (Chennai) Dr PG Talwalkar (Mumbai) Assistant Editors Dr Shashank R Joshi (Mumbai) Dr Manisha Talim (Mumbai) Dr Deven V Parmar (Mumbai) Regional Co-ordinators Dr AK Das (South) Dr D Maji (East) Dr PG Raman (Central) Editorial Advisors Dr JK Agrawal (Varanasi) Dr HB Chandalia (Mumbai) Dr DK Hazra (Agra) Dr SD Mehtalia (Mumbai) Dr CV Krishnaswamy (Chennai) Dr C Moonichoodappa (Bangalore) Dr Sam GP Moses (Chennai) Dr KD Nihalani (Mumbai) Dr Sharad Pendsey (Nagpur) Dr BS Raheja (Mumbai) Dr D Rama Rao (Bangalore) Dr BK Sahay (Hyderabad) Dr BB Tripathy (Cuttack)

Dr V Seshiah Mrs. Rupa Assar (Mumbai) Dr JS Ajmera (Mumbai) Dr Prabha Arora (Delhi) Dr Anil Bhoraskar (Mumbai) Dr Archana Bhate (Mumbai) Dr Arun Bal (Mumbai) Dr Jayshree Barua (Mumbai) Dr SM Munirathnum Chetty (Coimbatore) Dr Siddharth Das (Cuttack) Dr Sanjay Gupta (Nagpur) Dr Sunil Gupta (Nagpur) Dr Avi Hakim (Mumbai) Dr Aspi Irani (Mumbai) Dr Lily John (Bangalore) Dr K Kannan (Madurai) Dr KM Prasanna Kumar (Bangalore) Dr Sandhya Kamath (Mumbai) Dr PSN Menon (Delhi) Dr Anant Nigam (Jaipur) Dr HS Patel (Jabalpur) Dr RB Phatak (Mumbai) Dr SK Rajan (Chennai) Dr Shrenik V Shah (Mumbai) Dr SR Sathe (Mumbai) Dr CB Sridhar (Bangalore) Dr BT Shah (Mumbai) Dr Bharat B Trivedi (Ahmedabad) Dr CS Yajnik (Pune)

from the issue Editor Vijay Viswanathan, G Vijaya Kumar

6

research article

Use of Aspirin for Primary and Secondary Prevention of Cardiovascular Disease in Diabetic Patients in an Ambulatory Care Setting in Spain

9

Antoni Sicras-Mainar, Ruth Navarro-Artieda, Javier Rejas-Gutiérrez, Jaime Fernández-de-Bobadilla, Xavier Frías-Garrido, Rafael Ruiz-Riera

IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & Gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology Dr M Paul Anand Dr SK Parashar Cardiology

Dr CR Anand Moses Dr Sidharth Das Dr A Ramachandran Dr Samith A Shetty Diabetology Dr Ajay Kumar Gastroenterology Dr Koushik Lahiri Dermatology Dr Georgi Abraham Nephrology Dr Sidharth Kumar Das Rheumatology

review article

Diabetes and CVD Risk - Prevention with Antiplatelet Drugs

19

Vijay Viswanathan

Dr V Nagarajan Neurology Dr Kamala Selvaraj Dr Thankam Verma Obs and Gyne

Advisory Body Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Aspirin Resistance G Sengottuvelu, K Babu Chakkravarthy

23


The Asian Journal of

Diabetology

Volume 12, Number 4

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at Daryacha, 39, Hauz Khas Village New Delhi - 110 016 E-mail: editorial@ijcp.com

Clinical study

Printed at IG Printers Pvt. Ltd., New Delhi E-mail: igprinter@rediffmail.com, printer_ig@yahoo.com Š Copyright 2010 IJCP Publications Pvt. Ltd. All rights reserved. The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Pvt. Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Nicotine Addiction and Depressive Symptomatology in Type 2 Diabetes Mellitus in a Rural Area in Tamil Nadu 26 Semmal Syed Meerasa M, Jaiganesh K, Gladmohesh MI, Parthasarathy S

Prevalence of Dyslipidemic Hypertension

29

V Padma, NN Anand, SM Rajendran, PJ Parameaswari

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

case report

Recurrent Vascular Disease with Flash Pulmonary Edema in a Diabetic Patient 36 G Sengottuvelu

Note: The Asian Journal of Diabetology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

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From the Desk of Group editor-In-chief

CDC Study Predicts Increase in Diabetes Incidence in the US

Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group Editor-in-Chief, eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

Dear Colleague, A study from the CDC has forecast a rise in incidence of diabetes in the US. It states that upto one-third of US adults could have diabetes by 2050 assuming that current trends continue. Theodore J. Thompson, of the agency’s Division of Diabetes Translation, and colleagues report in the journal Population Health Metrics that if the recent increases in the incidence of diabetes persist and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle-ground scenario projects a prevalence of 25-28% by the year 2050. They also suggest that with low incidence and comparatively high mortality, total prevalence of diagnosed and undiagnosed diabetes could be no more than 21% by 2050, up from 14% in 2010. However, the incidence will go up sharply over the next 40 years due to an aging population more prone to develop type 2 diabetes, increases in minority groups that are at high risk for type 2 diabetes and increase in life expectancy of people with diabetes. According to the researchers, the previous lower estimates were outdated probably as they used 1990 census projections that did not account for the increasing size of the Hispanic and foreign-born US populations at higher risk for developing diabetes. These data also did not take into consideration undiagnosed cases and assumed that there would be no increase in incidence of the disease. In the present study, the authors used data from the US Census Bureau and the CDC. The census data were based on numbers from the 2000 census and include estimates of the 2007 population and estimates of mortality rates, net migration and births from 2008 through 2050. The CDC data included estimates of diagnosed diabetes for the US adult population (ages 18-79 years) from 1980 through 2007. n Asian Journal of Diabetology, Vol. 12, No. 4

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FROM THE ISSUE EDITOR

Editor

Joint Editor

Dr Vijay Viswanathan

Dr G Vijaya Kumar

Managing Director MV Hospital for Diabetes & Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes), Chennai

Diabetologist Diabetes Medicare Centre Consultant in Diabetology Apollo Hospital, Chennai Hony. Consultant, Dept. of Diabetes VHS Medical Centre, Chennai

Dear Colleague, Greetings of the Season!

A general thought is that it’s a curse to have a chronic disease. However, Sir William Osler (1849-1919) has mentioned that “The way to lead a long-life is to a get chronic disease and take care of it”. A chronic disease enforces discipline in a patient and most of the chronic disease patients choose their diet, go for a walk and have a well-planned and well-mannered life. This issue mainly revolves around cardiovascular diseases and their prevention. A paper from Antoni Sicras-Mainar et al discusses the use of aspirin for primary and secondary prevention of CVD. Sengottuvelu et al has highlighted the issue of aspirin resistance, the alternative pathway of platelet activation and nonatherothrombotic causes of vascular events. Another article on the usage of antiplatelet drug in CVD prevention, particularly in diabetic patients is also discussed. Apart from that, ‘prevalence of dyslipidemic hypertension’ and an interesting case of ‘recurrent vascular disease with flash pulmonary edema in a diabetic patient’ have also been discussed. The important modifiable risk factor of CVD ‘Nicotine addiction’ and its relation to depression as studied in a rural population has been reported. We hope the readers will be able to fine tune their knowledge in prevention of CVD with this particular issue. n



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Asian Journal of Diabetology, Vol. 12, No. 4


IJCP Publications Pvt. Ltd.

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Daryacha, 39, Hauz Khas Village, New Delhi - 110 016 Tel.: 26965874/75 E-mail: editorial@ijcp.com, emedinews@gmail.com, drveena@ijcp.com Subscription Office: Flat 5E, Merin Estate, Geetanjali, 25/8 diamond Harbour Road, Kolkata - 700 008 Mob.: 9831363901, E-mail: subscribe@ijcp.com, Website: www.ijcpgroup.com


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emedinews is now available online on www.emedinews.in or www.emedinews.org From the Desk of Editor in Chief Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal

President, Heart Care Foundation of India; Sr Consultant and Dean Medical Education, Moolchand Medcity; Member, Delhi Medical Council; Past President, Delhi Medical Association; Past President, IMA New Delhi Branch; Past Hony Director. IMA AKN Sinha Institute, Chairman IMA Academy of Medical Specialities & Hony Finance Secretary National IMA; Editor in Chief IJCP Group of Publications & Hony Visiting Professor (Clinical Research) DIPSAR

9th November 2010, Tuesday Screening Older Smokers, Ex-smokers for Lung Cancer may Save Lives Largest study ever of lung cancer screening indicates that it helps reduce the likelihood of death. Effectiveness of CT scanning for lung cancer has been debated for years, because the test can pick up lung abnormalities like scars from past infections that are not cancer. Such irregularities are common in heavy smokers and can result in costly anxiety producing tests. Radiation is also a concern, because a CT scan, even low dose, delivers about 15 times more radiation than a chest x–ray. However, the authors of the latest study concluded that low–dose spiral CT scan can actually help reduce the death rate from lung cancer. Chest X–rays, an earlier form of screening tested repeatedly in the 1970s, have never been shown to save lives. The current eight–year study conducted at 33 sites, known as the National Lung Screening Trial (NLST), is the first to provide ‘clear evidence’ of a significant reduction in lung–cancer deaths with screening in a randomized controlled trial. Researchers noted 20 % fewer deaths from lung cancer among those screened with spiral CTs than among those given chest X–rays. The results were so conclusive that the study was terminated ahead of schedule. Dr KK Aggarwal Editor in Chief Certain Type 2 Diabetes Patients at High Risk for CV Events Type 2 diabetes patients with gated myocardial perfusion single– photon computed tomography (SPECT) imaging abnormalities, who are otherwise asymptomatic, are at high risk for cardiovascular (CV) events and death according to the study published in Diabetes Care. Other significant risk factors were having a low estimated glomerular filtration rate and being a current smoker. Shopping for Shoes Here are few tips from The American Academy of Orthopaedic Surgeons on how to choose the right footwear and keep your feet happy: • • • •

Always measure both feet each time you go shoe shopping. Try on shoes late in the day, when the feet tend to be a bit larger. Women should opt for heels that are no higher than 2 1/4 inches. Make sure the shoes fit properly in the heels and the toes, with inch of space between the shoe and your longest toe. • Try on both shoes to be sure that they fit comfortably on both feet. Opt for the size that is most comfortable on your largest foot. • Walk around the store with both shoes on to make sure the fit is comfortable. Don’t count on ‘breaking them in.’ New Rules for Truck Drivers Returning after Stroke A U.S. expert panel has recommended that commercial truck and bus drivers who suffer a stroke should wait at least a year and be able to pass a driving test and a series of health assessments before getting in front of a wheel again. The panel, appointed by the Department of Transportation, also recommends annual check–ups on health and driving records as a requirement for continued driving. Levels of Coumarin in Cassia Cinnamon vary Greatly even in Bark from the Same Tree There is a vast variation in the amounts of coumarin in bark samples of cassia cinnamon from trees growing in Indonesia, scientists are reporting in a new study. That natural ingredient in the spice may carry a theoretical risk of causing liver damage in a small number of sensitive people who consume large amounts of cinnamon. The report appears in the Journal of Agricultural and Food Chemistry. —Dr Monica and Brahm Vasudev

Infertility Update What are the specific female causes for infertility? For a woman to conceive, certain things have to happen: intercourse must take place around the time when an egg is released from her ovary; the systems that produce eggs and sperm have to be working at optimum levels and her hormones must be balanced. Some women are infertile because their ovaries do not mature and release eggs. Problems affecting women include endometriosis or damage to the fallopian tubes. Other factors that can affect a woman’s chances of conceiving include being over– or underweight for her age. Female fertility declines sharply after the age of 35. Sometimes it can be a combination of factors, and sometimes a clear cause is never established. Some of the common causes of infertility of females include: ovulation problems, tubal blockage, age-related factors, uterine problems, previous tubal legation. —Dr Kaberi Banerjee, Infertility and IVF Specialist Max Hospital; Director Precious Baby Foundation

Medicolegal Update What is the approach to acute ethanol and isopropanol poisoning? • Do a full medical examination to exclude other causes of the patient’s condition, such as head injury • Correct fluid and electrolyte imbalance. • Hypoglycemia should be treated with oral or intravenous glucose. —Dr Sudhir Gupta, Associate Professor, Forensic Medicine & Toxicology, AIIMS

Question of the Day What is a malaria paroxysm? Malaria causes an acute febrile illness which, in its most typical form, consists of febrile paroxysms occurring every 48 hours followed by afebrile intervals. These regular paroxysms separated by virtually asymptomatic intervals represent the only typical clinical feature suggestive of malaria. Typically, the following sequence may be observed: A cold stage, followed by a hot stage and a sweating stage. The total duration of the attack is 8-12 hours. The febrile paroxysm may be preceded by symptoms of fatigue, headache, dizziness, nausea and vomiting for 2-3 days before the attack. Children may have convulsions. The interval between paroxysms is determined by the length of the erythrocytic cycle of the parasite species involved (“tertian” or every 48 hours for Plasmodium falciparum, Plasmodium vivax and Plasmodium ovale; “quartan” or every 72 hours for Plasmodium malariae). Splenomegaly may be the only reliable sign at this stage. Nail or palmar pallor (anemia) and dark–colored urine, may be suggestive. In case of falciparum malaria, the paroxysm may rapidly evolve towards a severe complication of the disease (e.g., cerebral malaria or severe anemia): This is a medical emergency where diagnosis needs to be confirmed urgently and treatment started. In non–falciparum infections, fever disappears after a few paroxysms, even in the absence of treatment; relapses or recrudescences may occur a few weeks or months later. Lab Update Uric acid To detect high levels of uric acid, which could be a sign of the condition gout, or to monitor uric acid levels when undergoing chemotherapy or radiation treatment. —Dr Arpan Gandhi and Dr Navin Dang

Drug Update List of Drugs Prohibited for Manufacture and Sale through Gazette Notifications under Section 26a of Drugs & Cosmetics Act 1940 by the Ministry of Health and Family Welfare Fixed dose combination containing Pectin and/or Kaolin with any drug which is systemically absorbed from GI tract except for combinations of Pectin and/or Kaolin with drugs not systemically absorbed.


Research Article

Use of Aspirin for Primary and Secondary Prevention of Cardiovascular Disease in Diabetic Patients in an Ambulatory Care Setting in Spain Antoni Sicras-Mainar, Ruth Navarro-Artieda, Javier Rejas-Gutiérrez, Jaime Fernández-de-Bobadilla, Xavier Frías-Garrido, Rafael Ruiz-Riera

Abstract Background: This study was conducted in order to determine the use of aspirin and to assess the achievement of therapeutic targets in diabetic patients according to primary (PP) or secondary prevention (SP). Methods: This is a retrospective, observational study including patients ≥18 years with diabetes mellitus followed in four primary care centers. Measurements included demographics, use of aspirin and/or anticoagulant drugs, comorbidities, clinical parameters and proportion of patient at therapeutic target (TT). Descriptive statistics, chi-square test and logistic regression model were used for significance. Results: A total of 4,140 patients were analyzed, 79.1% (95% confidence intervals [CI]: 77.7-80.5%) in PP and 20.9% (95% CI: 18.2-23.7%) in SP. Mean age was 64.1 (13.8) years, and 49.3% of patient were men (PP: 46.3, SP: 60.7, p = 0.001). Aspirin was prescribed routinely in 20.8% (95% CI: 19.4-22.2%) in PP and 60.8% (95% CI: 57.6-64.0%) in SP. Proportion of patient at TT was 48.0% for blood pressure and 59.8% for cholesterol. Use of aspirin was associated to increased age [OR‑= 1.01 (95% CI: 1.00-1.02); p = 0.011], cardiovascular-risk factors [OR = 1.14 (95% CI: 1.03-1.27); p = 0.013], LDL-C [OR‑= 1.42 (95% CI: 1.06-1.88); p = 0.017] and higher glycated hemoglobin [OR = 1.51 (95% CI: 1.22-1.89); p = 0.000] were covariates associated to the use of aspirin in PP. Conclusion: Treatment with aspirin is underused for PP in patients with diabetes mellitus in Primary Care. Achievement of TT should be improved. Key words: Anticoagulant drugs, therapeutic target, cardiovascular-risk factors, glycated hemoglobin

Background Arterial hypertension, hypercholesterolemia, smoking, obesity, lack of physical activity and diabetes mellitus represent the main modifiable risk factors for the occurrence of cardiovascular diseases in developed countries.1 Patients with diabetes mellitus have a cardiovascular risk two to four times higher than the general population. Complications attributable to atherosclerosis are responsible for 70-80% of all deaths in diabetic patients and account for more than 75% of all hospital admissions, causing high rates of disability and health resource utilization.2 There is currently a clear trend to an increased prevalence, due both to the progressive aging of the population and to the increased frequency of sedentary habits and obesity. This situation makes institution of drug measures for primary and secondary prevention in patients with cardiovascular disease (CVD) a primary objective. The American Diabetes Association3 (ADA) recommends use of antiaggregants (low-dose acetyl salicylic acid

Citation: Sicras-Mainar et al; Use of Aspirin for Primary and Secondary Prevention of Cardiovascular Disease in Diabetic Patients in an Ambulatory Care Setting in Spain. BMC Family Practice 2007, 8:60.

Asian Journal of Diabetology, Vol. 12, No. 4

[ASA], 75-325 mg/day) in all diabetic patients with established CVD (secondary prevention) and in those with no CVD who have a high risk of cardiovascular events (primary prevention) or are over 40 years of age, provided there is no documented contraindication, such as allergy to salicylates, bleeding risk, anticoagulant therapy, recent gastrointestinal bleeding, active liver disease, or the age (to prevent Reye syndrome). These recommendations are based on three studies (ETDRS,4 HOT,5 and the Physicians’ Health Study6 showing that this treatment decreases the incidence of myocardial infarction in people with diabetes. Two of these studies are included in the metaanalysis of the US Preventive Services Task Force,7 which confirmed the decrease in the incidence of myocardial infarction, but found no significant differences in mortality reduction. In this regard, the American Heart Association8 and the results reported by several meta-analyses9,10 recommend preventive treatment with ASA in people with a 10-year risk higher than 10%. Despite the fact that various Spanish scientific societies (such as the Catalan Societies of Diabetes, Neurology, Cardiology, Family and Community Medicine, etc.) also support the start of ASA therapy as one of the main cost-effective measures, the scant evidence reported in 


research article our setting11-13 suggest that it is underused. Additional studies conducted in other countries further support the consistency of these results.14-18

Methods

hypercholesterolemia (T93: partial), active smoker (P17), obesity (T82); presence of CVD: ischemic heart disease (K74: cardiac ischemia with angina, K75: acute myocardial infarction, K76: coronary ischemia), cerebrovascular accident (K90, K91: transient cerebral ischemia), and peripheral artery disease (K92: intermittent claudicating, Raynaud syndrome, arterial stenosis or embolism); and other comorbidities: congestive heart failure (K77), renal failure (U99), liver failure (D97), chronic obstructive pulmonary disease (R95: chronic airflow obstruction), depressive syndrome (P76), and benign prostate hypertrophy (Y87). Information was obtained from the computerized clinical records. Legal regulations on data confidentiality were complied with at all times.

Study Design and Data Extraction

Measurements

A retrospective, observational study was conducted based on the medical records of patients monitored on an outpatient basis and under standard clinical practice conditions. The study population consisted of people of either sex attending four primary care centers managed by Badalona Serveis Assistencials SA. All patients older than 18 years diagnosed of diabetes mellitus according to the criteria established by the ADA3 and seen at the center over the past two years (January 2004 and December 2005) were enrolled in the study. Patients with a doubtful diagnosis and patients in whom onset of the disease had occurred less than 3 months before were excluded from the study (n = 186).

The clinical parameters measured included the cardiovascular risk index (Framingham calculation adapted for primary care), body mass index (BMI <29, kg/m2), systolic (SBP, mmHg) and diastolic blood pressure (DBP, mmHg), total cholesterol (mg/ dL), low density lipoprotein cholesterol fraction (LDL-C, obtained by the Friedewald formula,20 high density lipoprotein cholesterol fraction (HDL-C), and glycated hemoglobin (HbA1C). Some of the established recommendations3,21 for blood pressure (SBP/DBP <130/80 mmHg), and LDL-C (<100 mg/dL), see Table 1. Besides, we followed modified criterion to adapt them to a real clinical practice conditions: glycated hemoglobin (<6.5%), total cholesterol (<200 mg/dL) and body mass index (BMI <29, kg/m2), they were considered as adequate follow-up or target objectives.

The rationale of the study was to review to what extent these recommendations/guidelines, which are evidence base medicine, are implemented in real world standard condition of care in a primary care setting in Spain. Then, the purpose of this study was to determine the use of ASA for cardiovascular prevention in patients with diabetes mellitus at several health care centers under standard clinical practice conditions, and to ascertain the extent to which some therapeutic control objectives are achieved in primary care setting.

Variables recorded included age, sex, social security status (active worker, retired), primary care center identification, time (months) since initial diagnosis of the disease, number of annual visits attended according to the protocol or clinical practice guideline for cardiovascular risk of the centers, number of cardiovascular risk factors, treatment prescribed, and regular use of ASA or other oral antiaggregant and/or anticoagulant drugs (including triflusal, clopidogrel, ticlopidine, warfarin and acenocoumarol). Aspirin regular use by a patient was established when a physician prescribed aspirin for more than 8 months per year. Clinical diagnoses or comorbidities associated to diabetes mellitus were obtained from the International Classification of Primary Care (ICPC-2).19 Nonrepeated events seen in the population considered included arterial hypertension (K86, K87), 10

The last measurement obtained during 2005 was considered in all cases. Statistical Methods

Data depuration and database refining from mistake or wrong records were carried out in order to obtain good data to run statistical analyses. Personal data were blinded before analysis in order to guarantee proper anonymity of patientâ&#x20AC;&#x2122;s data in accordance with present local regulations with data management and processing. Descriptive statistics (mean, standard deviation and 95% confidence interval) and testing of Gaussian distribution by means of the KolmogorovAsian Journal of Diabetology, Vol. 12, No. 4


research article Multiple logistic regression models (enter step procedure) were carried out in the total sample, and in the subgroups according with type of prevention. The use of ASA was the dependent variable, and all significant variables observed in the bivariate analysis were incorporated into the models as independent factors. These included mean age (years), sex (male), active workers, time since disease onset (months), number of visits in the annual cardiovascular risk protocol, presence of a cardiovascular history, hypercholesterolemia and active smoking, and achievement of the therapeutic control objectives (dichotomic variables): blood pressure (<130/80 mmHg), total cholesterol (<200 mg/dl), LDL C (<100 mg/dl) and HbA1C (<6.5%). SPSS version 14.0 for Windows software was used, and a value of p < 0.05 was established as the significant level.

Table 1. Therapeutic Targets in Prevention and Treatment of Cardiovascular Disease in Diabetes Metabolic control (normal blood glucose)  

Acceptable: blood glucose <140 mg/dL and HbA1C <7% Ideal: basal blood glucose <110 mg/dL and HbA1C <6%

Lipid normalization   

TC < 170 mg/dL and TG <150 mg/dL LDL-C <100 mg/dL (or non-HDL cholesterol <130 mg/dL) HDL-C >40 mg/dL.

Blood pressure control (BP <130/80 mmHg) Smoking cessation Weight loss (normal weight)  

Acceptable: BMI <27 kg/m2 Ideal: BMI <25 kg/m2

Frequent aerobic physical exercise Other measures: antiaggregants are under study to show their value in diabetes (use of low-dose ASA is recommended in some subjects with high cardiovascular risk) HbA1C = Glycated hemoglobin; LDL-C = Low density lipoprotein cholesterol; HDL-C = High density lipoprotein cholesterol; BMI = Body mass index; ASA = Acetyl salicylic acid. Source: “Grupo de Trabajo Diabetes mellitus. Diabetes mellitus y riesgo cardiovascular. Recomendaciones del Grupo de Trabajo Diabetes Mellitus y Enfermedad Cardiovascular de la Sociedad Española de Diabetes. Clin Invest Arterioscl 2004;16:74-8”.

Ethical Considerations

Smirnov test were performed for descriptive purposes. Bivariate analysis using t-test, Man-Whitney test or Chi2, as appropriated, were applied to compare main patients’ characteristics between primary and secondary prevention. To test for homogeneity of centers, we used an analysis of variance (ANOVA) or Chi2 tests.

The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. The authors show that in the elaboration of the study the basic principles for all medical research and the confidentiality of the data have been respected marked by the law.

Table 2. General Distribution of Patients with Diabetes Mellitus by Primary Care Center (PCC) Variables

PCC-1 (n = 978 )

PCC-2 (n = 1,486 )

PCC-3 (n = 902)

PCC-4 (n = 774)

p

CVD (events, %)

22.2

20.7

20.0

21.1

ns

Use of ASA (%)

29.1

35.3

20.0

28.2

0.000

Sex (males, %)

46.9

51.5

46.8

50.9

0.041

62.2 (14.2)

64.1 (13.5)

65.5 (13.5)

64.9 (13.9)

0.000

Hypertension

49.4

51.2

55.8

50.0

0.002

Hypercholesterolemia

35.8

39.5

37.7

36.2

ns

Active smoking

21.6

17.7

18.3

17.2

ns

Obesity (BMI <29)

48.5

46.9

46.4

43.9

ns

BP (<130/80 mmHg)

49.6

37.4

50.1

57.6

0.002

Total cholesterol (<200 mg/dL)

50.6

50.7

41.1

45.0

0.000

LDL-C (<100 mg/dL)

20.6

21.7

13.5

17.1

0.000

Glycated HbA1C (<6.5%)

33.3

34.4

32.0

33.6

ns

Mean age (SD), years CV history

Therapeutic targets

Values are given as percentage or mean (SD = Standard deviation); p = Statistical significance; CVD = Cardiovascular disease; ASA = Acetyl salicylic acid; CV = Cardiovascular; BMI = Body mass index; BP = Blood pressure (mmHg); LDL-C = Low density lipoprotein cholesterol (mg/dL); Hb = Hemoglobin.

Asian Journal of Diabetology, Vol. 12, No. 4

11


research article Table 3. General Characteristics of Patients with Diabetes Mellitus by Type of Cardiovascular Prevention (Primary, Secondary) Characteristics Primary Secondary Total p (n = 3,273) (n = 867) (n = 4,140) Mean age (SD), years 62.3 (14.1) 70.9 (10.0) 64.1 (13.8) 0.000 Sex (males, %) 46.3 60.7 49.3 0.000 SS status (active, %) 37.4 11.2 31.9 0.000 Time since diagnosis (SD), months 43.2 (37.5) 52.6 (49.1) 45.2 (40.4) 0.000 Follow-up per protocol (SD), visits 3.9 (3.2) 4.4 (3.5) 4.0 (3.3) 0.000 CV history Arterial hypertension 49.2 55.9 50.6 0.002 Hypercholesterolemia 34.9 47.5 37.6 0.001 Active smoking 19.3 16.0 18.9 0.026 Obesity (BMI <29) 47.0 45.2 46.6 ns Other comorbidities Heart failure 2.4 8.1 3.6 0.000 Renal failure 1.0 3.2 1.5 0.000 Liver failure 2.8 3.9 3.0 ns COPD 4.8 12.9 6.5 0.000 Depressive syndrome 14.2 14.6 14.3 ns Prostatic hypertrophy 4.3 11.1 5.7 0.000 Treatment Acetyl salicylic acid 20.8 60.8 29.2 Other antiaggregants, OACs 5.1 30.9 10.5 0.000 Clinical parameters Body mass index (SD) 30.3 (5.3) 29.9 (4.9) 30.2 (5.2) ns Systolic blood pressure (SD) 135.3 (17.2) 135.4 (17.9) 135.4 (17.4) ns Diastolic blood pressure (SD) 78.1 (9.4) 75.7 (9.0) 77.5 (9.3) 0.000 Total cholesterol (SD) 206.9 (41.3) 192.9 (39.9) 203.9 (41.4) 0.000 LDL-C (SD) 133.7 (35.4) 123.7 (35.5) 131.6 (35.6) 0.000 Glycated hemoglobin A1C (SD) 7.2 (1.5) 7.4 (1.4) 7.3 (1.5) 0.014 CVR index (SD) 21.1 (9.1) 25.2 (9.9) 22.1 (9.3) 0.000 Therapeutic targets BP (<130/80 mmHg) 46.1 48.0 46.5 ns Total cholesterol (<200 mg/dL) 44.1 59.8 47.5 0.000 LDL-C (<100 mg/dL) 16.5 26.9 18.7 0.000 Glycated hemoglobin A1C (<6.5%) 35.2 27.2 33.4 0.001

Values are given as percentage or mean (SD = Standard deviation); p = Statistical significance; SS = Social security; CV = Cardiovascular; OACs = Oral anticoagulants; CVR = Cardiovascular risk; BP = Blood pressure (mmHg); LDL-C = Low density lipoprotein cholesterol (mg/dL); COPD = Chronic obstructive pulmonary disease.

Results The number of patients with established diagnosis of diabetes mellitus was 4,140 (crude prevalence: 6.4% of the total population), 79.1% (CI: 77.7-80.5%) in primary prevention and 20.9% (CI: 18.2-23.7%) in secondary prevention. Overall, by December 2004, 14.6% of patients followed diet therapy, while 55.2% were receiving oral antidiabetics, 9.7% oral antidiabetics plus insulin, and 20.5% insulin alone. Table 2 shows the general characteristics of the studied series, the cardiovascular history, and the therapeutic 12

control objectives in patients with diabetes mellitus by primary care center. No differences were seen between centers in cardiovascular events (range, 20.0-22.2%) or cardiovascular history (except for arterial hypertension; range, 49.4-55.8%; p = 0.002), and the percentages seen for hypercholesterolemia, active smoking, and obesity showed a certain homogeneity. The greatest variability between centers was seen in percentage of use of ASA (ranging from 20.0 to 35.3%; p < 0.001), mean patient age (ranging from 62.2 [14.2] to 65.5 [13.5]; p < 0.001), and particularly achievement of therapeutic target objectives. Thus, target blood pressure Asian Journal of Diabetology, Vol. 12, No. 4


research article (<130/80 mmHg) was achieved in 37.4-57.6% of patients (p = 0.002); target total cholesterol (<200 mg/dL) in 42.1-50.7% of patients (p < 0.001); and target LDL-C (<100 mg/dL) in 13.5% to 21.7% of cases (p = 0.000).

No. of patients

Distribution of the study variables by type of prevention (primary or secondary) is shown in Table 3. Mean patient age was 64.1 (13.8) years, and the values for patients in primary and secondary prevention were 62.3 (14.1) years and 70.9 (10.0) years respectively (p = 0.000). There was a 2.8% primary prevention (PP) patients aged less than 30 years, as compared to none in the secondary prevention (SP) group. Males accounted for 49.3% of the population (PP: 46.3; SP: 60.7; p = 0.000). Of all patients, 29.2% (CI: 27.8%-30.6%) was prescribed in ASA, 20.8% (CI: 19.4%-22.2%) in PP and 60.8% (CI: 57.6%-64.0% in SP; 10.5% of patients were routinely prescribed some other oral antiaggregant or anticoagulant (PP: 5.1%; SP: 30.9%; p = 0.000). In SP, blood pressure (55.9%) and hypercholesterolemia (47.5%) were most prevalent in the history, and the conditions where better therapeutic control objectives were achieved (48.0% and 59.8% respectively; p = 0.000). The distribution of the number of cardiovascular risk factors associated to patients with diabetes mellitus (primary or secondary prevention) is shown in Figure 1. It should be noted that most diabetic patients with no presence of CVD have 2 (35.8%) or 3 (29.5%) cardiovascular risk factors.

Primary P.

Secondary P.

1259

1173

1200 900

Total patients

1474

1500

985 801 673

600

580 428 301

300 0

294

128

132

1

2

3

48 34 12

4

5

No. of CVRFs Figure 1. Distribution of the number of cardiovascular risk factors (CVRFs) associated to patients in primary or secondary prevention.

were significantly associated to the use of ASA in secondary prevention; OR = 1.50; CI: 1.02-2.21; p = 0.039. However, patients on primary prevention, were more likely to use ASA when age increases (OR = 1.01; IC: 1.00-1.02; p = 0.011), show a higher number of cardiovascular risk factors (OR = 1.14; CI: 1.03-1.27; p = 0.013), achieve therapeutic LDL-C targets (OR = 1.42; CI: 1.06-1.88; p = 0.017), and get a poor metabolic control of glycated hemoglobin (OR = 1.51; CI: 1.22-1.89; p = 0.000). Discussion Studies on the use of acetyl salicylic acid for primary and prevention of cardiovascular disease in adult diabetic patients and their adherence to the recommendations in clinical practice guidelines are heterogeneous in character.11-18,22-24 It is important to note that the different methods used for measuring some variables

The final regression logistic model (Table 4) showed that patients with controlled-total-cholesterol

Table 4. Correction of General and Control Variables Associated to Use of Acetyl Salicylic Acid in Primary and Secondary Prevention Correction of logistic model

Primary prevention (n = 3,273)

Secondary prevention (n = 867)

Total (n = 4,140)

Variables

OR

p

CI

OR

p

CI

OR

p

CI

Age

1.01

0.011

1.00-1.02

0.98

ns

-

1.02

0.000

1.01-1.03

Sex (males)

0.98

ns

-

1.04

ns

-

0.80

0.006

0.68-0.94

Number of CVRFs

1.14

0.013

1.03-1.27

1.03

ns

-

1.16

0.001

1.06-1.26

Total cholesterol

0.89

ns

-

1.50

0.039

1.02-2.21

1.30

0.005

1.08-1.55

LDL-C

1.42

0.017

1.06-1.88

0.83

ns

-

1.29

0.012

1.04-1.62

Glycated HbA1C

1.51

0.000

1.22-1.89

1.07

ns

-

1.47

0.000

1.18-1.79

CVRFs = Cardiovascular risk factors; LDL-C = Low density lipoprotein cholesterol; OR = Odds ratio adjusted by use of acetyl salicylic acid; CI = 95% confidence intervals. Control values incorporated into the final model: Total cholesterol (<200 mg/dL), LDL-C (<100 mg/dL), and glycated hemoglobin A1C (<6.5%), p = Statistical significance

Asian Journal of Diabetology, Vol. 12, No. 4

13


research article in the reviewed studies make comparisons difficult and requires caution when considering the external validity of results. However, such limitations do not invalidate the current knowledge obtained from such patients, resulting from observations under standard clinical practice conditions in an outpatient setting. Although explanations may arise when an attempt is made to analyze the general characteristics of patients based on their clinical history (direct correlation between age and arterial hypertension), some degree of uncertainty is generally shown in the care process,25 that may possibly be influenced by the health status of the population and the different existing clinical practice approaches, randomly distributed among the primary care centers reviewed. In our study, ASA was prescribed by 29.2% of diabetic patients (CI: 27.8-30.6%). However, the proportion increased to 39.4% when use of other antiaggregant or anticoagulant drugs was considered. It should be stressed that in SP the proportion reaches 91.7% of diabetic patients (as compared to 25.9% in PP). Diabetic patients with CVD are mostly older men with a longer time since disease onset and a higher number of associated comorbidities (arterial hypertension and hypercholesterolemia). Moreover, this group has been subject to a more extensive follow-up in the scheduled control visits, and has shown a better achievement of therapeutic goals (except for glycated hemoglobin). It should be noted that a history of CVD clearly suggests to the physician and patient the need for treatment, while the opposite occurs when there is no such history. While, by definition, diabetic patients with no history of cardiovascular disease are considered â&#x20AC;&#x153;primary preventionâ&#x20AC;? patients, the risk for diabetics with no coronary history is in some studies similar to the risk of post-myocardial infarction non-diabetic patients.26 This fact has caused the control objectives for risk factors in the diabetic population established by scientific associations to be similar to those recommended for secondary prevention patients. These observations demonstrate the potential relationship between monitoring and a better metabolic control.27,28 An increased awareness and a more decided action by the family physician when faced with a diabetic patient in secondary prevention may also exist.17 Use of ASA for primary prevention in patients with diabetes mellitus is considered in elderly diabetics with several cardiovascular risk factors, LDL-C therapeutic objectives, and poor metabolic control 14

of glycated hemoglobin. In these patients (with no cardiovascular event), both ASA use and achievement of control objectives can still be improved, particularly taking into account that most primary prevention patients meet criteria for antiaggregant therapy.3,11,22 Patients and/or healthcare professionals may possibly see regular use of ASA as a non-relevant or second level treatment, as discussed by some authors16,17 and demonstrated in our study. This suggests that patients with diabetes are not treated as a function of risk, but of the presence of CVD and the degree of metabolic control achieved. The results obtained, when compared to national studies,11-13 generally show some differences in the characteristics of the diabetic patients studied, possibly attributable to the population profile used, but the rates of ASA underused are similar. Other consulted series show incremental percentages over the years, but lower than desirable values.14-17,24 Therapeutic control objectives were achieved in similar or slightly higher percentages as compared to other series reviewed.28,29 It is paradoxical that while various renowned scientific associations3,8,21 recommend use of ASA or other antiaggregants for primary prevention in diabetic patients older than 40 years, or patients under 21 years of age having some associated risk factor, such advice is not followed in clinical practice. But the most important thing is that a CVD (often angina or infarction) is not prevented.11 In this regard, the cost of prevention of a cardiovascular event with ASA treatment would be much lower than the costs resulting from hospitalization and sequels, not to speak of the social and personal burden for these patients.2,11 The efficacy of ASA in clinical trials4-9,30 contrasts with various pathophysiological studies that would explain why patients with diabetes mellitus may be more resistant to the potential benefits of the drug. Some authors postulate that response to preventive ASA treatment could be different in diabetic patients for several reasons.31 These would include the fact that diabetes may be a form of resistance to ASA or to low doses of ASA; platelets of these patients could be activated by various mechanisms that would lead to thrombosis, or also because the inflammatory stimuli present in diabetic patients could induce a cyclooxygenase-2 enzyme poorly sensitive to ASA. It has also been postulated that hyperglycemia could Asian Journal of Diabetology, Vol. 12, No. 4


research article generate a significant amount of endoperoxides and thromboxan that would counteract the action of cyclooxygenases.32 Some limitations of the study require caution in the generalization of the results. Such limitations include the retrospective design of the study, the lack of clinical results in coordination with other care levels (care continuum), and the reasons given for contraindication or intolerance to the drugs, and the lack of measure of ASA with medicinal products excluded from or not financed by the National Health System. The study sample may not be representative of the general primary care population in Spain. However, our results should be interpreted with caution, as further research supporting these results should be conducted in larger patient populations under standard clinical practice conditions. Moreover, the potential specific contraindications for ASA therapy could not be established in our study. However, the organizational model and clinical action protocols31 of centers such as the ones participating in the study are very similar, and we agree with several authors11,12,14 on the need that scientific associations and the healthcare administration design approaches aimed at increasing information and training of healthcare personnel in effective cardiovascular prevention measures, particularly in patients who have not developed any cardiovascular event. The results obtained should be of use when considering, based on the available evidence,3,33 whether treatment should be started with ASA or other antiaggregant, when indicated, as it seems obvious that treatment with lowdose ASA is one of the most favorable cost-effective measures in cardiovascular prevention in diabetic patients.3,22,34-37 Future research in diabetic patients should explore monitoring of preventive measures, effectiveness of the optimum recommended doses,38 or the specific reasons for poor patient compliance. Conclusion In our study treatment with ASA was underused for primary cardiovascular prevention in patients with diabetes mellitus. Achievement of the established therapeutic objectives should be improved. New representative studies under standard clinical practice conditions would be required. Asian Journal of Diabetology, Vol. 12, No. 4

Competing interests The author(s) declare that they have no competing interests. Acknowledgements Authors wish to thank to all different professionals working in the participating primary care centers, as their daily collaboration made possible this study.

References 1. Mudaliar S: Intense management of diabetes mellitus: role of glucose control and antiplatelet agents. J Clin Pharmacol 2004, 44:414-22. 2. Nobles-James C, James EA, Sowers JR: Revention of cardiovascular complications of diabetes mellitus by aspirin. Cardiovasc Drug Rev 2004, 22:215-26. 3. American Diabetes Association: Aspirin therapy in diabetes. Diabetes Care 2004, 27:S72-3. 4. ETDRS Investigators: Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992, 268:1292-300. 5. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998, 351:1755-62. 6. Steering Committee of the Physiciansâ&#x20AC;&#x2122; Health Study Research Group: Final report on the aspirin component of the ongoing Physiciansâ&#x20AC;&#x2122; Health Study. N Engl J Med 1989, 321:129-35. 7. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002, 136:161-72. 8. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, Franklin BA, Goldstein LB, Greenland P, Grundy SM, Hong Y, Miller NH, Lauer RM, Ockene IS, Sacco RL, Sallis JF Jr, Smith SC Jr, Stone NJ, Taubert KA: AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002, 106:388-91. 9. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE: Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 2001, 85:265-71.

15


research article 10. Pueyo G, Elosua R, Marrugat J. Metaanálisis de la evidencia científica sobre la utilidad de la toma esporádica de ácido acetilsalicílico en la prevención de enfermedad coronaria. Med Clin (Barc) 2002, 118:166-9.

24. Hennekens CH, Knatterud GL, Pfeffer MA. Use of aspirin to reduce risks of cardiovascular disease in patients with diabetes: clinical and research challenges. Diabetes Care 2004, 27:2752-4.

11. López J, Escudero S, González AM, Mencía A, García LE, Morán B: Empleo de antiagregantes en la prevención primaria y secundaria cardiovascular del diabético en el medio urbano y rural del área de León. Aten Primaria 2003, 31:361-5.

25. Wenberg J: Dealing with medical practice variation: aproposal for action. Health Aff 1984, 3:6-31.

12. Esmatjes E, Castell C, Franch J, Puigoriol E, Hernáez R: Consumo de ácido acetilsalicílico en pacientes con diabetes mellitus. Med Clin (Barc) 2004, 122:96-8. 13. de Abajo FJ, Garcia Rodriguez LA: Consumo de ácido acetilsalicílico en pacientes con diabetes mellitus. Med Clin (Barc) 2004, 123:236. 14. Nguyen KX, Marinac JS, Sun C: Aspirin for primary prevention in patients with diabetes mellitus. Fam Med 2005, 37:112-7. 15. Klinke JA, Johnson JA, Guirguis LM, Toth EL, Lee TK, Lewanczuk RZ, Majumdar SR: Underuse of aspirin in type 2 diabetes mellitus: prevalence and correlates of therapy in rural Canada. Clin Ther 2004, 26:439-46. 16. Cull CA, Neil HA, Holman RR: Changing aspirin use in patients with Type 2 diabetes in the UKPDS. Diabet Med 2004, 21:1368-71. 17. Rolka DB, Fagot-Campagna A, Narayan KM: Aspirin use among adults with diabetes: estimates from the Third National Health and Nutrition Examination Survey. Diabetes Care 2001, 24:197-201. 18. Morimoto T, Fukui T, Lee TH, Matsui K. Application of U.S. guidelines in other countries: aspirin for the primary prevention of cardiovascular events in Japan. Am J Med 2004, 117:459-68. 19. Lamberts H, Wood M. Clasificación Internacional de la Atención Primaria CIAP-2. Clasificación de razones de consulta. Barcelona, Masson/SG; 1990. 20. Friedewald WT, Levy RJ, Frederickson DS: Estimation of the concentration of low-density lipoproteins cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972, 18:499-502. 21. Grupo de Trabajo Diabetes mellitus: Diabetes mellitus y riesgo cardiovascular. Recomendaciones del Grupo de Trabajo Diabetes Mellitus y Enfermedad Cardiovascular de la Sociedad Española de Diabetes. Clin Invest Arterioscl 2004, 1:74-8.

26. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229-34. 27. Krentz AJ. Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab 2003, 5(Suppl 1):S19-27. 28. de la Calle H, Costa A, Díez-Espino J, Franch J, Goday A: Evaluación del cumplimiento de los objetivos de control metabólico de la diabetes mellitus tipo 2. Estudio TranSTAR. Med Clin (Barc) 2003, 120:446-50. 29. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A, on behalf of the PPP Collaborative Group: Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003, 26:3264-72. 30. Ceriello A, Motz E. Prevention of vascular events in diabetes mellitus: which “antithrombotic” therapy? Diabetologia 1996, 39:1405-6. 31. Ezekowitz JA, Straus SE, Majumdar SR, McAlister FA: Stroke: strategies for primary prevention. Am Fam Physician 2003, 68:2379-86. 32. Colwell JA. Antiplatelet agents for the prevention of cardiovascular disease in diabetes mellitus. Am J Cardiovasc Drugs 2004, 4:87-106. 33. Sackett D, Rosenberg W, Gray J, Haynes Rb, Richardson WS: Evidence based medicine: what it is and what it isn’t. BMJ 1996, 312:71-2. 34. Ezekowitz JA, Straus SE, Majumdar SR, McAlister FA: Stroke: strategies for primary prevention. Am Fam Physician 2003, 68:2379-86. 35. Tendera M, Wojakowski W: Role of antiplatelet drugs in the prevention of cardiovascular events. Thromb Res 2003, 110:355-9. 36. Candido R, Srivastava P, Cooper ME, Burrell LM: Diabetes mellitus: a cardiovascular disease. Curr Opin Investig Drugs 2003, 4:1088-94.

22. Bueno H: Infrautilización del ácido acetilsalicílico en la prevención cardiovascular del paciente con diabetes mellitus. Med Clin (Barc) 2004, 122:101-3.

37. Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003, 26:2181-8.

23. Mahon J, Steel K, Feagan BG, Laupacis A, Pederson LL: Use of acetylsalicylic acid by physicians and in the community. CMAJ 1991, 145:1107-16.

38. Nowak SN, Jaber LA: Aspirin dose for prevention of cardiovascular disease in diabetics. Ann Pharmacother 2003, 37:116-21.

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PPIs may Cause Bone Fractures When Used for More Than One-year or at Higher Doses: FDA

H Dr KK Aggarwal

Group Editor-in-Chief Dr KK Aggarwal

Padma Shri and Dr BC Roy Awardee Sr Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group Chief Editor, eMedinewS Member, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) drkk@ijcp.com

igh doses or long-term use of PPIs or proton-pump inhibitors can lead to an increased risk of bone fractures. This holds especially true for those over the age of 50, and for people on the high dose. The latest warning is based on a FDA review of several studies of the treatment. These epidemiologic studies revealed an elevated fracture risk at the hip, wrist and spine. But the studies do not, definitively prove that PPIs are the cause of the fractures.

  

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Review Article

Diabetes and CVD Risk - Prevention with Antiplatelet Drugs Vijay Viswanathan

Abstract In diabetes mellitus, macrovascular complications including cardiovascular disease (CVD) form the major cause of death and are responsible for a significant amount of morbidity in this population. Moreover, patients with diabetes and established atherosclerotic disease are at especially high risk for additional ischemic vascular events, including myocardial infarction, stroke and vascular death. Diabetes and prediabetic conditions are associated with platelet and coagulation derangements. Since, platelet aggregation plays an integral role in thrombus formation, treatment strategies have focused on using antiplatelet agents to prevent subsequent ischemic events. Several studies have supported the use of aspirin as a primary prevention strategy in patients with diabetes who are at high risk for cardiovascular (CV) events. However, aspirin has been associated with major side effects including intracranial bleeding (hemorrhagic stroke) even at lower dosages. Triflusal represents a refreshing alternative to aspirin. Though it is chemically related to acetylsalicylic acid, this drug with its multiplicity of actions offers comparable antiplatelet activity to aspirin while presenting a more favorable safety profile. Triflusal can thus be recommended for patients at high risk for hemorrhagic complications (especially older persons) and patients receiving or requiring fibrinolytic treatment subsequently. Key words: Diabetes mellitus, antiplatelet, aspirin, triflusal

I

n patients with diabetes mellitus, the burden of cardiovascular disease (CVD) is immense. In these individuals there is usually upto four-fold increased risk of cardiovascular events compared to age- or-sexmatched controls without diabetes mellitus. Again, amongst elderly diabetics (>65 years), 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke.1 A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation, increased platelet reactivity and worsened endothelial dysfunction as shown in Figure 1.

Diabetes mellitus Hyperglycemia

Managing Director MV Hospital for Diabetes and Research Centre Chennai, Tamil Nadu

Asian Journal of Diabetology, Vol. 12, No. 4

Insulin resistance

Oxidative stress Protein kinase C activation Receptor for advanced glycation End product (RAGE) activation

Endothelium ↓Nitric oxide ↑Endothelin-1 ↑Angiotensin II

Altered Platelet Function in Diabetes Platelets from patients with type 1 and type 2 diabetes exhibit enhanced platelet aggregation activity early in the disease course that may precede the development of CVD.2 Numerous biochemical abnormalities have been found that correlate with platelet hyperreactivity.

Excess free fatty acids

Vasoconstriction

↓Nitric oxide ↑Activation of NF-κB ↑Angiotensin II ↑Activation of activator protein-1

Inflammation

↓Nitric oxide ↑Tissue factor ↑Plasminogen ↑activator inhibitor-1 ↓Prostacyclin

Thrombosis

Hypertension Release of chemokines Hypercoagulation Vascular smooth Release of cytokines Platelet activation Muscle cell growth Expression of cellular Decreased fibrinolysis Adhesion molecules

Atherogenesis Figure 1. Atherogenic risk with diabetes mellitus.

19


Review Article  

Reduced membrane fluidity Altered calcium (Ca) and magnesium (Mg) homeostasis (increased intracellular Ca mobilization and decreased intracellular Mg leading to platelet hyperaggregation) Increased arachidonic acid metabolism leading to increased thromboxane A2(TxA2) synthesis Decreased prostacyclin production and nitric oxide (NO) production thereby promoting platelet endothelium interaction Decreased antioxidant levels increasing platelet activation Increased expression of activation-dependent adhesion molecules (e.g., glycoprotein [GP] IIb-IIIa, P-selectin) (Fig. 2).

Fibrinogen receptors

α-granule Gp IIb-IIIa complex

Aspirin as a Primary Prevention Strategy in Diabetes Based on collaborative trial data (Table 1)3-5 the American Diabetes Association (ADA) recommends that enteric-coated aspirin be used as a primary prevention strategy in patients with diabetes who are classified as being at high risk for cardiovascular (CV) events on the basis of the following risk factors:1  Family history of CHD  Cigarette smoking 

Hypertension

Thrombin

Gp IV

P-selectin

ADP/ATP TxA2

Gp IV Gp Ib-IX complex

Gp Ib-IX complex Resting platelet

β-TG.PF4

Activated platelet

Figure 2. Changes in the structure of platelet following activation.

ADP

Clopidogrel bisulfate Ticlopidine HCI

Dipyridamole Phosphodiesterase

ADP ADP ↑cAMP

Antiplatelet Drugs There are several pathways and mediators of platelet activation and subsequent aggregation (Fig. 3). Antiplatelet agents prevent platelet aggregation by inhibiting a specfic pathway or mediator. Antiplatelet agents, including aspirin, clopidogrel and Gp IIb/ IIIa inhibitors, have shown significant efficacy in reducing recurrent ischemic events in patients with diabetes.

P-selectin Gp IIb-IIIa complex

Collagen thrombin TxA2

Activation

Gp llb-llla (fibrinogen receptor)

COX TxA2

Aspirin

Figure 3. Site of action for different antiplatelet drugs.   

Weight 120% of ideal body weight Microalbuminuria or macroalbuminuria Total cholesterol >200 mg/dl (LDL cholesterol >100, HDL cholesterol <55 in women and <45 in men, and triglycerides >150)

These controlled prospective clinical trials therefore justify the use of enteric-coated low-dose aspirin (75-325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >40 years) at high risk for CV events.6 Safety of Aspirin

The major adverse effects of aspirin therapy include intracranial bleeding (hemorrhagic stroke) and extracranial bleeding, principally gastrointestinal.

Table 1. Aspirin as a Primary Prevention Strategy in Diabetes: Evidence from Collaborative Trials3-5 Trial

Number of diabetic subjects

USPHS ETDRS HOT

5

Years of study

CV endpoints

Aspirin dose (mg)

Patients with events Aspirin

Placebo

RR

P

325 q.o.d.

4.0%

10.1%

0.39

NR

MI

650 q.o.d.

9.1%

12.3%

0.72

0.038

MI

75 q.d.

2.3*

3.6*

0.64

0.002

8.9*

10.5*

0.85

0.03

3

533

5

MI

4

3,711

5

1,501

3.8

Major CV events *Events per 1,000 patient-years. NR = Not reported.

20

Asian Journal of Diabetology, Vol. 12, No. 4


Review Article Table 2. Triflusal Clinical Trials Highlighting Its Efficacy and Safety Study

Treatment (mg/d)

No. of patients

Duration of follow-up

Illness

Primary endpoint* (%)

Hemorrhage incidence (%)

Pérez-Gómez, et al9

TFL 600 Acenoc (INR 2-3) TFL + Acenoc (INR 1.25-2.4)

242 237 235

Mean of 2.76 years

Atrial fibrillation

Hazard ratio = 0.33

0.4 1.8 0.9

Matías-Guiu10

TFL 600 ASA 325

1055 1052

48.3 months 46.3 months

Cerebral infarction

13.1 12.4

16.7 25.2

Culebras et al11

TFL 600 ASA 325

33 36

12-24 months 12-24 months

Cerebral infarction

12.7 13.9

2.8 8.3

Cruz-Fernández12

TFL 600 ASA 300

235 24

35 days 35 days

Acute myocardial infarction

9.1 10.2

2.39 3.6

*Composite or first occurrence of vascular death, TIA, Nonfatal ischemic stroke or AMI. TFL = Triflusal; ASA = Acetylsalicylic acid; Acenoc = Acenocoumarol.

Though low dosages of aspirin (between 75 and 162 mg) lower the incidence of gastrointestinal adverse effects, the same is not true for intracranial complications. Based on data from primary and secondary prevention trials conducted in mixed populations of patients with and without diabetes, low-dose aspirin was associated with a definite risk of hemorrhagic stroke.1 Moreover, in patients with acute myocardial infarction, the risk of aspirin-induced hemorrhagic events may be increased by concurrent fibrinolysis or heparin therapy.7 Triflusal Triflusal represents a refreshing alternative to aspirin. It is chemically-related to acetylsalicylic acid and inhibits cycloxygenase-1 in platelets, but seems to leave intact the arachidonic acid metabolic pathway in endothelial cells. It also favors the production of NO and increases the concentration of cyclic nucleotides. Due to this multiplicity of actions, this drug presents comparable antiplatelet activity to aspirin, while presenting a more favorable safety profile at the same time.8 Large-scale clinical trials consistently indicated that triflusal had a lower risk of minor and major bleeding complications than aspirin as shown in Table 2.9-12 In the study by Cruz-Fernández12 triflusal was associated with a numerically lower incidence of any bleeding. A significantly lower occurrence of CNSrelated bleeding was noted favoring triflusal (0.3% vs 1.0%; p = 0.033). An interesting subgroup analysis of the TIM study, showed that among patients treated Asian Journal of Diabetology, Vol. 12, No. 4

with fibrinolysis (alteplase or streptokinase), triflusal was associated with a significantly lower incidence of hemorrhagic stroke than aspirin (0.1% vs 1.1%; p = 0.04); this differential was wider in an analysis of patients treated with alteplase (0% vs 1.6%; p = 0.01).13 Similarly, a meta-analysis by Costa et al14 revealed that the incidence of hemorrhagic complications (fatal or nonfatal hemorrhagic stroke, intracranial or major systemic hemorrhage) was significantly lower than in aspirin-treated patients. In addition to these data, a brief report on 26 patients with asthma and aspirin intolerance who received triflusal is noteworthy, as none of the patients developed triflusal intolerance or respiratory problems.8 Conclusion Diabetes mellitus increases the risk of cardiovascular complications including microvascular and macrovascular. Despite this challenge, many primary care physicians have not yet adopted evidence-based management strategies. The traditional therapeutic approaches emphasize glycemic control, which limits microvascular disease but lacks an established benefit in macrovascular disease. Evidence supports aggressive antiatherosclerotic management strategies upon diagnosis of type 2 diabetes to minimize the risk of cardiovascular morbidity and mortality. In such situations, aspirin enjoys a well-established effective clinical function with universal acceptance. However, aspirin increases the risk of severe extracranial hemorrhage by approximately 50%. This is equivalent 21


Review Article to 1-2 severe bleeding episodes per 1,000 patients per year and 1-2 hemorrhagic strokes per 10,000 patients per year.15 Similarly, addition of clopidogrel to low-dose aspirin showed further incremental risk of bleeding. This was evident in the CHARISMA trial,16 a doubleblind, placebo-controlled, randomized trial comparing long-term clopidogrel (75 mg/day) versus placebo supplementation to aspirin (75-162 mg). Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. The results showed that the risk of bleeding increased with clopidogrel supplementation that was strongly associated with mortality. Triflusal is an antiplatelet agent that is chemically related to aspirin and has similar effectiveness, but appears to have a better tolerability profile, especially as regards hemorrhagic complications Empirical data and results from large scale clinical trials suggest that its use may be preferable to that of aspirin, in several clinical settings where antiplatelet therapy is indicated especially in cases of geriatric patients, in cases of aspirin resistance, or when combination with fibrinolytic or anticoagulant is necessary. References 1. Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukkarjee D, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. American Diabetes Association; American Heart Association; American College of Cardiology Foundation. J Am Coll Cardiol 2010;55(25):2878-86. 2. Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26(7):2181-8. 3. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321(3):129-35. 4. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early treatment study report 14. JAMA 1992;268(10): 1292‑300. 5. Hansson L, Zanchetti A, Carruthers SG, Dahilóf B, Elmfeldt D, Julius S, et al; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.

6. Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30(1):162-72. 7. Culebras A. Triflusal: an effective antiplatelet agent with significantly lower hemorrhagic risk than ASA. Todays Ther Trends 2001;19(4):271-81. 8. Murdoch D, Plosker GL. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. Drugs 2006; 66(5):671-92. 9. Pérez-Gómez F, Alegría E, Berjón J, Iriate JA, Zumalde J, Salvador A, et al.; NASPEAF Investigators. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44(8):1557-66. 10. Matías-Guiu J, Ferro JM, Álvarez-Sabín J, Torres F, Jiménez MD, Logo A, et al.; TACIP investigators. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP study: a randomized, double-blind multicenter trial. Stroke 2003;34(4):840-8. 11. Culebras A, Rotta-Escalante R, Vila J, Dominguez R, Abiusi G, Famulari A, et al.; TAPIRSS Investigadors. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 2004;62(7):1073-80. 12. Cruz-Fernández JM, López-Bescós L, GarcíaDorado D, López García-Aranda V, Cabadés A, Martin-Jadraque L, et al. Randomized comparative trial of triflusal and aspirin following acute myocardial infarction. Eur Heart J 2000;21(6):457-65. 13. López Bescós L, et al. Incidence of vascular stroke in patients with acute myocardial infarction receiving fibrinolytic treatment. Eur Heart J Suppl 1999;1 Suppl. F:F19-23. 14. Costa J, Ferro JM, Matías-Guiu J, Álvarez-Sabín J, Torres F. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005;(3):CD004296. 15. Patrono C, García LA, Landolfi R, Baigent C. Low dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353:2373-83. 16. Berger PB, Bhatt DL, Fuster V, Steg PG, Fox KA, Shao M, et al. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation 2010;121(23):2575‑83.

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Review Article

Aspirin Resistance G Sengottuvelu*, K Babu Chakkravarthy

Abstract Aspirin is the cornerstone of therapy in atherothrombosis, encompassing a wide-spectrum of clinical entities. Evidence is growing to indicate that there are subpopulations that do not respond to antithrombotic action of aspirin. The term ‘aspirin resistance’ has been used to describe a number of different phenomena. Key words: Atherothrombosis, antiplatelet therapy

A

spirin is the cornerstone of therapy in atherothrombosis, encompassing a widespectrum of clinical entities. A meta-analysis of 287 clinical trials on aspirin in the prevention of cardiovascular disease has provided firm evidence that antiplatelet therapy, mainly aspirin, can reduce by approximately 25% the risk of nonfatal myocardial infarction (MI), nonfatal stroke or vascular death in high-risk patients, regardless of sex, age, presence of arterial hypertension or diabetes. An absolute reduction in the risk of having a serious vascular event was 36 per 1,000 MI survivors treated for two years. Undoubtedly, clinical benefits of aspirin are most apparent in patients with acute MI, which has been convincingly demonstrated in the landmark infarction trial, Second International Study of Infarct Survival (ISIS-2). Treatment failures occur with any drug and aspirin is no exception. Evidence is growing to indicate that there are subpopulations that do not respond to antithrombotic action of aspirin. The term ‘aspirin resistance’ has been used to describe a number of different phenomena, including inability of aspirin to: Protect against cardiovascular events despite its  regular intake To affect various laboratory tests, reflecting platelet  activity. *Senior Consultant and Interventional Cardiologist Dept. of Cardiology Apollo Hospitals, Chennai Address for correspondence Dr G Sengottuvelu Dept. of Cardiology Apollo Hospitals, Greams Lane Chennai - 600 006 E-mail: drgseng@gmail.com

Asian Journal of Diabetology, Vol. 12, No. 4

Possible Causes of Recurrent Ischemic Vascular Events among Patients Taking Aspirin Nonatherothrombotic Causes of Vascular Events 

Embolism from the heart (red fibrin thrombi, vegetations, calcium, tumor, prostheses) Arteritis

Reduced Bioavailability of Aspirin   

Inadequate intake of aspirin (poor compliance) Inadequate dose of aspirin Concurrent intake of certain nonsteroidal antiinflammatory drugs (NSAIDs) (ibuprofen, indomethacin), possibly preventing the access of aspirin to cyclo-oxygenase-1 binding site.

Alternative Pathways of Platelet Activation 

Platelet activation by pathways that are not blocked by aspirin (for example, red cell-induced platelet activation: Stimulation of collagen, adenosine diphosphate, epinephrine and thrombin receptors on platelets). Increased platelet sensitivity to collagen and adenosine diphosphate. Biosynthesis of thromboxane by pathways that are not blocked by aspirin (for example, by cyclooxygenase-2 in monocytes and macrophages and vascular endothelial cells).

Increased Turnover of Platelets

Increased production of platelets by the bone marrow in response to stress (for example, after 23


Review Article coronary artery bypass surgery), introducing into blood stream newly formed platelets unexposed to aspirin during the 24-hour dose interval (aspirin is given once-daily and has only a 20-minute half-life). Genetic Polymorphisms ď Ź

ď Ź

ď Ź

Polymorphisms involving platelet glycoprotein Ia/IIa, Ib/V/IX and IIb/IIIa receptors, and collagen and von Willebrand factor receptors. Polymorphisms of cyclo-oxygenase-1, cyclooxygenase-2, thromboxane A2-synthase or other arachidonate metabolism enzymes. Factor XIII Val 34 Leu polymorphism, leading to variable inhibition of factor XIII activation by low-dose aspirin.

How Common is Biochemical Aspirin Resistance? In studies investigating the prevalence of biochemical aspirin resistance, the range of prevalence estimates for biochemical aspirin resistance varied from 5.5% to 56.8%, depending on the method of assessing platelet function, the definition of biochemical

aspirin resistance, and the patients tested. These studies suggest that biochemical aspirin resistance is a measurable phenomenon in a substantial proportion of patients prescribed aspirin. However, the studies have several limitations, including small sample sizes, lack of agreement between different platelet function tests, different dose regimens and nonadherence, and little information about measurement stability over time (Table 1). Conclusions and Clinical Implications No current evidence shows that patients with biochemical aspirin resistance would respond better to alternative antiplatelet treatment regimens. Identifying such patients directly may be less cost-effective than prescribing aspirin to everyone at risk and accepting some treatment failures. We do not want to risk depriving some patients of a treatment that may benefit them, even though the effect may be small. Despite treatment failures, aspirin remains the single most cost-effective drug for the secondary prevention of atherothrombotic disease. To optimize its clinical effectiveness, clinicians should be aware of the potential causes of aspirin treatment failure, prescribe aspirin

Table 1. Laboratory Tests Used to Investigate Platelet Function

24

Test

Method

Advantages

Disadvantages

Platelet aggregation

Optical

Widely available Correlated with clinical events

Not specific Labor intensive Operator- and interpreter-dependent Assesses platelet function in the absence of erythrocytes and blood flow (shear stress)

Semi-automated PFA-100, verify now aspirin assay

Simple Rapid Correlated with clinical events Assesses platelet function in presence of erythrocytes and high shear

Moderately expensive Uncertain sensitivity and specificity Platelet membrane receptor expression

Platelet membrane receptor Expression

P-selectin flow cytometry

Expression indicates platelet activation

Uncertain sensitivity and specificity Uncertain reproducibility Uncertain correlation with clinical events Results highly dependent on flow models Expensive Labor intensive

Platelet-release products

Soluble P-selectin

Simple Correlated with clinical events Long-term storage

Uncertain sensitivity and specificity Uncertain reproducibility

Urinary thromboxane excretion

Simple Correlated with clinical events Long-term storage

Uncertain sensitivity and specificity Uncertain reproducibility

Asian Journal of Diabetology, Vol. 12, No. 4


Review Article in appropriate doses and encourage patients to take aspirin, stop smoking and avoid regular use of NSAIDs and add other antiplatelet drugs. Suggested Reading 1. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. 2. Second International Study of Infarct Survival (ISIS-2) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. 3. Juul-Móller S, Edvardsson N, Jahnmatz B, Rosén A, Sørensen S, Omblus R. The Swedish Angina Pectorics Aspirin Trial (SAPAT) group. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 1992;340:1421-5. 4. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004;292(15): 1867-74. 5. Evangelista V, Totani L, Rotondo S, Lorenzet‑R, Tognoni G, De Berardis, et al. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin? Thromb Haemost 2005;93(1):8-16. 6. De Gaetano G; Collaborative. Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet 2001;357:89-95. 7. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomized trials. Heart 2001;85(3):265-71. 8. Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier B, et al.; European Society of Cardiology. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J 2004;25(2):166-81. 9. Rocca B, Seccheiero P, Ciabattoni G, Ranelletti‑FO, Guitani L, Guidotti L, at al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002;99(11):7634-9. 10. Valles J, Santos MT, Aznar J, Osa A, Lago P, Cosin J, et al. Erythrocyte promotion of platelet reactivity

decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity. Circulation 1998;97(4):350-5. 11. Karim S, Habib A, Lévy-Toledano S, Maclouf J. Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem 1996;271(20):12042-8. 12. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara‑AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345(25):1809-17. 13. FitzGerald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet 2003; 361:542‑4. 14. Undas A, Brummel K, Musial J, Mann KG, Szczeklik‑A. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation 2001;104(22):2666-72. 15. Szczeklik A, Musial J, Undas A, Swadzba S, Góra PF, Piwowarska W, et al. Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996;16(8):948-54. 16. Szczeklik A, Musial J, Undas A, Gajenski P, Góra P, Swadzba J, et al. Inhibition of thrombin generation by simvastatin andlack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999;33(5):1286-93. 17. Steering Committee of the Physicians_ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians_Health Study. New Engl J Med 1989;321(3):129-35. 18. Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomized controlled trial. BMJ 2000;321:13-7. 19. Kawasaki T, Ozeki Y, Igawa T, Kambayashi J. Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke 2000;31(3):591-5. 20. Kunicki TJ. The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol 2002;22(1):14-20. 21. Mustonen P, van Willigen G, Lassila R. Epinephrine‑ viaactivation of p38-MAPK - abolishes the effect of aspirin on platelet deposition to collagen. Thromb Res 2001;104(6):439-49.

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clinical study

Nicotine Addiction and Depressive Symptomatology in Type 2 Diabetes Mellitus in a Rural Area in Tamil Nadu Semmal Syed Meerasa M*, Jaiganesh K**, Gladmohesh MI†, Parthasarathy S‡

Abstract Aim: This study was undertaken to evaluate the association between nicotine addiction and depression levels among patients of type 2 diabetes mellitus in a rural population in Tamil Nadu. Methodology: The study was conducted at a Primary Health Care Centre at Salem, South India. One hundred fifty diabetic subjects were taken for the study, which included 88 males and 62 females. Beck’s Depression Inventory scale was used to measure the level of depression. The nicotine addiction level was assessed using the Fagerstrom nicotine addiction evaluation standard questionnaire. Results: Depression was prevalent among 54.7% (82 patients) of diabetics; 24.7% of the 150 subjects were smokers whereas 75.3% people were nonsmokers. Among the cigarette smokers, subjects with greater levels of depression also score more in the levels of nicotine addiction i.e. nicotine addiction is more when the depression scores are more. Conclusion: Among patients of type 2 diabetes mellitus, there exists a greater prevalence and severity of depression. Those who are more depressed are also more addicted to nicotine. Measures to reduce the levels of depression among the diabetic population need to be stressed and it should begin at the primary care level itself. Nicotine addiction does not answer the problem of depression in type 2 diabetic subjects. Key words: Diabetes mellitus, depression, nicotine, addiction

T

he World Health Organization (WHO) estimates that one-third of the global adult population smoke. Because tobacco use is on the rise in developing countries, morbidity and mortality resulting from tobacco use continues to rise. Tobacco use is more intense in psychiatric patients. The comorbidity with mental illness is particularly high for depression, as these individuals are more susceptible to nicotine addiction because tobacco provides desired positive mood influences.1 Addiction is a global publichealth crisis and exerts corrosive effects at family and societal levels.2

structures. The frontal cortex mediates the ruminative ideation of depression and it also plays an important role in the dynamics of cigarette smoking. Subjects with depressive disorders are especially vulnerable to nicotine addiction. There are links between smoking and neuroticism, neurotic symptoms, poor coping skills and low self-esteem. Psychophysiological studies have proved that the symptoms of depression predict poor health status outcomes in hospitalized persons; thus, the efforts to identify the psychological component of the chronic ailments would improve the ultimate outcome.

Depression is a complex psychiatric disorder due to alteration in the intracellular pathways and target genes in multiple limbic brain regions. It alters glucose metabolism, modulates blood flow, electroencephalographic activities and causes remodeling of hippocampal neurons and other limbic

Tobacco is the single greatest preventable cause of death due to cancer. Major depression plays a causal role in smoking, increasing the risk for smoking initiation and the progression to regular and heavy smoking and decreasing the potential for smoking cessation. The smokers use nicotine to medicate their depressed mood and that the reinforcing effects of nicotine’s mood-altering properties are especially powerful in depressed smokers. There are also effects of long-term nicotine exposure on neurobiologic systems that are implicated in the etiology of depression. Nicotine, the main addictive component of tobacco, initiates synaptic and cellular changes that underline the motivational and behavioral alterations that culminate in addiction. Smoking is a conditional behavior reinforced by nicotine. Cigarettes are excellent vehicles

*Assistant Professor, Dept. of Physiology Sri Ramachandra University, Chennai **Assistant Professor, Dept. of Physiology Mahatma Gandhi Medical College and Research Institute, Puducherry † Assistant Professor, Shri Satya Sai Medical College and Research Institute Nellikuppam, Tamil Nadu ‡ Consultant Diabetologist, Govt. Dist. Headquarters Hospital Kumbakonam Address for correspondence Dr Semmal Syed Meerasa M Assistant Professor, Dept. of Physiology Sri Ramachandra University, Chennai E-mail: drsemmal@gmail.com

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Asian Journal of Diabetology, Vol. 12, No. 4


clinical study for this conditioning because the dosing via puff is precise and repeated very often.1 Nicotine has a positive reinforcing and rewarding effects that affects the people with mood disorders as smoking is also used as a ‘relief medication’ in order to ameliorate symptoms of depression. Nicotine, the major psychoactive ingredient in tobacco, acts as an antidepressant. The smoking - depression relationship is influenced by the genes that predispose to both conditions. Other potential shared etiologies are factors in the social environment, personality and coping styles.3 Individuals with a familial vulnerability for major depression, even without a personal history of major depression, are more likely to smoke despite a serious illness and to report nervousness, restlessness, difficulty in concentrating and depressed mood during past quit attempts. Low confidence and self-esteem among smokers are significant predictors of failure during smoking cessation attempts.4 Dependence is the need for continued drug exposure to avoid the withdrawal syndrome while addiction is the compulsive seeking and administration of the drug despite the grave adverse consequences. Smokers differ from nonsmokers with respect to reward processing with depressed subjects being less successful to quit smoking. India is becoming the diabetic capital of the world. With such a phenomenal increase in this chronic disease, the affected people tend to get depressed and resort to more and more of addictive drugs. Hence, we decided to undertake this study, which tries to find out the prevalence of depression in diabetics and level of addiction with nicotine among such depressed diabetics. Material and Methods A pilot study was conducted among 150 diabetic subjects in a rural area in Tamil Nadu attending a primary care facility in Salem district. All subjects gave written informed consent and were then recruited for the study. The subjects were divided into two groups, smokers and nonsmokers. A questionnaire survey which included age, sex, duration of diabetes, smoking, was done and the demographic data was collected. The presence and severity of depression as measured using the Beck Depression Inventory (BDI). The nicotine addiction level was assessed by using the Fagerstróm Nicotine addiction evaluation standard questionnaire. Both the values were then analyzed Asian Journal of Diabetology, Vol. 12, No. 4

statistically. Chi-square test, Pearson correlation were used in appropriate situations. Results One hundred fifty known diabetic patients who visited the primary health clinic in Salem were recruited for this continuous randomized prospective observational study. Out of the 150 subjects recruited for the study, 88 (58.7%) were males, 62 (41.3%) were females, with the mean age and standard deviation (SD) of 51.86 ± 11.4 years. Thirty- seven patients (24%) were smokers and 113 (76%) were nonsmokers. The mean duration of diabetes was 9.4 years, and the mean duration of smoking was 14.19 years. Among the smokers, the minimum BDI score is 10 and the maximum is 29, the mean is 14.97 ± 3.5, the minimum Fagerstróm score was 3 and the maximum 8; mean and SD 5.86 ± 1.27. Among the nonsmokers, the minimum BDI score was 0 and the maximum 19; mean 8.23 ± 2.12 (Tables 1 and 2). Data were analyzed using Pearson’s correlation, using SPSS software 14 in the computer, a statistically significant positive correlation (p < 0.05) was found existing between the duration of diabetes mellitus, depressive symptomatology and the nicotine addiction (Fig. 1). There exists a significant positive relationship between the severity of depressive symptomatology and cigarette smoking in type 2 diabetics (Table 3). Discussion Depression in diabetes mellitus was incidentally high due to the variety of complications it brings to the patient. The frequency of depressive symptomatology Table 1. Showing Demographic Data Mean Age

51.86 years

Duration of type 2 diabetes

9.4 years

Sex ratio (M/F)

88:62

Duration of smoking

14.19 years

Table 2. Showing Various Scores Smokers

Nonsmokers

BDI (Depression)

14.97

8.23

Fagerstróm (Nicotine)

5.86

27


clinical study

12

Mean duration of DM

10 8 6 4 2 0 Depressed

BDI

Not depressed

Figure 1. Showing depression scores with duration of diabetes mellitus.

Table 3. Showing Statistical Significance Correlations Duration BDI Fscore of DM score Duration of Pearson correlation 1 .180* .366* DM Sig. (2-tailed) .028 .026 N 150 150 37 BDI score Pearson correlation .180* 1 .337* Sig. (2-tailed) .028* .042 N 150 150 37 Fscore Pearson correlation .336* .337* 1 Sig. (2-tailed) .026 .042 37 37 37 N *Correlation is significant at the 0.05 level (2-tailed) DM = Diabetes mellitus; BDI = Beck depression inventory.

in diabetes patients is more and has been found to be closely associated with high level of blood glucose.3 Subjects with depressive symptoms or major depression may be susceptible to develop type 2 diabetes mellitus. The major cause behind this depression problem is physical inactivity and obesity; these two factors are part of the multifactorial etiology of diabetes mellitus Depression, after the occurrence of diabetes mellitus occurs as a secondary emotional response to its complications and results with increased lapses in taking oral hypoglycemic medication and less self care.5,6 We demonstrated a very high incidence of depression in patients with diabetes mellitus which correlates with earlier studies. Nicotine alters the neuronal morphology, survival and gene expression in nearly every system that has been examined including the cholinergic, dopaminergic, 28

serotonergic and adrenergic systems.7 Nicotine is an addictive substance that reduces serotonin, norepinephrine, monoamine oxidase and dopamine levels in the brain and leads to neurocognitive changes leading to adverse influence in the emotional control in subjects with diabetes. The neural substrates for the addictive properties have been identified as the mesocorticolimbic dopaminergic system. Depression is also associated with neurohormonal changes, like activation of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system. It alters the hypothalamic growth hormone axis, which leads to an increase in counter regulatory hormones like cortisol, catecholamines and growth hormone which antagonize the hypoglycemic effects of insulin leading to insulin resistance.8 Depression is also associated with alterations in glucose transport. Depression leads to increased inflammatory activation; chronic cytokinemia can lead to insulin resistance and impaired B cell function leading to worsening of type 2 diabetes mellitus. Depression gives a negative impact on behavioral factors, such as dietary intake and smoking which increases the risk for type 2 diabetes mellitus. It is clear from our study that smoking scores are high when the depression scores are also high. Hence, smoking creates a negative impact on diabetes and worsens depression. Our work states that with increased duration of diabetes, the depression scores and nicotine addiction are more which goes along with earlier studies. Smoking generally increases insulin resistance by altering the distribution of body fat or by exerting a direct toxic effect on the pancreatic tissue.9,10 The chemical components, of cigarettes may directly alter intracellular glucose transport or may indirectly alter it through changes in serum chemistry or by diminishing the vascular blood flow. Cigarettes contain about 3,500 different compounds in the particulate phase and 500 gaseous compounds in the volatile phase. Precisely elucidating mechanisms of action of different compounds is for the prospective future studies.11 Our study can be criticized under the following. It does not show nondiabetic individuals to effectively make certain statements. The sample size may be bigger. We have not separated the chemicals of smoke and we have taken for granted as nicotine, as it is the major component of cigarette smoke. Contâ&#x20AC;&#x2122;d on page 35... Asian Journal of Diabetology, Vol. 12, No. 4


clinical study

Prevalence of Dyslipidemic Hypertension V Padma*, NN Anand*, SM Rajendran**, PJ Parameaswari†

Abstract Background: Dyslipidemic hypertension is part of a distinct metabolic syndrome related to insulin resistance. This paper describes the prevalence and cross-sectional relations of dyslipidemic hypertension in a population-based sample of men and women. Methods: We studied 500 hypertensive patients attending HT clinic from January 2009 to April 2010. Investigations like ECG, echocardiagram, lipid profile were conducted for patients with ischemic heart disease/diabetes mellitus (IHD/DM). Other co-morbid illnessess were excluded from the study. Results: Prevalence of dyslipidemia was observed in 461 out of 500 patients. Among the dyslipidemics, 53.4% were males and 46.6% were females; 61.8% of the dyslipidemic hypertensives were between 40-60 years of age (p = 0.000); 44.7% had diastolic dysfunction, 26.5% had left ventricular hypertrophy (LVH) and 22.3% had systolic dysfunction (p = 0.000). Of the ECGs taken, 11.1% had intraventricular conduction disturbances and 26.5% had LVH, 29.3% had total cholesterol (TC) above 200 mg/dl (p = 0.000), 70.5% had a triglyceride level (TGL) >150, (p = 0.000) 42.1% had high-density lipoprotein (HDL) <40 in males and <50 in females (p = 0.001); 70.1% had low-density lipoprotein (LDL) >100 (p = 0.000) and found to be statistically significant. Conclusion: Dyslipidemia is highly prevalent in hypertensive adults. Dyslipidemia and hypertension are two of the several modifiable risk factors for cardiovascular disease morbidity and mortality. Dyslipidemia is reported in 92.2% of hypertensives particularly in our study. Carr ship lipid level has shown to reduce the risk of stroke and myocardial infarction. Key words: Hypertension, dyslipidemia, prevalence, lipid profile, co-morbid illness, myocardial infarction

D

yslipidemia and hypertension are two of several modifiable risk factors for cardiovascular disease morbidity and mortality. Dyslipidemia1,8 is reported in 50-80% of hypertensive patients in India. The co-occurrence of dyslipidemia and hypertension increases the risk of coronary heart disease (CHD)2 more than the sum of the risks associated with these component factors occurring alone. Medication directed at regulating lipids in hypertensive subjects has been shown to significantly lower the risk of stroke and myocardial infarction. Moreover, normalization of lipid levels in dyslipidemic patients with treated but uncontrolled hypertension may reduce the risk of CHD more than normalization of blood pressure.8 Aim To identify associated lipid abnormality and cardiac dysfunction in hypertensive patients. *Associate Professor, Dept. of Medicine **Professor and Head, Dept. of Medicine † Biostatistician, Dept. of Community Medicine Sree Balaji Medical College and Hospital, Chennai

Asian Journal of Diabetology, Vol. 12, No. 4

Material and Methods The sample consisted of 500 patients attending Hypertension OPD at Shree Balaji Medical College Hospital. ECG, lipid profile, echocardiogram were taken by skilled professionals. Exclusion Criteria

Patients with ischemic heart disease (IHD), diabetes mellitus previous dyslipidemia, hyperuricemia were excluded from the study. Inclusion Criteria

All hypertensive patients diagnosed according to criteria were included after obtaining a written informed consent. Study Design

Cross-sectional study3 Statistical Analysis

The data was analysed using statistical package SPSS 15.0 version. Results for Gaussian4 distributed continuous variables were expressed as the mean ± SE (mean). The descriptive and inferential statistics5 29


clinical study for the hypothetical parameters are provided in (Tables 1 and 2). The quantitative informations are provided as box plot in Figs. 1-6. For difference analysis, chi-square test6 for non-Gaussian variables and student’s t-test for Gaussian variables were used. A p < 0.05 was considered to be statistically ignificant.7

Diastolic dysfunction was present in 206 (44.7%) of hypertensive dyslipidemic patients; 13 (26.5%) had left ventricular hypertrophy (LVH); 30 (6.5%) had systolic dysfunction and 103 (22.3%) were found to have normal values. The chi-square test value of 38.689 with a p = 0.000 was found to be statistically significant.

Period of Study

Among the hypertensive dyslipidemic patients, 51 (11.1%) had conduction disturbance and 13 (26.5%) had LVH. The chi-square value 43.463 with a p = 0.000 implies statistical significance; 135 (29.3%) of the hypertensive dyslipidemic patients were found to have the total cholesterol above 200 and the chisquare of 15.645 shares a statistically significant value with a p = 0.000. Three hundred twenty-five (70.5%) had a triglycerides (TGL) >150, which was statistically significant with a chi-square 67.906 and a p = 0.000; 194 (42.1%) of hypertensive dyslipidemic patients were found to have high-density lipoprotein (HDL) <40 in males and <50 among females and it was found to be statistically significant with a chi-square value of 10.745 and a p = 0.001; 323 (70.1%) of 461 hypertensive dyslipidemic were found to have an lowdensity lipoprotein (LDL) >100 and it statistically differed from the normal LDL patients with a chisquare of 66.649 and a p = 0.000; 177 (38.4%) out of 461 hypertensive dyslipidemic patients were observed to have very LDL (VLDL) value of >35 and it was statistically significant with a chi-square value 17.314 and p = 0.000.

January 2009 to April 2010 Results Of the 500 patients enrolled in the study, 215 (46.6%) were females and 246 (53.4%) were males. Of these, 461 (92.2%) were dyslipidemic and 39 (7.8%) had normal lipid levels. Among 461 dyslipidemic patients, one (0.2%) patient was <25 years of age; 94 (20.4%) belonged to age group 25-40 years; 285 (61.8%) were between 40-60 years and 81 (17.5%) were above 60 years. Chi-square value of 27.306 was observed with a p = 0.000 which was found statistically significant. Table 1. Hypertensive dyslipidemia (461/500) = 92.2% Qualitative Analysis Parameter

Hypertensive n (%)

Hypertensive dyslipidemic n (%)

Chisquare value

p value

TC

326 (70.7)

135 (29.3)

15.645

0.000

TGL

136 (29.5)

325 (70.5)

67.905

0.000

HDL

267 (57.9)

194 (42.1)

10.745

0.001

LDL

138 (29.9)

323 (70.1)

66.649

0.000

VLDL

284 (61.6)

177 (38.4)

17.314

0.000

TC/HDL ratio

392 (85.0)

69 (15.0)

119.087

0.000

Discussion Evidence suggests that hypertension may share a similar pathophysiology with cardiovascular disease. Thus dyslipidemia, a strong predictor of EVD, may also predict incident hypertension. Dyslipidemia is highly prevalent in hypertensives, nine of 10 dyslipidemic

Table 2. Quantitative Analysis Parameter

Hypertensive dyslipidemic (mean ± SE)

Hypertensive (mean ± SE)

Student-t value

p value

TC

188.2 ± 1.4

155.2 ± 2.8

6.698

0.000

TGL

170.7 ± 2.0

126.9 ± 4.2

6.187

0.000

HDL

40.5 ± 13.6

43.1 ± 1.2

1.149

0.251(NS)

LDL

112.4 ± 27.8

86.9 ± 2.0

5.662

0.000

VLDL

35.2 ± 0.65

25.3 ± 0.8

4.386

0.000

TC/HDL ratio

4.7 ± 0.04

3.6 ± 0.09

7.047

0.000

NS = Not significant

30

Asian Journal of Diabetology, Vol. 12, No. 4


TGL Figure 2. Box plot for TGL.

Figure 4. Box plot for LDL.

Total cholesterol/HDL ratio

Figure 3. Box plot for HDL.

VLDL

LDL

Figure 1. Box plot for total cholesterol.

HDL

Total cholesterol

clinical study

Figure 5. Box plot for VLDL.

Figure 6. Box plot for TC/HDL ratio.

Asian Journal of Diabetology, Vol. 12, No. 4

31


clinical study hypertensive adults have untreated or undertreated dyslipidemia.8 Dyslipidemic hypertension is a part of a distinct metabolic syndrome related to insulin resistance.9 Studies showed that when prevalence of concomitant hypertension dyslipidemia was approximately 32%,10 the rate of myocardial infarction was more than tripled and 13.3% had cardiovascular accident in hypertension dyslipidemia. Thus patients with hypertension dyslipidemia were found to be at much greater risk for cardiovascular disease and stroke than those with hypertension or dyslipidemia alone. Williams et al11 have demonstrated a familial association of dyslipidemia and hypertension in 58 Utah families at risk for CHD and labeled this entry familial dyslipidemic hypertension. They calculated that the prevalence of familial dyslipidemic hypertension would be 12% of all patients with essential hypertension. It is well-accepted that LDL cholesterol is involved in the pathogenesis of atherosclerosis and is a risk factor for cardiovascular disease.12,13 The role of triglyceride disorders is less clear.14 Familial combined hyperlipidemia15,16 and type III dysbetalipoprotenemia17 are lipid disorders associated with CHD that present as hypertriglyceridemia in many subjects. Isolated low levels of HDL cholesterol is a common lipid disorder and is well-documented risk factor for early coronary artery disease.14,18 Several investigators have noted increased frequency of dyslipidemia with familial hypertension.15,16,21-23 The term dyslipidemia has been coined to define subjects with either elevated TGL, low HDL cholesterol or elevated LDL cholesterol or a combination of the above that are associated with increased incidence of coronary artery disease. Most recognized heart diseases are familial combined hyperlipidemia and isolated low HDL cholesterol (II), atherogenic phenotype small dense LDL cholesterol20-22 and apolipoprotein B excess23-25 also have been used to describe dyslipidemic syndromes. Dyslipidemia Patients with presence of one or more of the following criteria:

32

LDL cholesterol

>100 mg/dl

HDL cholesterol

<40 mg/dl in males <50 mg/dl in females

TG level

>150 mg/dl

S-cholesterol

>200 mg/dl

Hypertension Defined as the presence of blood pressure elevation to a level that places patients at increased risk for target organ damage in several vascular beds including the retina, brain, heart, kidney and large conduit arteries. blood presure >140/90 is considered as hypertension-stage (140-159/ 90-99) stage II-(>160/>100). Results of the study on prevalence of hypertension, and dyslipidemia9 showed that the frequency of dyslipidemia was 38% and of hypertension was 36.5% and conjoint out frequency was 15% which is 1.49 times. The expected value of two diseases were independent. In the NHANES study, the prevalence of hypertension was 41% in white men and 32% in white women. The prevalence of dyslipidemia in this study was 38%. Dyslipidemia was reported in 50-80% of hypertensive patients.8 Physiciansâ&#x20AC;&#x2122; Health Study by Sesso et al26 suggested that elevated lipid levels predate the onset of hypertension by years. Lipids offer a potentially important screening tool to identify men who are likely to develop hypertension over time. Improving dyslipidemia may reduce their risk of developing high blood pressure in later life, a new means of preventing hypertension. CHD risk in patients with co-morbid hypertension and dyslipidemia is greater than the sum of CHD risks for hypertension and dyslipidemia when they occur alone (Johnson et al, 2004; Kannel, 2000). Third National Health and Nutrition Examination survey in US-estimates the prevalence of concomitant hypertension and dyslipidemia to be about 15% in adults. Meta-analyses and clinical trials have found that antihypertensives and lipid-lowering medications significantly reduce the risk of cardiovascular disease and all-cause mortality in patients with CHD risk factors (La Rosa et al, 1999; Ross et al, 1999; Law et al, 2003). Conclusions Dyslipidemic hypertension is common and found more often than would be dictated by chance alone, which is consistent with a distinct syndrome. Given our present state of knowledge about the possible cause of dyslipidemic hypertension, coupled with the association of exercise and weight loss with increased insulin sensitivity,27 lower levels of triglycerides,28 reduced blood presure in modulating hypertensive subjects29 and higher HDL cholesterol,30,31 it seems prudent that treatment of dyslipidemic hypertensive Asian Journal of Diabetology, Vol. 12, No. 4


clinical study patients should focus on weight loss and exercise and lipid-lowering drug therapy. Control of dyslipidemia represents an opportunity to improve the overall management of individuals with hypertension and thereby reduce morbidity and mortality from atherosclerotic complications. The co-occurrence of dyslipidemia and hypertension increases the risk of coronary artery disease more than the sum of the risks associated with these component factors occurring alone. Medications directed at regulating lipids in hypertensive subjects have been shown to significantly lower the risk of stroke and myocardial infarction.32 Moreover, normalization of lipid levels in dyslipidemic patients with treated but uncontrolled hypertension may reduce the risk of CHD more than normalization of blood presure.33 Suggested Reading 1. Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology. The Essentials. 2nd edition, William and Wilkins, Baltimore. 2. Hennekens CH, Burings JE. Epidemiology in Medicine, LittleBrown and Company, Boston/Toronto. 3. Klienbaum DG, Kupper LL, Morganstern H. Epidemiologic research: principles and quantitative methods. Van Nostrand Reinhold, New York; 1982. 4. Kirkwood BR. Essentials of Medical Statistics. Kwell Scientific Publications Ltd., London. 5. Clinical Epidemiology and Biostatistics. Knapp, National Medical Series. 6. Detels R, Mc Ewen J, Beaglehole R, Tanaka H. Oxford Textbook of Public Health, 4th edition, Volume-II. 7. PSS Sundar Rao. An Introduction to Biostatistics. J Richard 1983. 8. O’Meara JG, Kardia SL, Armon JJ, Brown CA, Boerwinkle E, Turner ST. Ethnic and sex differences in the prevalence, treatment and control of dyslipidemia among hypertensive adults. GENOA Study. Arch Intern Med 2004;164(12):1313-8. 9. Eaton CB, Feldman HA, Assaf AR, McPhillips JB, Hume AL, Lasater TM, et al. Prevalence of hypertension, dyslipidemia, and dyslipidemia hypertension. J Fam Prac 1994;38(5):17-23. 10. Johnson M, Beyth R, Pietz K, Healoy Sr P, Battleman D; Academy Health. Prevalence of concomitant hypertension dyslipidemia and associated cardiovascular disease in veterans affairs healthcare system: a multicenter study. Abstr AcademyHealth Meet 2004;21:abstract no.1718. 11. Williams RR, Hunt SC, Hopkins PN, Stults BB, Wu LL, Hasstedt SJ, et al. Famlial dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present in Asian Journal of Diabetology, Vol. 12, No. 4

12. 13.

14. 15.

16. 17. 18.

19.

20.

21.

22.

23.

24.

25.

approximately 12% patients with essential hypertension. JAMA 1988;259(24):3578-86. Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977;46:897-930. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults. The Expert Panel Arch Intern Med 1988;148(1):36-69. NIH consensus Development Panel. Triglycerides HDL and corona heart disease. JAMA 1991;269:505-10. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973;52(7):1544-68. Grundy SM, Chait A, Brunzell JD. Familial combined hyperlipidemia workshop. Arteriosclerosis 1987;7:203-7. Morganroth J, Levy Rl, Fredrickson DS. The biochemical, clinical and genetic features of type III hyperlipoproteinemia. Ann Intern Med 1975;82(2):158-74. Okene IS, Okene JK, (Eds). Pathobiology of hypercholestrolemia and atherosclerosis: genetic and environmental determinants of elevated lipoprotein levels. In: Prevention of Coronary Heart Disease. Little Brown and Company, Boston, Mass; 1992:69-102. Williams RR, Hopkins PN, Hunt SC, Wu LL, Hasstedt SJ, Lalouel JM, et al. Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah. Arch Intern Med 1990;150:582‑8. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker of coronary heart disease risk. Circulation 1990;82(2):495-506. Austin MA, King MC, Vranizan KM, Newman B, Krauss RM. Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet 1988;43(6):838-46. Austin MA, Brunzell JD, Fitch WL, Krauss RM. Inheritance of low-density lipoprotein subclass patterns found in familial combined hyperlipidemia Arteriosclerosis 1990;10(4):520-30. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988;260(13):1917-21. Brunzell JD, Schrott HG, Motulsky AG, Bierman EL. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism 1976;25 (3):313-20. Krause RM, Albers JJ, Brunzell JD. An apolipoprotein B-enriched low-density lipoprotein sub species in familial combined hyperlipidemia. Clin Res 1983;31:503a.

Cont’d on page 35...

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clinical study ...Cont’d from page 33 26. Physicians’ Health study by Dr. Howard D Sesso, Dr. Rupert O Halpein, December 12, 2005-Hypertension Jan 1,2006. 27. Stern E, Blau J, Rufecki Y, Rafaelovsky M, Cohen MP. Prevalence of diabetes in Israel. Epidemiologic survey. Diabetes 1988;37(3):297-302. 28. Lampman RM, Santinga JT, Savage PJ, Bassett DR, Hydrick CR, Flora JD Jr, et al. Effect of exercise training on glucose tolerance, in vivo insulin sensitivity, lipid and lipoprotein concentrations in middle-aged men with mild hypertriglyceridemia. Metabolism 1985;34(3): 205-11. 29. Duncan JJ, Farr JE, Upton SJ, Hagan RD, Oglesby ME, Blair SN. The effects of aerobic exercise on plasma catecholamines and blood pressure in patients with mild essential hypertension. JAMA 1985;254:2609-13. 30. Thompson PD, Cullinane EM, Sady SP, Flynn MM, Bernier DN, Kantor MA, et al. Modest changes in high density lipoprotein concentration and metabolism

with prolonged exercise training. Circulation 1988;78(1):25‑34. 31. Wood PD, Stefanick ME, Dreon DM, Frey-Hewitt B, Garay SC, Williams PT, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting and compared with exercise. N Engl J Med 1988;319(18):1173-9. 32. Server PS, Dahlóf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA); a multicentre randomized controlled trial. Lancet 2003;361:1149-58. 33. Perreault S, Dorais M, Coupal L, Paradis G, Joffres MR, Grover SA. Impact of treating hyperlipidemia or hypertension to reduce the risk of death from coronary artery disease. CMAJ 1999;160(10):1449-55.

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...Cont’d from page 28 Suggestion Awareness about the ill-effects of nicotine addiction needs to be spread across the rural population and the primary care centers can play a major role in it. Large scale screening should be done at all rural points and a strict advertisement drive in the population about the ill-effects of smoking and depression in relation to diabetes mellitus should be done. Conclusion Among type 2 diabetes mellitus patients, there exists a greater prevalence and severity of depression. Those who are more depressed are also more addicted to nicotine. The addiction to smoking does not solve but possibly aggravates depression in type 2 diabetic patients. Measures to reduce the levels of depression among the diabetic population need to be stressed and it should begin at the primary care level itself. References 1. Dani JA, Harris RA. Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci 2005;8(11):1465-70. 2. Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet 2005;6(7):521-32.

3. Téllez-Zenteno JF, Cardiel MH. Risk factors associated with depression in patients with type 2 diabetes mellitus. Arch Med Res 2002;33(1):53-60. 4. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med 2000;160(21):3278‑85. 5. Ismail K. Depression and diabetes. Psychiatr Med 2009;8:6. 6. Ischaki E. Smoking and depression: is smoking cessation effective? Therap Adv Respir Dis 2009;3(1):31-8. 7. Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 2002;53(4):606-17. 8. Golden SH, Lee HB, Schreiner PJ, Roux AD, Fitzpatrick AL, Szklo M, et al. Depression and type 2 diabetes mellitus: the multiethnic study of atherosclerosis. Phychasom Med 2007;69(6):529-36. 9. Fagard RH, Nilsson PM. Smoking amplifies cardiovascular risk in patients with hypertension and diabetes. Diabetes Care 2009;32(Suppl 2):S429-S431. 10. Attvall S, Fowelin J, Lager I, Von Schenck H, Smith U. Smoking induces insulin resistancea potential link with the insulin resistance syndrome. J Intern Med 1993;233(4):327-32. 11. Will JC, Galuska DA, Ford ES, Mokdad A, Calle EE. Cigarette smoking and diabetes mellitus: evidence of a positive association from a large prospective cohort study. Int J Epidemiol 2001;30(3):540-6.

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case report

Recurrent Vascular Disease with Flash Pulmonary Edema in a Diabetic Patient G Sengottuvelu

Abstract The occurrence of recurrent vascular disease in a diabetic patient following coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) is seen in this case. When long stents are used, it can cause stent fracture leading to re-stenosis as in this case. Flash pulmonary edema is diagnostic of bilateral renal artery stenosis (RAS) particularly in a person with normal left ventricular (LV) function. This case illustrates the difficulty in diagnosing an important and treatable cause of acute pulmonary edema. The association of proven cardiac disease and pulmonary edema can lead to difficulty in correct diagnosis. Key words: Stent fracture, re-stenosis, bilateral renal artery stenosis, acute pulmonary edema

I

n this case study an elderly male hypertensive, diabetic with prior history of coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) presented with recurrent angina, orthopnea and pulmonary edema. This case illustrates the recurrent vascular disease in a diabetic patient1 and complications associated with long stenting and difficulty in diagnosing an important and treatable cause of acute pulmonary edema. Case Report A 73-year-old male, diabetic since six years, hypertensive since 25 years with past history of cerebrovascular accident (CVA) and CABG surgery in 2002, psychiatric disease and history of Parkinsonism and chronic renal failure developed unstable angina in 2005 and subsequently underwent percutaneous transluminal coronary angioplasty (PTCA) + stenting to ostial protected left main/LCX (left circumflex artery) with two overlapping drug-eluting stents (Cypher 33 mm and 23 mm) in September 2005.

with normal left ventricular (LV) function. Laboratory parameters showed anemia with worsening renal failure. Coronary angiogram done by radial approach showed occluded native left anterior descending (LAD), native right coronary artery (RCA) and saphenous vein graft to obtuse marginal branch (OM) and RCA. Left internal mammary artery (LIMA) graft to LAD was patent. Stent fracture (Fig. 1) of long circumflex stents was seen with focal in-stent re-stenosis. Hence, he underwent ad hoc PTCA and re-stenting with drugeluting stent (Cypher), with abciximab cover. He was discharged in a stable condition. After one week he again developed episodes of angina and orthopnea and was readmitted with acute pulmonary edema. During this admission, his ECG showed gross changes and troponin T was mildly positive.

He presented with recent history of chest discomfort, breathing difficulty and increasing pedal edema. Electrocardiogram (ECG) showed posterolateral ischemic changes; troponin T was negative. ECG showed wall motion abnormalities in inferobasal segments Senior Consultant and Interventional Cardiologist Dept. of Cardiology, Apollo Hospitals, Chennai Address for correspondence Dr G Sengottuvelu, Dept. of Cardiology, Apollo Hospitals Greams Lane, Chennai 600 006 E-mail: drgseng@gmail.com

36

Figure 1. Stent fracture of long circumflex stents with focal in-stent re-stenosis.

Asian Journal of Diabetology, Vol. 12, No. 4


Case Report

Figure 2. Selective renal angiogram showing significant bilateral renal artery stenosis.

ECG showed similar wall motion abnormalities with normal LV function. His renal parameters were found worsening but were managed conservatively without dialysis. Though the possibility of stent thrombosis was considered in view of his high risk for stent thrombosis (diabetes, renal failure and long stents) the absence of ST elevation in the ECG and normal LV function excluded it. Elevated B-type natriuretic peptide (BNP) factor and troponin T was considered insignificant in the presence of renal failure. He was stabilized with intravenous diuretic and nitrate infusion and increasing antihypertensive doses. After combined discussion with nephrologist and cardiologist, a check coronary angiogram and renal angiogram was done which showed left main/LCX Cypher stents Selective renal angiogram showed significant bilateral renal artery stenosis (RAS) (Fig. 2). Flash pulmonary edema is known to occur in bilateral RAS and it is an absolute indication for RAS. Therefore, he underwent successful bilateral RAS. Both the renal arteries were directly stented using Genesis stent and the ostium flared at high pressure (Fig. 3). Subsequent clinical follow-up showed marked improvement in his symptoms with no orthopnea. His renal functions stabilized but did not return completely to normal. Discussion The increased risk of recurrent vascular disease in diabetic patients is well-known and mechanisms are multifactorial and involve vascular, hematologic and metabolic factors acting in concert. Diabetic patients have a higher incidence of fissured plaques, with increased vulnerability for abrupt closure, increased blood viscosity, enhanced platelet aggregation and resultant acute myocardial infarction.1 When long stents are used, stent fracture can occur as in this case and can lead to thrombosis or re-stenosis. Asian Journal of Diabetology, Vol. 12, No. 4

Figure 3. Direct stenting of both the renal arteries using Genesis stent.

Stent fracture was likely to be affected by mechanical stress provoked by rigid structures and hinge points. Stent fracture might be associated with the high incidence of target lesion revascularization.2,3 Studies have shown that screening for RAS at the time of coronary angiogram in hypertensive, renal insufficient or flash pulmonary edema patients has a high diagnostic yield (20% prevalence) which is even greater in older and diabetic patients.4 Flash pulmonary edema is a diagnosis for both the cardiologist and the nephrologist probably because it falls into the watershed between cardiology and nephrology.5 These patients have pulmonary edema but neither severely impaired LV function nor severely impaired renal function. Acute and unprovoked, abrupt nature of the pulmonary edema gives it its usual name - flash pulmonary edema. Pickering et al6 first described this condition in 1988 following which there have been a number of papers confirming it as a distinct clinical entity.7 Vascular disease in a diabetic patient is often progressive and can involve multiple systems. RAS is a potentially correctable problem. It can be the cause of hypertension and can contribute to progressive renal failure. 37


Case Report Atherosclerosis accounts for 90% of cases of RAS; fibromuscular dysplasia results in 10% of cases of RAS. Incidence of atherosclerotic RAS increases with age and presence of disease in other vascular territory. Atherosclerotic disease usually involves proximal onethird of renal arteries. RAS is the most common cause of secondary hypertension and should be suspected if there is sudden worsening of blood pressure control, difficult to control blood pressure despite multiple medications, recurrent pulmonary edema despite a normal LV systolic function, sudden worsening of renal function with introduction of angiotensinconverting enzyme inhibitors, unexplained discrepancy of >1.5 cm in size of kidneys, unexplained azotemia, unexplained hypokalemia, abdominal bruit, flank bruit or both, severe retinopathy and presence of carotid, coronary or peripheral vascular disease. Renal failure and resistant hypertension are pointers towards RAS more so in an elderly patient. A renal angiogram is the gold standard to diagnose atherosclerotic renovascular disease. Conclusion This case illustrates the occurrence of recurrent vascular disease in a diabetic patient. These patients have high incidence of recurrent disease following CABG surgery and PTCA. When long stents are used, stent fracture can occur as in this case and can lead to re-stenosis as also in this case. In a diabetic patient, recurrent vascular disease in one territory such as coronary artery disease, cerebrovascular disease as in this case, associated RAS should be suspected particularly when there is worsening hypertension or renal function. Also, renal cause

should be suspected when pulmonary edema occurs in a person with normal LV function. This case illustrates the difficulty in diagnosing an important and treatable cause of acute pulmonary edema. References 1. Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes 1993;42(1):1-7. 2. Aoki J, Nakazawa G, Tanabe K, Hoye A, Yamamoto H, Nakayama T, et al. Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation. Catheter Cardiovasc Interv 2007;69(3):380-6. 3. Hecht HS, Polena S, Jelnin V, Jimenez M, Bhatti T, Parikh M, et al. Stent gap by 64-detector computed tomographic angiography relationship to in-stent restenosis, fracture, and overlap failure. J Am Coll Cardiol 2009;54(21):1949-59. 4. Sameer Sengottuvelu G, et al. Prevalence and safety of renal artery stenosis screening in a selected population undergoing coronary angiogram. Am J Cardiol 2003;92(6A):158L. 5. Mansoor S, Shah A, Scoble JE. Flash pulmonary oedema- a diagnosis for both the cardiologist and the nephrologist? Nephrol Dial Transplant 2001; 16(7):1311-3. 6. Pickering TG, Herman L, Devereux RB, Sotelo JE, James GD, Sos TA, et al. Recurrent pulmonary edema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 1988;2(8610):551â&#x20AC;&#x2018;2. 7. Kramer K, Kirkman P, Kitzman D, Little WC. Flash pulmonary edema: association with hypertension and reoccurrence despite coronary revascularization. Am Heart J 2000;140(3):451-5.

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AJD-Oct-Dec -2010