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Pharmacovigilance Study of Diabetes Mellitus Patients with Cardiovascular Complication in Bangladesh

Chapter 1 Literature Review 1.1 Introduction Diabetes comes from Greek, and it means a siphon. Aretus the Cappadocian, a Greek physician during the second century A.D., named the condition diabainein. He described patients who were passing too much water (polyuria) - like a siphon. The word became "diabetes" from the English adoption of the Medieval Latin diabetes. In 1675 Thomas Willis added mellitus to the term, although it is commonly referred to simply as diabetes. Mel in Latin means honey; the urine and blood of people with diabetes has excess glucose, and glucose is sweet like honey. Diabetes mellitus could literally mean "siphoning off sweet water". In ancient China people observed that ants would be attracted to some people's urine, because it was sweet. The term "Sweet Urine Disease" was coined. [1] Diabetes (diabetes mellitus) is classed as a metabolism disorder. Metabolism refers to the way our bodies use digested food for energy and growth. Most of what we eat is broken down into glucose. Glucose is a form of sugar in the blood - it is the principal source of fuel for our bodies. When our food is digested the glucose makes its way into our bloodstream. Our cells use the glucose for energy and growth. However, glucose cannot enter our cells without insulin being present - insulin makes it possible for our cells to take in the glucose. Insulin is a hormone that is produced by the pancreas. After eating, the pancreas automatically releases an adequate quantity of insulin to move the glucose present in our blood into the cells, and lowers the blood sugar level. A person with diabetes has a condition in which the quantity of glucose in the blood is too elevated (hyperglycemia). This is because the body does not produce enough insulin, produces no insulin, or has cells that do not respond properly to the insulin the pancreas


produces. This results in too much glucose building up in the blood. This excess blood glucose eventually passes out of the body in urine. So, even though the blood has plenty of glucose, the cells are not getting it for their essential energy and growth requirements. Diabetes is a metabolic disorder that is characterized by high blood glucose and either insufficient or ineffective insulin. 5.9% of the population in the United States has diabetes, and diabetes is the seventh leading cause of death in our country. Diabetes is a chronic disease without a cure, however, with proper management and treatment, diabetics can live a normal, healthy lives.[1]

1.2 Diabetes Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels that result from defects in insulin secretion, or its action, or both. Diabetes mellitus, commonly referred to as diabetes (as it will be in this article) was first identified as a disease associated with "sweet urine," and excessive muscle loss in the ancient world. Elevated levels of blood glucose (hyperglycemia) lead to spillage of glucose into the urine, hence the term sweet urine.[2] • Normally, blood glucose levels are tightly controlled by insulin, a hormone produced by the pancreas. Insulin lowers the blood glucose level. When the blood glucose elevates (for example, after eating food), insulin is released from the pancreas to normalize the glucose level. In patients with diabetes, the absence or insufficient production of insulin causes hyperglycemia. Diabetes is a chronic medical condition, meaning that although it can be controlled, it lasts a lifetime.[2] [3]

Figure 1: Diabetes can lead to heart and blood vessel disease 1.3 Cardiovascular Disease Cardiovascular disease is a class of diseases that involve the heart or blood vessels (arteries and veins).[4] Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease.[5] The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common. 1.4 Diabetes Mellitus with cardiovascular disease


This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, "Diabetes is a cardiovascular disease." [6] 1.4.1 Diabetes as a Major Risk Factor A large body of epidemiological and pathological data documents that diabetes is an independent risk factor for CVD in both men and women. Women with diabetes seem to lose most of their inherent protection against developing CVD. CVDs are listed as the cause of death in ≈65% of persons with diabetes. Diabetes acts as an independent risk factor for several forms of CVD. To make matters worse, when patients with diabetes develop clinical CVD, they sustain a worse prognosis for survival than do CVD patients without diabetes. These considerations have convinced the Scientific Advisory and Coordinating Committee of the American Heart Association (AHA) that diabetes mellitus deserves to be designated a major risk factor for CVD. This formal designation commits the AHA to a greater emphasis on diabetes as a risk factor in its scientific and educational programs. This statement provides the scientific rationale for the decision to classify diabetes as a major risk factor for CVD. [8] 1.4.2 Diabetes and Specific CVD Atherosclerotic Both type 1 diabetes and type 2 diabetes is independent risk factors for CHD. Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes. As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients. [7] 1.4.3 Diabetic Cardiomyopathy One reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated heart failure (diabetic cardiomyopathy). Thus, patients with diabetes are unusually prone to congestive heart failure. Several factors probably underlie diabetic cardiomyopathy: severe coronary atherosclerosis, prolonged hypertension, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins, and autonomic neuropathy. Improved glycemic control, better control of hypertension, and prevention of atherosclerosis with cholesterollowering therapy may prevent or mitigate diabetic cardiomyopathy. An early clinical trial suggested that sulfonyl ureas used for control of hyperglycemias are cardiotoxic and may exacerbate diabetic cardiomyopathy. This side effect, however, was not confirmed in a recent large clinical trial. [11]


Fig 2: Cardiovascular Disease and diabetes cardiovascular disease and diabetes 1.4.4 Stroke Mortality from stroke is increased almost 3-fold when patients with diabetes are matched to those without diabetes. The most common site of cerebrovascular disease in patients with diabetes is occlusion of small paramedial penetrating arteries. Diabetes also increases the likelihood of severe carotid atherosclerosis. Patients with diabetes, moreover, are likely to suffer irreversible brain damage with carotid emboli that otherwise would produce only transient ischemic attacks in persons without diabetes. Approximately 13% of patients with diabetes >65 years old have had a stroke. [13] 1.4.5 Renal Disease Renal disease is a common and often severe complication of diabetes. Approximately 35% of patients with type 1 diabetes of 18 years' duration will have signs of diabetic renal involvement. Up to 35% of new patients beginning dialysis therapy have type 2 diabetes. End-stage renal disease (ESRD) appears to be especially common among Hispanics, blacks, and Native Americans with diabetes. For patients with diabetes who are on renal dialysis, mortality rates probably exceed 20% per year. When diabetes is present, CVD is the leading cause of death among patients with ESRD. [15]

1.5 Classification of Diabetes Mellitus: [2] [3] The three main types of diabetes mellitus (DM) are: • Type 1 DM results from the body's failure to produce insulin, and presently requires the person to inject insulin. (Also referred to as insulin-dependent diabetes mellitus (IDDM) or "juvenile" diabetes) • Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. (Formerly


referred to as noninsulin-dependent diabetes mellitus (NIDDM) or "adult-onset" diabetes) • Gestational diabetes is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy. It may precede development of type 2 DM. 1.5.1 Type 1 diabetes (T1D): The body stops producing insulin or produces too little insulin to regulate blood glucose level. • Type 1 diabetes involves about 10% of all people with diabetes in the United States. • Type 1 diabetes is typically diagnosed during childhood or adolescence. It used to be referred to as juvenile-onset diabetes or insulin-dependent diabetes mellitus. • Type 1 diabetes can occur in an older individual due to destruction of the pancreas by alcohol, disease, or removal by surgery. It also results from progressive failure of the pancreatic beta cells, the only cell type that produces significant amounts of insulin. • People with type 1 diabetes require insulin treatment daily to sustain life. 1.5.2Type 2 diabetes (T2D): Although the pancreas still secretes insulin, the body of someone with type 2 diabetes is partially or completely unable to use this insulin. This is sometimes referred to as insulin resistance. The pancreas tries to overcome this resistance by secreting more and more insulin. People with insulin resistance develop type 2 diabetes when they fail to secrete enough insulin to cope with their higher demands. • At least 90% of adult individuals with diabetes have type 2 diabetes. • Type 2 diabetes is typically diagnosed in adulthood, usually after age 45 years. It used to be called adult-onset diabetes mellitus, or non-insulin-dependent diabetes mellitus. These names are no longer used because type 2 diabetes does occur in younger people, and some people with type 2 diabetes require insulin therapy. • Type 2 diabetes is usually controlled with diet, weight loss, exercise, and oral medications. However, more than half of all people with type 2 diabetes require insulin to control their blood sugar levels at some point in the course of their illness. 1.5.3 Gestational diabetes (GDM) is a form of diabetes that occurs during the second half of pregnancy. • Although gestational diabetes typically resolves after delivery of the baby, a woman who develop gestational diabetes is more likely than other women to develop type 2 diabetes later in life. • Women with gestational diabetes are more likely to have large babies. Metabolic syndrome (also referred to as syndrome X) is a set of abnormalities in which insulin-resistant diabetes (type 2 diabetes) is almost always present along with hypertension (high blood pressure), high fat levels in the blood (increased serum lipids, predominant elevation of LDL cholesterol, decreased HDL cholesterol, and elevated triglycerides), central obesity, and abnormalities in blood clotting and inflammatory responses. A high rate of cardiovascular disease is associated with metabolic syndrome.

1.6 Diabetes Causes 1.6.1 Causes of type 1 diabetes In type 1 diabetes, your immune system which normally fights harmful bacteria or viruses attacks and destroys your insulin-producing cells in the pancreas. This leaves you with little


or no insulin. Instead of being transported into your cells, sugar builds up in your bloodstream. Type 1 is thought to be caused by a combination of genetic susceptibility and environmental factors, though exactly what those factors are is still unclear. [17] 1.6.2 Causes of prediabetes and type 2 diabetes In prediabetes — which can lead to type 2 diabetes — and in type 2 diabetes, your cells become resistant to the action of insulin, and your pancreas is unable to make enough insulin to overcome this resistance. Instead of moving into your cells, sugar builds up in your bloodstream. Exactly why this happens is uncertain, although as in type 1 diabetes, it's believed that genetic and environmental factors play a role in the development of type 2. Being overweight is strongly linked to the development of type 2 diabetes, but not everyone with type 2 is overweight. 1.6.3 Causes of gestational diabetes During pregnancy, the placenta produces hormones to sustain your pregnancy. These hormones make your cells more resistant to insulin. As your placenta grows larger in the second and third trimesters, it secretes more of these hormones — making it even harder for insulin to do its job. Normally, your pancreas responds by producing enough extra insulin to overcome this resistance. But sometimes your pancreas can't keep up. When this happens, too little glucose gets into your cells and too much stays in your blood. This is gestational diabetes. [16] [17]

1.7 Connection between diabetes, heart disease, and stroke If you have diabetes, you are at least twice as likely as someone who does not have diabetes to have heart disease or a stroke. People with diabetes also tend to develop heart disease or have strokes at an earlier age than other people. If you are middle-aged and have type 2 diabetes, some studies suggest that your chance of having a heart attack is as high as someone without diabetes who has already had one heart attack. Women who have not gone through menopause usually have less risk of heart disease than men of the same age. But women of all ages with diabetes have an increased risk of heart disease because diabetes cancels out the protective effects of being a woman in her child-bearing years. [18] People with diabetes who have already had one heart attack run an even greater risk of having a second one. In addition, heart attacks in people with diabetes are more serious and more likely to result in death. High blood glucose levels over time can lead to increased deposits of fatty materials on the insides of the blood vessel walls. These deposits may affect blood flow, increasing the chance of clogging and hardening of blood vessels (atherosclerosis).[19]


Figure 3: Connection between diabetes, heart disease, and stroke

1.8 Risk factors for heart disease and stroke in people with diabetes [19] Diabetes itself is a risk factor for heart disease and stroke. Also, many people with diabetes have other conditions that increase their chance of developing heart disease and stroke. These conditions are called risk factors. One risk factor for heart disease and stroke is having a family history of heart disease. If one or more members of your family had a heart attack at an early age (before age 55 for men or 65 for women), you may be at increased risk. You can't change whether heart disease runs in your family, but you can take steps to control the other risk factors for heart disease listed here: • Having central obesity. Central obesity means carrying extra weight around the waist, as opposed to the hips. A waist measurement of more than 40 inches for men and more than 35 inches for women means you have central obesity. Your risk of heart disease is higher • because abdominal fat can increase the production of LDL (bad) cholesterol, the type of blood fat that can be deposited on the inside of blood vessel walls. [19] [21] •

Having abnormal blood fat (cholesterol) levels.- LDL cholesterol can build up inside your blood vessels, leading to narrowing and hardening of your arteries-the blood vessels that carry blood from the heart to the rest of the body. Arteries can then become blocked. Therefore, high levels of LDL cholesterol raise your risk of getting heart disease. - Triglycerides are another type of blood fat that can raise your risk of heart disease when the levels are high. - HDL (good) cholesterol removes deposits from inside your blood vessels and takes them to the liver for removal. Low levels of HDL cholesterol increase your risk for heart disease. [19][21]


Having high blood pressure. If you have high blood pressure, also called hypertension, your heart must work harder to pump blood. High blood pressure can strain the heart, damage blood vessels, and increase your risk of heart attack, stroke, eye problems, and kidney problems. Smoking. Smoking doubles your risk of getting heart disease. Stopping smoking is especially important for people with diabetes because both smoking and diabetes narrow blood vessels. Smoking also increases the risk of other long-term complications, such as eye problems. In addition, smoking can damage the blood vessels in your legs and increase the risk of amputation. [21]

1.9 Diabetes Symptoms [22] Diabetes symptoms vary depending on how high your blood sugar is elevated. Some people, especially those with prediabetes or type 2 diabetes, may not experience symptoms initially. In type 1 diabetes, however, symptoms tend to come on quickly and be more severe. Some of the signs and symptoms of type 1 and type 2 diabetes include: • Increased thirst • Frequent urination • Extreme hunger • Unexplained weight loss • Presence of ketones in the urine (ketones are a byproduct of the breakdown of muscle and fat that happens when there's not enough insulin) • Fatigue • Blurred vision • Slow-healing sores • Mild high blood pressure • Frequent infections, such as gum or skin infections and vaginal or bladder infections Although type 1 diabetes can develop at any age, it typically appears during childhood or adolescence. Type 2 diabetes, the most common type, can develop at any age and is often preventable

1.10 Complications of diabetes [2] Both type 1 and type 2 diabetes ultimately lead to high blood sugar levels, a condition called hyperglycemia. Over a long period of time, hyperglycemia damages the retina of the eye, the blood vessels of the kidneys, the nerves, and other blood vessels. • Damage to the retina from diabetes (diabetic retinopathy) is a leading cause of blindness. • Damage to the kidneys from diabetes (diabetic nephropathy) is a leading cause of kidney failure. • Damage to the nerves from diabetes (diabetic neuropathy) is a leading cause of foot wounds and ulcers, which frequently lead to foot and leg amputations. • Damage to the nerves in the autonomic nervous system can lead to paralysis of the stomach (gastroparesis), chronic diarrhea, and an inability to control heart rate and blood pressure during postural changes. • Diabetes accelerates atherosclerosis, (the formation of fatty plaques inside the arteries), which can lead to blockages or a clot (thrombus). Such changes can then


lead to heart attack, stroke, and decreased circulation in the arms and legs (peripheral vascular disease). • Diabetes predisposes people to elevated blood pressure, high levels of cholesterol and triglycerides. These conditions both independently and together with hyperglycemia, increase the risk of heart disease, kidney disease, and other blood vessel complications. Diabetes can contribute to a number of acute (short-lived) medical problems. • Many infections are associated with diabetes, and infections are frequently more dangerous in someone with diabetes because the body's normal ability to fight infections is impaired. To compound the problem, infections may worsen glucose control, which further delays recovery from infection. • Hypoglycemia or low blood sugar, occurs intermittently in most people with diabetes. It can result from taking too much diabetes medication or insulin (sometimes called an insulin reaction), missing a meal, exercising more than usual, drinking too much alcohol, or taking certain medications for other conditions. It is very important to recognize hypoglycemia and be prepared to treat it at all times. Headache, feeling dizzy, poor concentration, tremor of the hands, and sweating are common symptoms of hypoglycemia. A person can faint or have a seizure if blood sugar level becomes too low. • Diabetic ketoacidosis (DKA) is a serious condition in which uncontrolled hyperglycemia (usually due to complete lack of insulin or a relative deficiency of insulin) over time creates a buildup of ketones (acidic waste products) in the blood. High levels of ketones can be very harmful. This typically happens to people with type 1 diabetes who do not have good blood glucose control. Diabetic ketoacidosis can be precipitated by infection, stress, trauma, missing medications like insulin, or medical emergencies such as a stroke and heart attack. • Hyperosmolar hyperglycemic nonketotic syndrome is a serious condition in which the blood sugar level gets very high. The body tries to get rid of the excess blood sugar by eliminating it in the urine. This increases the amount of urine significantly, and often leads to dehydration so severe that it can cause seizures, coma, and even death. This syndrome typically occurs in people with type 2 diabetes who are not controlling their blood sugar levels, who have become dehydrated, or who have stress, injury, stroke, or are taking certain medications, like steroids. 1.10.1Other Complications •

Uncontrolled diabetes often leads to biochemical imbalances that can cause acute life-threatening events, such as diabetic ketoacidosis and hyperosmolar—nonketotic —coma. People with diabetes are more susceptible to many other illnesses. Once they acquire these illnesses, they often have worse prognoses. For example, they are more likely to die with pneumonia or influenza than people who do not have diabetes. People with diabetes ages 60 years or older are 2 to 3 times more likely to report an inability to walk one-quarter of a mile, climb stairs, or do housework compared with people without diabetes in the same age group.


People with diabetes are twice as likely to have depression, which can complicate diabetes management, than people without diabetes. In addition, depression is associated with a 60 percent increased risk of developing type 2 diabetes. As indicated above, diabetes can affect many parts of the body and can lead to serious complications such as blindness, kidney damage, and lower-limb amputations. Working together, people with diabetes, their support network, and their health care providers can reduce the occurrence of these and other diabetes complications by controlling the levels of blood glucose, blood pressure, and blood lipids, and by receiving other preventive care practices in a timely manner. •

1.11 Preventing Diabetes Complications [20] Glucose Control •

Studies in the United States and abroad have found that improved glycemic control benefits people with either type 1 or type 2 diabetes. In general, every percentage point drop in A1C blood test results, for example, from 8.0 to 7.0 percent, can reduce the risk of microvascular complications—eye, kidney, and nerve diseases—by 40 percent. The absolute difference in risk may vary for certain subgroups of people. In patients with type 1 diabetes, intensive insulin therapy has long-term beneficial effects on the risk of cardiovascular disease.

Blood Pressure Control •

• • •

Blood pressure control reduces the risk of cardiovascular disease—heart disease or stroke—among people with diabetes by 33 to 50 percent and the risk of microvascular complications—eye, kidney, and nerve diseases—by about 33 percent. In general, for every 10 mmHg reduction in systolic blood pressure, the risk for any complication related to diabetes is reduced by 12 percent. No benefit of reducing systolic blood pressure below 140 mmHg has been demonstrated in randomized clinical trials. Reducing diastolic blood pressure from 90 mmHg to 80 mmHg in people with diabetes reduces the risk of major cardiovascular events by 50 percent.

Control of Blood Lipids •

Improved control of LDL, or bad, cholesterol can reduce cardiovascular complications by 20 to 50 percent.

Preventive Care Practices for Eyes, Feet, and Kidneys • • •

Detecting and treating diabetic eye disease with laser therapy can reduce the development of severe vision loss by an estimated 50 to 60 percent. About 65 percent of adults with diabetes and poor vision can be helped by appropriate eyeglasses. Comprehensive foot care programs—ones that include risk assessment, foot-care education and preventive therapy, treatment of foot problems, and referral to specialists—can reduce amputation rates by 45 to 85 percent. Detecting and treating early diabetic kidney disease by lowering blood pressure can reduce the decline in kidney function by 30 to 70 percent. Treatment with particular medications for hypertension called angiotensin-converting enzyme (ACE) inhibitors


and angiotensin receptor blockers (ARBs) is more effective in reducing the decline in kidney function than is treatment with other blood pressure lowering drugs. In addition to lowering blood pressure, ARBs and ACE inhibitors reduce proteinuria, a risk factor for developing kidney disease, by about 35 percent.

1.12 Metabolic syndrome and it linked to heart disease: Metabolic syndrome is a grouping of traits and medical conditions that puts people at risk for both heart disease and type 2 diabetes. It is defined by the National Cholesterol Education Program as having any three of the following five traits and medical conditions: Traits and Medical Conditions

Definition

Elevated waist circumference

Waist measurement of

Elevated levels of triglycerides

40 inches or more in men

35 inches or more in women

150

mg/dL

or

higher

or •

Taking medication for elevated triglyceride levels

Low

levels

of

HDL

(good)

cholesterol

Below 40 mg/dL in men

Below

50

mg/dL

in

women

or Taking medication for low HDL cholesterol levels Elevated blood pressure levels

130 mm Hg or higher for systolic blood pressure or

85 mm Hg or higher for diastolic blood pressure or Taking medication for elevated blood pressure levels

Elevated fasting blood glucose

levels

100

mg/dL

or

higher

or •

Taking medication for elevated blood glucose


Traits and Medical Conditions

Definition levels

Table: Metabolic syndrome and it linked to heart disease

1.13 Prevent or delay heart disease and stroke. [23] Even if you are at high risk for heart disease and stroke, you can help keep your heart and blood vessels healthy. You can do so by taking the following steps: • Make sure that your diet is "heart-healthy." Meet with a registered dietitian to plan a diet that meets these goals: • Include at least 14 grams of fiber daily for every 1,000 calories consumed. Foods high in fiber may help lower blood cholesterol. Oat bran, oatmeal, whole-grain breads and cereals, dried beans and peas (such as kidney beans, pinto beans, and black-eyed peas), fruits, and vegetables are all good sources of fiber. Increase the amount of fiber in your diet gradually to avoid digestive problems. • Cut down on saturated fat. It raises your blood cholesterol level. Saturated fat is found in meats, poultry skin, butter, dairy products with fat, shortening, lard, and tropical oils such as palm and coconut oil. Your dietitian can figure out how many grams of saturated fat should be your daily maximum amount. • Keep the cholesterol in your diet to less than 300 milligrams a day. Cholesterol is found in meat, dairy products, and eggs. • Keep the amount of trans fat in your diet to a minimum. It's a type of fat in foods that raises blood cholesterol. Limit your intake of crackers, cookies, snack foods, commercially prepared baked goods, cake mixes, microwave popcorn, fried foods, salad dressings, and other foods made with partially hydrogenated oil. In addition, some kinds of vegetable shortening and margarines have trans fat. Check for trans fat in the Nutrition Facts section on the food package. • Make physical activity part of your routine. Aim for at least 30 minutes of exercise most days of the week. Think of ways to increase physical activity, such as taking the stairs instead of the elevator. If you haven't been physically active recently, see your doctor for a checkup before you start an exercise program. • Reach and maintain a healthy body weight. If you are overweight, try to be physically active for at least 30 minutes a day, most days of the week. Consult a registered dietitian for help in planning meals and lowering the fat and calorie content of your diet to reach and maintain a healthy weight. Aim for a loss of no more than 1 to 2 pounds a week. • If you smoke, quit. Your doctor can help you find ways to quit smoking. • Ask your doctor whether you should take aspirin. Studies have shown that taking a low dose of aspirin every day can help reduce the risk of heart disease and stroke. However, aspirin is not safe for everyone. Your doctor can tell you whether taking aspirin is right for you and exactly how much to take.


•

Get prompt treatment for transient ischemic attacks (TIAs). Early treatment for TIAs, sometimes called mini-strokes, may help prevent or delay a future stroke. Signs of a TIA are sudden weakness, loss of balance, numbness, confusion, blindness in one or both eyes, double vision, difficulty speaking, or a severe headache.

1.14 Types of heart and blood vessel disease occur in people with diabetes Two major types of heart and blood vessel disease, also called cardiovascular disease, are common in people with diabetes: coronary artery disease (CAD) and cerebral vascular disease. People with diabetes are also at risk for heart failure. Narrowing or blockage of the blood vessels in the legs, a condition called peripheral arterial disease, can also occur in people with diabetes. 1.14.1 Coronary Artery Disease Coronary artery disease, also called ischemic heart disease, is caused by a hardening or thickening of the walls of the blood vessels that go to your heart. Your blood supplies oxygen and other materials your heart needs for normal functioning. If the blood vessels to your heart become narrowed or blocked by fatty deposits, the blood supply is reduced or cut off, resulting in a heart attack.[24] 1.14.2 Cerebral Vascular Disease Cerebral vascular disease affects blood flow to the brain, leading to strokes and TIAs. It is caused by narrowing, blocking, or hardening of the blood vessels that go to the brain or by high blood pressure. Stroke A stroke results when the blood supply to the brain is suddenly cut off, which can occur when a blood vessel in the brain or neck is blocked or bursts. Brain cells are then deprived of oxygen and die. A stroke can result in problems with speech or vision or can cause weakness or paralysis. Most strokes are caused by fatty deposits or blood clots-jelly-like clumps of blood cells-that narrow or block one of the blood vessels in the brain or neck. A blood clot may stay where it formed or can travel within the body. People with diabetes are at increased risk for strokes caused by blood clots. A stroke may also be caused by a bleeding blood vessel in the brain. Called an aneurysm, a break in a blood vessel can occur as a result of high blood pressure or a weak spot in a blood vessel wall. TIAs TIAs are caused by a temporary blockage of a blood vessel to the brain. This blockage leads to a brief, sudden change in brain function, such as temporary numbness or weakness on one side of the body. Sudden changes in brain function also can lead to loss of balance, confusion, blindness in one or both eyes, double vision, difficulty speaking, or a severe headache. However, most symptoms disappear quickly and permanent damage is unlikely. If symptoms do not resolve in a few minutes, rather than a TIA, the event could be a stroke. The occurrence of a TIA means that a person is at risk for a stroke sometime in the future. See page 3 for more information on risk factors for stroke.


Heart Failure Heart failure is a chronic condition in which the heart cannot pump blood properly-it does not mean that the heart suddenly stops working. Heart failure develops over a period of years, and symptoms can get worse over time. People with diabetes have at least twice the risk of heart failure as other people. One type of heart failure is congestive heart failure, in which fluid builds up inside body tissues. If the buildup is in the lungs, breathing becomes difficult. Blockage of the blood vessels and high blood glucose levels also can damage heart muscle and cause irregular heartbeats. People with damage to heart muscle, a condition called cardiomyopathy, may have no symptoms in the early stages, but later they may experience weakness, shortness of breath, a severe cough, fatigue, and swelling of the legs and feet. Diabetes can also interfere with pain signals normally carried by the nerves, explaining why a person with diabetes may not experience the typical warning signs of a heart attack. Peripheral Arterial Disease Another condition related to heart disease and common in people with diabetes is peripheral arterial disease (PAD). With this condition, the blood vessels in the legs are narrowed or blocked by fatty deposits, decreasing blood flow to the legs and feet. PAD increases the chances of a heart attack or stroke occurring. Poor circulation in the legs and feet also raises the risk of amputation. Sometimes people with PAD develop pain in the calf or other parts of the leg when walking, which is relieved by resting for a few minutes. [24]

1.15 Treatment options for heart disease Treatment for heart disease includes meal planning to ensure a heart-healthy diet and physical activity. In addition, you may need medications to treat heart damage or to lower your blood glucose, blood pressure, and cholesterol. If you are not already taking a low dose of aspirin every day, your doctor may suggest it. You also may need surgery or some other medical procedure.[25] 1.15.1 How will I know whether I have had a stroke? The following signs may mean that you have had a stroke: • sudden weakness or numbness of your face, arm, or leg on one side of your body • sudden confusion, trouble talking, or trouble understanding • sudden dizziness, loss of balance, or trouble walking • sudden trouble seeing out of one or both eyes or sudden double vision • sudden severe headache If you have any of these symptoms, call 911 right away. You can help prevent permanent damage by getting to a hospital within an hour of a stroke. If your doctor thinks you have had a stroke, you may have tests such as a neurological examination to check your nervous system, special scans, blood tests, ultrasound examinations, or x rays. You also may be given medication that dissolves blood clots. [25][26]

1.15.2 Treatment options for stroke? At the first sign of a stroke, you should get medical care right away. If blood vessels to your brain are blocked by blood clots, the doctor can give you a "clot-busting" drug. The drug must be given soon after a stroke to be effective. Subsequent treatment for stroke includes


medications and physical therapy, as well as surgery to repair the damage. Meal planning and physical activity may be part of your ongoing care. In addition, you may need medications to lower your blood glucose, blood pressure, and cholesterol and to prevent blood clots. [26] Points to Remember • If you have diabetes, you are at least twice as likely as other people to have heart disease or a stroke. • Controlling the ABCs of diabetes-A1C (blood glucose), blood pressure, and cholesterol-can cut your risk of heart disease and stroke. • Choosing foods wisely, being physically active, losing weight, quitting smoking, and taking medications (if needed) can all help lower your risk of heart disease and stroke. • If you have any warning signs of a heart attack or a stroke, get medical care immediately-don't delay. Early treatment of heart attack and stroke in a hospital emergency room can reduce damage to the heart and the brain.

Fig 4: Intensive diabetes treatment and cardiovascular disease in patients

1.16 Fact sheet: Diabetes and Cardiovascular Disease (CVD) [27] It is well established that diabetes is a major risk factor for cardiovascular disease (CVD), a term that refers to disease of the heart and circulatory system. Both type 1 and type 2 diabetes are closely linked to CVD and it is the main cause of death in people with diabetes. 1.15.1 Major clinical manifestations of CVD These can be divided into three groups: 1. Those affecting the heart and coronary circulation (coronary heart disease - CHD) A thickening of the walls in the coronary arteries or the occurrence of a blood clot in the coronary arteries will prevent blood reaching the heart, causing strain on the heart, which can ultimately lead to angina, myocardial infarction, or sudden death. 2. Those affecting the brain and cerebral circulation An interruption of blood supply to the brain (as a result of cerebral haemorrhage or a cerebral thrombosis) will lead to a stroke, a sudden loss of function of part of the brain resulting in death (infarction) of an area within the brain. 3. Those affecting the lower limbs and feet (peripheral vascular disease)


Peripheral vascular disease often results from a narrowing of the vessels that carry blood to leg and arm muscles. The loss of blood supply can cause gangrene (death of tissue which can ultimately lead to amputation) and intermittent claudication. Facts: • Cardiovascular disease is the major cause of death in diabetes, accounting for some 50% of all diabetes fatalities, and much disability.1 • On average, people with type 2 diabetes will die 5-10 years before people without diabetes and most of this excess mortality is due to cardiovascular disease.2 • People with type 2 diabetes are over twice as likely to have a heart attack or stroke as people who do not have diabetes. Indeed, people with type 2 diabetes are as likely to suffer a heart attack as people without diabetes who have already had a heart attack.3 • Strokes occur twice as often in people with diabetes and hypertension as in those with hypertension alone.3 • People with diabetes are 15-40 times more likely to have a lower limb amputation compared to the general population.3 • People with diabetes have two to four times the risk of developing atherosclerosis compared to people without diabetes.3 • The treatment of cardiovascular disease accounts for a large part of the huge healthcare costs attributable to type 2 diabetes, that have been estimated to account for 10-12% of European health care expenditure. • Part of the cardiovascular risk associated with IGT and diabetes is undoubtedly due to their association with other cardiovascular risk factors such as hypertension, high LDL-cholesterol and low HDL-cholesterol and smoking. • Lifestyle changes that improve blood glucose control e.g. weight loss, dietary changes and increased physical activity are also likely to improve these other cardiovascular risk factors. Glossary Angina: a pain in the chest due to reduced blood supply to the heart. Myocardial infarction (also called a heart attack): an interruption of blood supply to the area of the heart muscle due to narrowed or blocked vessels. Sudden death: the result from the sudden abrupt loss of heart function. Atherosclerosis: the clogging of the arteries that in this case nourish the heart. For people with diabetes, too much glucose in the blood contributes to atherosclerosis. Stroke: a sudden loss of function of part of the brain due to the interruption of its blood supply, resulting in death (infarction) of an area within the brain. Gangrene: death of tissue due to a loss of blood supply which can ultimately lead to amputation. Intermittent claudication: a pain usually in the calves when walking, due to impaired blood supply to the calf muscles which results from atherosclerosis. Diabetes and Cardiovascular Disease: Time to Act


In 2001, IDF produced a publication on diabetes and cardiovascular disease aimed at raising awareness of the link between the two conditions and recommending courses of action to prevent or delay cardiovascular complications of diabetes. Diabetes and Cardiovascular Disease: Time to Act is directed at decision makers in the health and social policy sectors, with the aim of raising awareness and influencing policy. It also serves to sensitize healthcare professionals to the need for the aggressive management of all cardiovascular risk factors in people with diabetes.

1.17 Global Prevalence of Diabetes [26] Estimates for the year 2000 and projections for 2030 The prevalence estimates were applied to population estimates for individual countries for 2000 and 2030, which were produced by the United Nations Population Division [28]. Conventional, albeit simplistic, definitions of developed countries (Europe including former socialist economies, North America, Japan, Australia, and New Zealand) and less developed countries (all other countries) were used. In keeping with previous estimates, prevalence of diabetes was assumed to be similar in urban and rural areas of developed countries [31]. For developing countries, urbanization was used as a proxy measure of the increased risk of diabetes associated with altered diet, obesity, decreased physical activity, and other factors such as stress, which are assumed to differ between urban and rural populations. For most developing countries, the prevalence of diabetes in rural areas was assumed to be one-half that of urban areas, based on the ratio observed in a number of population studies and as used in previous estimates [30]. For some populations in developing countries (small islands and populations for which prevalence data were derived from studies combining urban and rural populations), a single estimate of diabetes prevalence was used. In the current estimates, on the advice of local experts, the prevalence of diabetes in rural areas was assumed to be one-quarter that of urban areas for Bangladesh, Bhutan, India, the Maldives, Nepal, and Sri Lanka [29].

Figure — Global diabetes prevalence by age and sex for 2000 1.17.1 Diagnosed and Undiagnosed Diabetes among People Ages 20 Years or Older, United States, 2010 Group Number or percentage who have diabetes Ages 20 years or 25.6 million, or 11.3 percent, of all people in this age group


older Ages 65 years or 10.9 million, or 26.9 percent, of all people in this age group older Men

13.0 million, or 11.8 percent, of all men ages 20 years or older

Women

12.6 million, or 10.8 percent, of all women ages 20 years or older

Non-Hispanic whites 15.7 million, or 10.2 percent, of all non-Hispanic whites ages 20 years or older Non-Hispanic blacks

4.9 million, or 18.7 percent, of all non-Hispanic blacks ages 20 years or older

Table: Diagnosed and Undiagnosed Diabetes among People Ages 20 Years or Older, United States, 2010 1.17.2Diagnosed and Undiagnosed Diabetes

Figure 5: 2005–2008 National Health and Nutrition Examination Survey

1.17.3 Country and regional data on diabetes [32] WHO South-East Asia Region Prevalence of diabetes in the WHO South-East Asia Region

2000

2030

Country Bangladesh

3,196,000

11,140,000

Bhutan

35,000

109,000


Dem. People's Rep. of Korea 367,000

635,000

India

31,705,00 0

79,441,000

Indonesia

8,426,000

21,257,000

Maldives

6,000

25,000

Myanmar

543,000

1,330,000

Nepal

436,000

1,328,000

Sri Lanka

653,000

1,537,000

Thailand

1,536,000

2,739,000

Total

46,903,00 0

119,541,000

1.18 When to Seek Medical Care If a person has diabetes and experiences any of the following, call a health care professional: • Experiencing diabetes symptoms: this may mean that the person's blood sugar level is not being controlled despite treatment • Blood sugar levels, when tested, are consistently high (more than 200 mg/dL): Persistently high blood sugar levels are the root cause of all of the complications of diabetes. • The patient's blood sugar level is often low (less than 70 mg/dL): this may mean that the diabetes management strategy is too aggressive. It also may be a sign of infection or other stress on the body's organs such as kidney failure, liver failure, adrenal gland failure, or the concomitant use of certain medications. • An injury to the foot or leg, no matter how minor: even the tiniest cut or blister can become very serious in a person with diabetes. Early diagnosis and treatment of problems with the feet and lower extremities, along with regular diabetic foot care, are critical in preserving the function of the legs and preventing amputation. • Low-grade fever (less than 101.5 F or 38.6 C): Fever is a sign of infection. In patients with diabetes, many common infections can potentially be more dangerous for them than for other people. Note any symptoms, such as painful urination, redness or swelling of the skin, abdominal pain, chest pain, or cough, that may indicate where the infection is located. • Nausea or vomiting, but can keep liquids down: The health care professional may adjust medications while the patient is sick, and will probably recommend an urgent office visit or a visit to the emergency department. Persistent nausea and vomiting can be a sign of diabetic ketoacidosis, a potentially life-threatening condition, as well as several other serious illnesses.


Small sore(s) (ulcer) on the foot or le:. Any non-healing sore or ulcer on the feet or legs of someone with diabetes needs to be seen by a medical professional right away. A sore less than 1 inch across, not draining pus, and not exposing deep tissue or bone, can safely be evaluated by a health care professional, as long as the patient does not have fever and their blood sugar levels are under control. When you call a health care professional, tell them that you or someone you know has diabetes and are concerned. •

The patient will probably be referred to a nurse who will ask questions and make a recommendation about what to do. • Be prepared for this conversation. Have a list of medications, medical problems, allergies to medicines, and a blood sugar diary handy by the phone. • The nurse may need any or all of this information to decide both the urgency of the patient's condition and how best to recommend treatment for the problem.[23] 1.18.1 Diabetic emergencies The following situations can become 911 medical emergencies and warrant an immediate visit to a hospital emergency department. • The person with a severe diabetic complication may travel to the emergency department by car or ambulance. • A companion should go along to speak for the person if the person is not able to speak for him or herself with the emergency care professional. • Bring a list of medical problems, medications, allergies to medications, and the person's blood sugar diary to the emergency department. This information will help the emergency care professional diagnose the problem and treat it appropriately. The following are signs and symptoms of diabetic complications that warrant emergency care. • Altered mental status: Lethargy, agitation, forgetfulness, or just strange behavior can be a sign of very low or very high blood sugar levels. If a person has diabetes with an altered mental status: • Try giving them some fruit juice (about 6 ounces) or cake icing if the person is awake enough to swallow normally without choking. Avoid giving things such as hard candy that can lodge in the throat. The health care provider can prescribe glucose wafers or gels that melt under the tongue. • Does not wake up and behave normally within about 15 minutes, call 911. • Is not a known diabetic, these symptoms can be signs of stroke, drug intoxication, alcohol intoxication, oxygen starvation, and other serious medical conditions? Call 911 immediately. • Nausea or vomiting: If the patient is known to have diabetes and cannot keep food, medications, or fluids down at all, they may have diabetic ketoacidosis, hyperosmolar hyperglycemic nonketotic syndrome, or another complication of diabetes. If the person: • Has not already taken the latest insulin dose or oral diabetes medicine, do not take it without talking to a medical professional. • Already has low blood sugar levels, taking additional insulin or medication will drive the blood sugar level down even further, possibly to dangerous levels. •


Fever above 101.5 F (38.6 C): If the primary health care professional cannot see the patient right away, seek emergency care for a person with diabetes with a high fever. Note any other symptoms such as cough, painful urination, abdominal pain, or chest pain. High blood sugar level: If the patient's blood sugar level is above 400 mg/dL, and the primary health care professional cannot see them right away, go to the closest emergency department. Very high blood sugar levels can be a sign of diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome, depending on the type of diabetes the person has. Both of these conditions can be fatal if not treated promptly. Large sores or ulcers on the feet or legs: If the person has diabetes, a non-healing sore larger than 1 inch in diameter can be a sign of a potentially limb-threatening infection. • Other signs and symptoms that merit immediate care are exposed bone or deep tissue in the wound, large areas of surrounding redness and warmth, swelling, and severe pain in the foot or leg. • If left untreated, such a sore may ultimately require amputation of the limb. Cuts or lacerations: Any cut penetrating all the layers of skin, especially on the legs, is a potential danger to a person with diabetes. Proper wound care, although important to anyone's recovery, is especially important in diabetics to assure proper wound healing. Chest pain: If the person has diabetes, take very seriously any pain in the chest, particularly in the middle or on the left side, and seek medical attention immediately. • People with diabetes are more likely than non-diabetic people to have a heart attack, with or without experiencing chest pain. • Irregular heartbeats and unexplained shortness of breath may also be signs of heart attack. Severe abdominal pain: Depending on the location, this can be a sign of heart attack, abdominal aortic aneurysm (widening of the large artery in the abdomen), diabetic ketoacidosis, or interrupted blood flow to the bowels. • All of these are more common in people with diabetes than in the general population, and are potentially life-threatening. • People with diabetes also get other common causes of severe abdominal pain such as appendicitis, perforated ulcer, inflammation and infection of the gallbladder, kidney stones, and bowel obstruction. • Severe pain anywhere in the body is a signal for timely medical attention.

1.19 Drugs used in diabetes [33] It should be remembered that control of modifiable cardiovascular risk factors such as lipids and blood pressure are the most important interventions to be made in patients with type II diabetes. Healthy eating should be tried first, and drug therapy added if glycaemic control is unsatisfactory after a 3 month trial of dietary restrictions and an increase in physical activity. 1.19.1Dual Therapy


For patients who have not reached HbA 1c <6.5% (or their agreed target) on metformin monotherapy, add in a sulphonylurea as the standard second line agent. Consider a gliptin (or a glitazone) to metformin if hypoglycaemia on a sulfonylurea is a potential problem, or if a sulphonylurea is not tolerated or contraindicated. A gliptin may be preferable to a glitazone in patients where further weight gain would be problematic, or where a glitazone is contraindicated (e.g. heart failure), not tolerated/effective. Continue either only if 0.7% reduction in HbA1c in 6 months. 1.19.2 Triple Therapy For patients who have not reached HbA1c <7.5% (or their agreed target) on metformin and a sulphonylurea, consider adding a gliptin (or a glitazone). If human insulin likely to be unacceptable or ineffective (because of employment (e.g. HGV drivers), social, recreational or other personal issues, or obesity/metabolic syndrome) consider use of GLP-1 receptor agonist. Continue only if 0.7% reduction in HbA1c in 6 months. Sitagliptin is the only gliptin licensed for use in a triple combination. Insulins Short-acting insulins GREEN Human Actrapid® GREEN Humulin S® The insulin analogues have a faster onset and shorter duration of action than standard soluble insulin. They should be injected immediately before or, when necessary, shortly after a meal. GREEN Humalog® (insulin lispro) GREEN NovoRapid®(insulin aspart) GREEN Apidra® (insulin glulisine) Intermediate and long-acting insulins Intermediate GREEN Insulatard® GREEN Humulin I® Long acting Long-acting recombinant human insulin analogues should be used in accordance with NICE guidance. GREEN Lantus® (insulin glargine) GREEN Levemir®(insulin detemir) Biphasic GREEN Mixtard 30® - Will be withdrawn. See notes below. GREEN Humulin M3® GREEN Insuman Comb 25® Human Mixtard 30 will be withdrawn from the market. Guidance agreed by the East Lancs diabetologists & endorsed by MMB. Patients currently on Mixtard 30/70 should be offered Insuman Comb 25 instead as the preferred alternative human biphasic mixed insulin, as a vial and syringes, cartridges or as Solostart pens, depending on patient preference. GREEN GREEN

Humalog Mix25®, Humalog Mix50® (insulin lispro) NovoMix 30®


Biphasic analogue insulins (e.g. Novomix, Humalog Mix) do not offer any advantage over conventional human biphasic insulins in terms of efficacy, long term outcomes or safety but cost considerably more. The above brands of insulin are recommended for new diabetics and are available in a variety of vial, cartridge and pre-loaded pen presentations. The hospital pharmacy will keep stocks of other brands and species for established diabetics. Insulin is usually available in 3mL cartridges, 10mL vials, and 3mL disposable pens. Not all insulin cartridges fit all pens. Pens are available on prescription except OptiPen® and HumaPen®. The National Patient Safety Agency issued an alert in June 2010 for the safer administration of insulin. Click here to access the full documents online. 1.19.3 Oral antidiabetic drugs 1.19.4 Sulphonylureas Act by augmenting insulin secretion. For patients who have not reached HbA1c <6.5% (or their agreed target) on metformin monotherapy, add in a sulphonylurea as the standard second line agent. Re-assess patients after 2-6 months on first line therapy, including checking concordance with therapy and asking about adverse effects. Reinforce lifestyle measures, especially weight loss. However, sulphonylureas can also be used first line in the following situations: • the person is not overweight or • the person does not tolerate metformin (or it is contraindicated) or • A rapid response to therapy is required because of hyperglycaemic symptoms. Prescribe a sulfonylurea with a low acquisition cost (not glibenclamide) when an sulphonylurea is indicated. When drug concordance is a problem, offer a once-daily, long-acting sulfonylurea such as glimepiride. Avoid long acting products in those at risk of severe hypoglycaemia (e.g. elderly). Educate the person about the risk of hypoglycaemia, particularly if he or she has renal impairment. Sulphonylureas can cause weight gain. Glibenclamide and chlorpropamide are specifically not recommended and should not be used due to the greater risk of hypoglycaemia, especially in the elderly. GREEN Gliclazide tablets 80mg GREEN Glimepiride tablets 1mg, 2mg, 4mg GREEN Tolbutamide tablets 500mg 1.19.5 Biguanides For patients who have not reached HbA1c <6.5% (or their own target) with lifestyle interventions, use metformin as the first line choice, whether patients are overweight/obese or are not, unless contraindicated or not tolerated. Patients frequently report gastrointestinal (GI) side effects such as diarrhoea or nausea when initiated on any formulation of metformin. Such adverse effects are often transient, and can be minimised by slow dose titration. Dose: Step up metformin over several weeks to minimise risk of gastrointestinal (GI) side effects. Give 500 mg with evening meal for at least 1 week then 500 mg with breakfast and evening meal for at least 1 week then 500 mg with breakfast and 1 gram with evening meal; usual max. 2 g daily in two divided doses The benefits of metformin therapy should be discussed with a person with mild to moderate liver dysfunction or cardiac impairment so that:


due consideration can be given to the cardiovascular-protective effects of the drug • An informed decision can be made on whether to continue, reduce the dose or stop the metformin. GREEN Metformin tablets 500mg, 850mg GREEN Metformin sachets 500mg, 1000mg Review metformin dose when serum creatinine >130 micromol/litre or eGFR <45ml/min/1.73 m2. • Stop metformin if serum creatinine >150 micromol/litre or eGFR <30 ml/min/1.73 m2 . • Prescribe metformin with caution in those at risk of sudden deterioration of kidney function, or at risk of a decline of eGFR to <45 ml/min/1.73 m 2. 1.19.6 Meformin Sustained Release (SR) Tablets In patients in whom slow dose titration does not reduce GI adverse effects, metformin sustained release tablets should be used ONLY where intolerance to the immediate release preparation had been clearly documented and where it prevents continuation of metformin therapy. A review of the evidence on the use of sustained release metformin preparations did not find that their use in unselected patients reduced gastro-intestinal side effects. Metformin sustained release tablets are supported purely as an attempt to ensure the largest number of patients is able to stay on metformin therapy, hopefully delaying progression to other new drugs which often have a reduced evidence base and/or additional safety concerns. GREEN Metformin sustained release (SR) tablets 500mg, 750mg, 1000mg 1.19.7 Other antidiabetic drugs Repaglinide & Nateglinide Repaglinide and nateglinide stimulate insulin release. They have a rapid onset of action and short duration of activity, and only need to be taken at mealtimes (shortly before each main meal). This makes them particularly useful alternatives to sulphonylureas for patients with irregular meal patterns or lifestyles (where hypoglycaemia would otherwise pose a risk). Repaglinide may be given as monotherapy for patients who are not overweight or for those in whom metformin is contra-indicated or not tolerated, or it may be given in combination with metformin. GREEN Nateglinide tablets 60mg, 120mg, and 180mg GREEN Repaglinide tablets 1mg, 2mg 1.19.8 Thiazolidinediones (Glitazones) 1.19.8.1Dual Therapy For patients who have not reached HbA1c <6.5% (or their agreed target) on metformin monotherapy, add in a sulphonylurea as the standard second line agent. Consider pioglitazone or a gliptin to metformin if hypoglycaemia or a sulphonylurea is a potential problem, or if a sulphonylurea is not tolerated or is contraindicated. Pioglitazone may be preferable to a gliptin in patients with evidence of metabolic syndrome, or where a gliptin is contraindicated (e.g. renal impairment), not tolerated/effective. Continue only if 0.7% reduction in HbA1c achieved in 6 months. 1.19.8.2 Triple Therapy For patients who have not reached HbA1c <7.5% (or thier agreed target) on metformin and a sulphonylurea, consider adding pioglitazone (or a gliptin) if human insulin is likely to be •


unacceptable or ineffective (because of employment [e.g. HGV drivers], social/recreational or other personal issues, or obesity/metabolic syndrome). Continue only if 0.7% reduction in HbA1c achieved in 6 months. 1.19.8.3 In combination with insulin Consider pioglitazone in combination with insulin if a glitazone has been effective previously or high-dose insulin is providing inadequate control. Consider continuing pioglitazone when starting insulin therapy when a reduction in HbA1c of >1.5% previously seen with pioglitazone. This should be done only under specialist supervision. Combining pioglitazone with insulin significantly increases the risk of heart failure. Warn the patient to discontinue pioglitazone if clinically significant fluid retention occurs, or heart failure develops. 1.19.8.4 Glitazone Safety Concerns Pioglitazone causes weight gain and increases the risk of heart failure (especially in combination with insulin). It may also worsen existing heart failure. Do not start or continue pioglitazone if the patient has current evidence or a history or heart failure, or is at a higher risk of fracture. If prescribing pioglitazone, warn about significant oedema and tell the patient what to do if this happens. Patients should be closely monitored for signs of heart failure. There are no restrictions on the use of pioglitazone in acute coronary syndrome, ischaemic heart disease or peripheral arterial disease. Remembered that the dose of a glitazone should beaft a dose The European Committee on Medicinal Products for Human Use has recommended the suspension of the marketing authorisations of Rosiglitazone (Avandia速) and it's combination product with metformin (Avandamet速) across the European Union. Full details can be found under Drug Alerts & Withdrawals Pioglitazone to be prescribed in accordance with NICE guidance (CG87). LFT measurements are needed prior to treatment and periodically thereafter. It should be remembered that control of modifiable cardiovascular risk factors such as smoking cessation, lipids and blood pressure are the most important interventions to be made in patients with type II diabetes. GREEN Pioglitazone tablets 15mg, 30mg, and 45mg (generic only) GREEN Competact速 tablets - Pioglitazone 15mg plus metformin 850mg


1.19.8.5 Intestinal alpha glucosidase inhibitor Consider acarbose for a person unable to use other oral glucose-lowering medications. Delays the digestion and absorption of starch and sucrose. Timing of doses is crucial: tablets should be chewed or swallowed whole with the first mouthful of food. GREEN Acarbose tablets 50mg, 100mg (Glucobay®) Gliptins Sitagliptin is licensed for monotherapy, combination oral therapy (metformin, sulphonylurea and/or glitazone) and also in combination with insulin. Requires dose adjustment in patients with renal impairment (please refer to SPC for details). Linagliptin is licensed for monotherapy and combination oral therapy (metformin and sulphonylurea), is a once daily dosage and does not require dose adjustment for patients with renal impairment. GREEN Sitagliptin 25mg, 50mg, 100mg tablets (Januvia® ) ® GREEN Linagliptin 5mg (Trajenta ) 1.19.8.6 Glucagon-like Peptide-1 agonists Exenatide It should be remembered that control of modifiable cardiovascular risk factors such as lipids and blood pressure are the most important interventions to be made in patients with type II diabetes. Consider adding exenatide to metformin and a sulfonylurea if a person has: • a body mass index (BMI) ≥ 35 kg/m 2 in those of European descent, with appropriate adjustment in tailoring this advice for other ethnic groups and other specific psychological or medical problems associated with high body weight • a BMI < 35 kg/m2 and for whom initiation of insulin therapy would have significant occupational implications, or where weight loss would benefit other significant comorbidities such as sleep apnoea. • Continue exenatide only if beneficial response occurs and is maintained (≥ 1.0 percentage point HbA1c reduction in 6 months and weight loss ≥ 5% at 1 year). Exenatide is licensed for use with metformin, sulphonylurea and pioglitazone. Exenatide is not licensed for use with any other oral antidiabetic drug. Up to 50% of patients experience nausea and vomiting, and due to its effects on slowing gastric emptying, may interact with a variety of drugs including the contraceptive pill and antibiotics. Exenatide 5mcg and 10mcg only is licensed as adjunct to basal insulin. Exenatide 2mg is a long acting formulation administered once a week GREEN Exenatide pre-filled pen 5 micrograms, 10 micrograms (Byetta®) Exenatide 2mg vial with solvent (Bydureon®) Liraglutide Liraglutide is a treatment option for patients whose diabetes is not controlled with Metformin, and or sulphonylure and/or glitazone. Patients prescribed liraglutide should be regularly reviewed and treatment should be in line with the recommedations of NICE TAG203: only continue liraglutide if reduction in HbA1c of at least 1 percentage point and weight loss of at least 3% of initial body weight at 6 months. Liraglutide should only be used at a maximum dose of 1.2mg daily; the 1.8mg/day dose should not be used. GREEN Liraglutide pre-filled pen 18mg (Victoza®)


1.19.9 Treatment of hypoglycaemia In the unconscious diabetic glucagon is an alternative to IV glucose 50%. GREEN Glucagon injection 1 mg (GlucaGenÂŽ HypoKit) All material in this section is aimed at health professionals, but is information currently held within the public domain. Members of the public seeking advice on medicine-related matters are encouraged to speak with their GP, pharmacist or nurse, or contact NHS Direct on 0845 46 47.

Chapter -2 Study on patient profile 2.1 Objectives of the study Several drugs are used to treat the diabetes and other cardiac patients in Bangladesh, The main objectives of the study are: â&#x20AC;˘

To find out the commonly used drugs for diabetes and other cardiac disease. â&#x20AC;˘ To find out the impact of different other risk factors on diabetes and associated cardiac

diseases like age, sex, smoking habit, habitual physical activity, salt consumption, family history, social class etc.

2.2 Significance of the study Diabetes is a global burden arising from complex and interrelated etiologies. This is a rapidly progressing cardiac disease throughout the world as well as in Bangladesh.

Diabetes is a well documented risk factor for fatal and nonfatal cardiovascular disease (CVD) and substantially contributes to the global burden of disease. Randomized controlled trials have convincingly shown that treatment of diabetes reduce the risk of stroke, coronary heart disease, congestive heart failure, and mortality. Since diabetes is a major marker of different cardiac diseases, adequate control of blood pressure is of enormous public health importance. This survey gives us useful information about the cure rate, side effect, different drugs composition etc.


2.3 Type of study This was a cross sectional observational study that was attempted to find out the commonly used drugs for the treatment of diabetes and to determine the impact of different other risk factors on diabetes and associated cardiac disease. 2.4 Place of study) and The study was being conducted in Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorder (BIRDEM) [34] About (BIRDEM) TEACHING AND TRAINING HOSPITAL, BIRDEM BIRDEM Hospital is the teaching hospital of the college. It is a 600 bedded multidisciplinary Hospital Complex at Shahbag, yet another prestigious institution of the Diabetic Association of Bangladesh. It has already earned national and international reputation as center of excellence for medical services and research. The hospital is housed in two magnificent buildings – one is 5 storied & other is 15 storied twin-towers. The 15 storied twin-towers accommodates the hospital, while the 5 storied building houses the outpatient services, intensive care unit and a modern sophisticated cardiac center – Ibrahim Cardiac Hospital & Research Institute (ICHRI). Over 3000 patients are attending outpatient departments daily. The in-patient departments have a total of 600 beds of which over 100 (number is flexible) are free. Internal Medicine & sub-specialties have a total of 220 beds. General Surgery & sub-specialties have a total of 165 beds, while gynaecology and obstetrics have 60 beds. Emergency Units have a total of 30 beds, which include emergency (10), Intensive care unit (10) and Coronary care unit (10). Besides it has 120 cabins. Following successful completion of First Professional MBBS Examination (after 1½ years), students (in batches of 12-15) are placed in different departments/units of BIRDEM Hospital for total period of 3½ years for clinical training and ward-duties as per roster suggested in the BM&DC Curriculum.

2.5 Study Population


Patient’s diabetes who visits BIRDEM in Shahbag Branch to meets with doctor and doctor given them medication. 2.6 Sample size Sample size was 200. 2.7 Sampling Technique In this study, purposive sampling technique was followed 2.8 Research Equipments

The following equipments were used in this study: •

Interview schedule(both patient and doctor)

Prescription

Telephone conversation

2.9 Data collection method After explaining the purpose of the study to the respondents and obtaining their verbal consent, the researcher interviewed all the respondents by asking questions in Bengali and using a thoroughly pre–tested questionnaire. The questionnaire consisted of three parts. Part-1 consisted of the respondent’s general information, Part-2 consisted of behavioral characteristics and Part-3 consisted of information on prescribed drugs. Part-4 on Telephone conversation to find out present condition. 2.10 Study period Study period Was 6 month commencing from January 2012 to June 2012. To complete the study in time, a work schedule was prepared depending on different tasks of the study. 2.11 DATA COLLECTION FORM


Questionnaires 1. Identification 1.1 I.D. Code: 1.2 Name: 1.3 Sex:

1.4 Address: 1.5 Telephone no. 1.6 Religion: 1.7 Nationality: 2. Personal history

2.1 Area of residence: Rural Urban S-Urban Others

2.2 occupations: Student Business Service holder House wife Unemployed

Male

Female


Others

2.3 Impression about social class Rich Upper middle Lower middle Poor

3. Prescription Rx, 4. Persent condition 4.1 cure range: 4.2 side effects;

Chapter 3 Data and Result For the evaluation and management of Diabetes we went to the Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorder (BIRDEM) and National Heart Foundation (NHF) . I have researched on this topic till last six month. Where I have consults with the doctors and patients, collect patients profile, their disease state, prescribed drugs, there effect and side effects. We are analyzing it on the basis of the following data.

3.1 Age distribution table of total patients of Diabetes Mellitus with Cardiovascular Complication


Age Range

Number of patients

20-30

10

31-41

21

42-52

44

53-63

60

64-74

65

Fig: Age distribution of total patients with diabetes with cardiovascular

The figure shows that the patients of age of about (64-74), 33% are more affected by diabetes with cardiac disease, then patient age (53-63)years of about 30%, (42-52)years of about 22%, (31-41) years of about 10% and (20-30)years of about 5%. 3.2 Table of Diabetes Mellitus with Cardiovascular Complication patients according to Occupation Occupation

Number of patients

Business

76

Service

60

House wife

24

Day labor

40


Fig: Diabetes Mellitus with Cardiovascular Complication of Patients According Occupations The curve shows that the patients of Business are mostly affected by the Diabetes Mellitus with Cardiovascular Complication of about 38% then the patients with occupation service are affected of about 30% and then the patients with occupation day labor of about 20% and housewife of about 12% were affected by the Diabetes Mellitus with Cardiovascular Complication 3.3 Table of Diabetes Mellitus with Cardiovascular Complication according to sex Sex

Number of patient

Male

140

Female

60

Fig: Diabetes Mellitus with Cardiovascular Complication of patients according to sex The figure shows that majority of the Diabetes Mellitus with Cardiovascular Complication of patients are male of about 70% and the female are of about 30%. 3.4 Distribution of patients on the basis of prescribed drug by doctors No of drugs

No. of patients


4 drugs

20

Less than 4 drugs

10

More than 4 drugs

170

Fig: Distribution of no of drug by the doctor The figure shows that the doctor prescribed more than 4 drugs of about 85% and less than 4 drugs of about 5% and only 4 drugs of about 10% for the treatment of Diabetes Mellitus with Cardiovascular Complication. 3.5 Cured range of the treatment of Diabetes Mellitus with Cardiovascular Complication Cured range

Number of patient

Partial improvement

130

Maximum improvement

70

Fig: Cured range of the Diabetes Mellitus with Cardiovascular Complication The figure shows that 65% patients of Diabetes Mellitus with Cardiovascular Complication were partially cured and 35% patients of Diabetes Mellitus with Cardiovascular Complication were totally cured for a certain period. 3.6 Table of patient on the basis of Side Effect Profile Side effect

Number of patient

Weakness

55

Vomiting

30

Headach

60

Dizziness

25

Muscle pain

30


Fig: Side effect of the Diabetes Mellitus with Cardiovascular Complication The figure shows that most of the patients have Weakness of about 23%, vomiting of about 13%, Headach of about 25%, Dizziness of about 11%, and 13% patients have Muscle pain 3.7 Drugs which are used for the treatment of Diabetes Mellitus with Cardiovascular Complication Drugs name

No. of patients

Ecosprine(atorvastatin)

89

Lopirel (Clopidogrel)

20

Pantonix(pantoprazole)

30

Nidocard Rtd(clyceryl trinitrate)

11

Vastarel (trimetazidine)

15

Atova(atorvastatine calcium)

25

Other

10

Fig: Drugs which are used for the treatment of Diabetes Mellitus with Cardiovascular Complication The statistics shows that Ecosprine are the most prescribed drugs by the doctors of about 44%, Lopirel of about 10%, Pantonix of about 15%, Nidocard Rtd of about 5%, vastarel of about 8% Atova of about 13%and 5% prescribed others drugs.

Chapter -4 Discussion To find out the impact of risk factors of Diabetes Mellitus with Cardiovascular Complication and the drugs that are commonly used for the treatment of Diabetes Mellitus with


Cardiovascular Complication this study was performed in BIRDEM and NHF the data were collected from the admitted patients. Patientâ&#x20AC;&#x2122;s personal and medical history like blood pressure and diagnosis profile were also collected. All the patients were prescribed different medications. They were interviewed by asking question in Bengali, using a thoroughly preplanned questionnaire. The most important observation of the study is that the age group of 64-74 years had the highest incidence of Diabetes Mellitus with Cardiovascular Complication of about 33% and the age among 53-63 patients are about 30%.Then the age limit among 42-52(22%), 3141(10%) and 20-30(5%). . Considering Bangladesh perspective, older aged group people mostly suffered from Diabetes Mellitus with Cardiovascular Complication. Another important finding is that male patients (70%) are affected by Diabetes Mellitus with Cardiovascular Complication in a greater extent compared to female patient (30%). Another important issue is that about Business are mostly affected by the Diabetes Mellitus with Cardiovascular Complication of about 38% then the patients with occupation Daylabor are affected of about 20% and then the patients with occupation service of about 30% and housewife of about 12% were affected by the lung cancer. This is to notice that day labor and businessmen suffered more from Diabetes Mellitus with Cardiovascular Complication than other professionals. Total number of prescribed drugs for the treatment of Diabetes Mellitus with Cardiovascular Complication with other associated problems was variable the doctor prescribed more than 4 drugs of about 85% and less than 4 drugs of about 5% and only 4 drugs of about 10% for the treatment of Diabetes Mellitus with Cardiovascular Complication . Nearly all the Diabetes Mellitus with Cardiovascular Complication patients suffered from other associated problems. Among them weakness problem of about 23%, vomiting of about 13%, headach count of about 25%, dizziness of about 11%, and 13% patients have mucle pain. The most important feature of the study was to find out commonly prescribed drugs by physicians for the treatment of Diabetes Mellitus with Cardiovascular Complication Ecosprine are the most prescribed drugs by the doctors of about 44%, Lopirel of about 10%, Pantonix of about 15%, Nidocard Rtd of about 5%, Vastarel of about 8%,Alova of about 13% and 5% prescribed others drugs.

Conclusion


In modern times, Diabetes has emerged as one of the leading cause of death worldwide countries. Especially in the developed countries. Diabetes has no actual treatment. So the mortality rate is very high. If the cancer is detected early then it would be prevented. The data I have collect from the patients there I have seen lower numbers of the patients were partially or poorly cured. The patient who is partially or poorly cured they are affected by various diseases like ,cardiac disease, kidney disease, blindness and blood vessel complication. Most of the people of our country have no much more idea about the diabets. We need to create social awareness about the life threatening disease diabetes. As diabetes is a disease which has no proper treatment, so the management of diabetes will be helpful to lower the mortality rate. My topic was diabetes with cardiovascular diease that I have discussed above. The World Health Organization reported that 16.7 million deaths in 2003 (29.2% of total global deaths) were caused by some form of cardiovascular disease. Though the rate of cardiac disease is highest in developed countries, developing countries are seeing an increase in the occurrence of cardiac disease, as well as a corresponding rise in the number of heart-related deaths. From the statistics we have seen that male were much affected than the female. The main cause of cardiac disease is diabetes. About 65 percent of cardiac disease cases are caused by diabetes. As Diabetes is the main reason for, so we have to create social awareness of about the danger of the Diabetes and thier complecation.

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