Isradipine in Diabetic Patients With Hypertension by OEM65

CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 6, DECEMBER 1993

ANTIHYPERTENSIVE THERAPY WITH THE CALCIUM CHANNEL BLOCKER ISRADIPINE: AN APPROPRIATE CHOICE FOR THE DIABETIC PATIENT WITH HYPERTENSION A Review A L A N O. M A R C U S

USC School of Medicine, Los Angeles, California

ABSTRACT

Treatment of hypertension in diabetic patients or patients with impaired glucose tolerance requires a specialized approach. Such hypertensive, glucose-impaired patients often have multiple medical problems, possibly f r o m common causes, such as renal impairment, atherosclerosis, electrolyte disturbance, neuropathy, or cardiac dysfunction. Antihypertensive therapy in these high-risk, medically compromised patients must reduce blood pressure while having a beneficial or neutral effect on the diabetic state and other coexisting diseases with possible catastrophic end points. Isradipine is a secondgeneration, dihydropyridine-type calcium channel blocker shown to be efficacious, safe, and well tolerated in the treatment of diabetic patients with hypertension. In clinical trials of patients with insulindependent or non-insulin-dependent diabetes mellitus, monotherapy with isradipine normalized blood pressure in a majority of patients with minimal adverse reactions and no clinically significant alteration of heart rate. More importantly, isradipine had either a neutral or a beneficial effect on glucose homeostasis and lipid metabolism. In studies of nondiabetic patients with hypertension, isradipine has been shown to facilitate renal function by decreasing renal vascular resistance, increasing renal plasma flow, and maintaining or improving glomerular filtration rate and filtration fraction. These physiological effects may benefit patients with coexisting diabetes and hypertension, in whom end-stage renal disease is a common consequence. Studies to evaluate the effects of isradipine on a number of parameters or conditions important to the diabetic patient, including serum lipids, atherosclerosis, and proteinuria, are currently in progress. INTRODUCTION

Control of h y p e r t e n s i o n in t h e m e d i c a l l y c o m p r o m i s e d p a t i e n t is often a difficult goal to achieve. H i g h blood p r e s s u r e in t h e s e h i g h - r i s k p a t i e n t s is u s u a l l y l o n g - s t a n d i n g a n d r e f r a c t o r y to c o n v e n t i o n a l t h e r a p y . F u r t h e r -

Address correspondence to: Alan O. Marcus, M.D., South Orange County Endocrinology, 23961 Calle de la Magdalena, Ste. 531, Laguna Hills, California 92653. Received for publication on July 19, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 763

0011-393X/93/$3.50

ANTIHYPERTENSIVE THERAPY WITH ISRADIPINE

more, hypertension rarely exists as the sole medical abnormality. These patients are usually older (age >45 years) and present with multiple illnesses or conditions that are progressive in nature (Table I). 1 Patients in this group often require and receive multiple drugs, and, due to the refractory nature of their hypertension and multiple disease states, require frequent medication adjustments to achieve normotension, avoid adverse drug interactions, and prevent adverse drug reactions. Therefore, the choice of an effective, safe antihypertensive agent becomes a selective process based on physiology, etiology, and individual patient characteristics. The diabetic and impaired glucose tolerance population constitutes one of the largest groups of patients with high blood pressure. ~ Indeed, the prevalence of hypertension in diabetic patients is twice that in nondiabetics. 3 At present, close to 3 million people in the United States are estimated to have both diabetes and hypertension.4'5 When patients with coexisting hypertension and hyperinsulinemia are factored in, the number increases dramatically. For example, in a selected adult population aged 50 to 89 years (n = 2233) in Rancho Bernardo, California, 13.5% of patients had diabetes and nearly one fourth had impaired glucose tolerance (24.6%). Among those patients who had impaired glucose tolerance, nearly half were classified as having "overall hypertension. ''~ In terms of medical complications, hypertension and diabetes result in Table I. Pretreatment factors influencing use of antihypertensive treatment. (Adapted, with permission, from Shea et al. 1) Treated (n = 544)

Untreated (n = 2127)

63/37 57 177 106 85

46/54 54 160 102 84

% Women/% men Age (yr) Systolic blood pressure (mmHg) Diastolic blood pressure (mml-lg) Glucose (mg/dL) Glucose intolerance(%) Cholesterol (mg/dL)o Cigarette smoking (%) Relativeweight (%) 8-Year predicted risk of heart disease (%) Left ventricularhypertrophy (%) Abnormal electrocardiographtcfindings (%) Cardiomegalyon chest roentgenogram (%) Proteinuria (%) Any of preceding four (%) Preexistingcoronary artery disease (%) Preexisting cardiovasculardisease (%) Any of preceding seven abnormalities (%)

256 35 112 13.7 4 18 10 4 27

254 40 112

P Value*

0.0001 0.0001 0.0001 0.0001 NS NS NS NS NS

11.7 2 13 6 3 19

0.0001 <0.01 <0.01 <0.01 NS 0.0001

10 14

6 0

<0.01 0.0001

0.0001

* Independent sample t test or chi-squaredtest for comparison of treated group versus untreated group. 764

A.O. MARCUS

similar end-organ damage, which is exacerbated when the diseases coexist in an uncontrolled state. The morbidity and mortality associated with cardiovascular, cerebrovascular, renal, and neurologic diseases are reported to increase dramatically in patients with diabetes mellitus and hypertension.5'7 In particular, when diabetes, proteinuria, and hypertension coexist, the risk of coronary artery disease may increase significantly. The predictive values of microalbuminuria in five studies are shown in Table II. s Optimal control of blood pressure and glucose levels is the primary goal when treating the patient who has hypertension and impaired glucose homeostasis. This results in the relief of acute symptoms and the prevention of subsequent long-term complications due to end-organ damage that result in an increase in mortality. 5'7 In recent years, calcium channel blockers have emerged as a viable first-choice treatment for patients with hypertension and abnormal glucose control. Calcium channel blockers as a pharmacological group are well known to effectively reduce blood pressure, and no adverse metabolic effects have been reported in diabetic patients 9 treated with calcium channel blockers when metabolic parameters were measured and evaluated. Isradipine is a dihydropyridine-type calcium channel blocker. 1째 This agent is similar to other "second-generation" dihydropyridines. Isradipine is structurally related to nifedipine, but has been developed to specifically provide greater vascular selectivity, less direct myocardial depression, and improved tolerability. 1째'11 In diabetic patients, isradipine has been shown to safely and effectively reduce blood pressure while having a neutral and possibly a beneficial effect on glucose and lipid levels.12-17 This review will evaluate the use of isradipine in the treatment of diabetic patients who have hypertension. In addition, the effects of isradipine on other related issues important to the diabetic and impaired-glucose-tolerant or hyperinsulinemic patient (atherosclerosis, renal hemodynamics, proteinuria, natriuresis) will be briefly discussed.

Table II. Levels of albumin excretion rates predictive of late nephropathy or premature cardiovascular mortality in diabetic patients. (Reprinted with permission from Viberti. s)

Study

Type of Diabetes

Albumin Excretion Rate (l~g/min)

Follow-up (years)

Guy's Hospital Steno Memorial Hospital Aarhus University Guy's Hospital Aarhus University

IDDM IDDM IDDM NIDDM NIDDM

30 70 15 10 15"

14 6 10 14 10

IDDM = insulin-dependent diabetes mellitus. NIDDM = non-insulin-dependent diabetes mellitus. * ~g/ml. 765

ANTIHYPERTENSIVETHERAPYWITHISRADIPINE

R E V I E W OF CLINICAL TRIALS OF ISRADIPINE IN H Y P E R T E N S I V E DIABETIC P A T I E N T S

Clinical Efficacy Monotherapy with isradipine at doses of 1.25 to 10 mg BID produced significant, dose-related decreases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in comparative and noncomparative trials of hypertensive patients with insulin-dependent (type I) or non-insulindependent (type II) diabetes mellitus.

Noncomparative Studies Most recently, Parreira et a117 demonstrated that among 28 hypertensive patients with type I (n --- 13) or type II (n = 15) diabetes, t r e a t m e n t with isradipine 1.25 to 5 mg BID for 6 months normalized blood pressure in all but one patient; isradipine reduced mean SBP/DBP from 168 -+ 9/102 -+ 6 m m H g to 141 -+ 12/82 -+ 8 mmHg (P < 0.00005). No difference in antihypertensive response was noted between type I and type II diabetics. Isradipine had no significant effect on heart rate. 17 Rosenqvist et a115 also evaluated the efficacy of isradipine in a wellcontrolled study of 12 patients with hypertension and stable type II diabetes as determined by hemoglobin Ale readings. After 3 weeks of placebo therapy, patients received isradipine at dosages of 2.5, 5, and 10 mg BID, respectively, for 3-week increments in a single-blind, forced titration study. Thereafter, patients received isradipine 10 mg BID or placebo for 3 weeks in a double-blind manner. The authors noted that isradipine effectively reduced m e a n SBP and DBP in a dose-dependent manner. The mean reduction in supine blood pressure at the highest isradipine dosage (20 mg/day) was 11.7 -+ 12.2/14.6 -+ 14.9 mmHg (P < 0.01). T r e a t m e n t with isradipine again had no significant effect on cardiac r h y t h m throughout all dosage ranges, la

Comparative Studies In two independent double-blind, randomized trials, isradipine was compared with nifedipine. In the earlier study, J a n k a and Mehnert, 14 using a double-blind, random crossover study design, treated 21 hypertensive type II diabetic patients with isradipine and slow-release nifedipine. Treatment time was 4 weeks and mean dosage at the end of therapy was 3 mg BID for isradipine and 21 mg BID for nifedipine. Both calcium channel blockers effectively reduced SBP and DBP to a similar extent. Despite the equal efficacy in treating hypertension, heart rate increased significantly during treatment with nifedipine 14 as compared with isradipine, which had no adverse effect on cardiac rhythm. 766

A, O. MARCUS

In a subsequent study, Gomis et al ~ compared the effects of isradipine 2.5 mg BID with the effects of slow-release nifedipine 20 mg/day in this same population type, studying 20 hypertensive type II diabetic patients by using a 6-month, parallel-group, double-blind study design. Both agents decreased SBP and DBP (P < 0.001) to normal levels compared with pretreatment values. There was a 4% decrease (P < 0.05) in heart rate at the end of treatment with isradipine.l~ Nifedipine had no effect on heart rate.

Clinical Safety and Tolerability According to all clinical studies performed to date, isradipine is well tolerated in hypertensive diabetic patients with a dosage of 10 mg/day or less. Most adverse effects reported are mild and transient and are related to vasodilation, which occurs with the use of calcium channel blocking agents. Those adverse effects observed with isradipine are noted to occur in a dose-dependent manner. At dosages greater than 10 mg/day, there is usually minimal further blood pressure reduction (compared with dosages less than 10 mg/day), although adverse effects increase in frequency, resulting in a decrease of the "benefit:risk" ratio at this and greater dosage levels. Tolerability of isradipine was evaluated in a study of 28 patients conducted by Parreira et a117 and was reported to be "very good" in 85.7% of patients and "good" in 14.3% of patients; 4 patients reported slight or moderate headache during treatment with isradipine. In the study by Rosenqvist et al, 15 6 patients were withdrawn from the evaluation because of the vasodilatory effects of isradipine. The authors noted, however, that, as in other studies, side effects related to vasodilation were provoked at higher dosage levels of isradipine (20 mg/day). In the comparative trial by Janka and Mehnert, 14 side effects were considered rare, but a comparison of all side effects demonstrated an increase in incidence and severity with nifedipine as compared with isradipine. These side effects consisted mainly of flushing, dizziness, headache, and palpitation.

Metabolic Effects In a compilation of all clinical trials of hypertensive patients with type I or type II diabetes (longest study time period was 6 months), treatment with isradipine resulted in no adverse effects on glucose homeostasis or lipid metabolism (Table III). Of particular importance is a double-blind trial that compared the effects of isradipine and hydrochlorothiazide (HCTZ) in 22 type II diabetic patients with slightly elevated blood pressure. In this study, Klauser et a112 reported that treatment with isradipine in patients for 8 weeks had no disturbing influence on glucose or insulin levels (figure). Isradipine had no interaction with the efficacy of oral hypoglycemic agents or adverse-effect 767

ANTIHYPERTENSIVE THERAPY WITH ISRADIPINE

Table III. Effect of isradipine on glycosylated hemoglobin Ale (HbAlc) and serum lipids in normotensive and hypertensive patients with type I or type II diabetes.

Study (year)

Length of Therapy

Dosage (mg/day)

Effect on HbAlc Level

Effect on SerumLipids

Parreira et al (1992) 17 (3omis et al (1992) T6 Joubert and Moagi (1992) 13 Klauser et al (1991)12 -15 Rosenqvist et al (1988) Janka and Mehnert (1988) 14

28 10 91 11 12 21

6 mo 6 mo 1 mo 8 wk 12 wk 4 wk

2.5-10 5 5 10-20 5-20 6 (mean)

NS NS NS NS NS $

NE NS 1' HDL-C NE NS NE

NS = no significant effect; HDL-C = high-density lipoprotein cholesterol; NE = not evaluated. 1" = statistically significant increase. ~, = statistically significant decrease. * Isradipine-treated patients only. 1 Normotensive patients.

potentiation. In dramatic contrast, treatment with HCTZ resulted in a statistically and clinically significant (P < 0.05 versus placebo) deterioration of metabolic control, and increased the already-present impairment of peripheral insulin sensitivity that is one of the causative factors in the development of type II diabetes. Serum potassium levels, important in physiological homeostasis, were unchanged after isradipine therapy and, of clinical concern, were reported slightly lowered after HCTZ therapy. Interestingly, Janka and Mehnert 14 found that isradipine independently demonstrated a pronounced antihyperglycemic effect. During the 4-week treatment period, isradipine significantly reduced fasting blood glucose and glycosylated hemoglobin (P values not provided) compared with nifedipine and placebo. 14 Fasting blood glucose is indicative of insulin-dependent tissue sensitivity, giving rise to a presumption of increased insulin sensitivity as a result of isradipine therapy in these patientsJ 4 Rosenqvist et a115 and Gomis et al, 16 studying the various parameters of lipid metabolism, reported on the effect of isradipine on total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, TC:HDL ratio, LDL:HDL ratio, and triglycerides. All levels were unchanged after isradipine administration for 3 or 6 months in patients with type II diabetes and hypertension. 15,~eRosenqvist et al t5 also found that isradipine had no effect on plasma renin activity or serum and 24-hour urinary aldosterone values. This is important in view of the prevalence and tendency toward hyporeninemia and hypoaldosteronism in this group of patients. Finally, Joubert and Moagi,13 in a randomized, double-blind, crossover study, evaluated nine normotensive native African men with type I diabetes who were treated with isradipine 2.5 mg BID for 1 month. Total cholesterol and triglycerides were unchanged; however, HDL cholesterol and HDL:TC ratio were significantly (P ~< 0.05) increased after isradipine 768

A. O. M A R C U S

400 "

A 100-

300 •

== oo

_= ¢3

50200 -

100

6•0

i 120

i 180

Time (Min)

Time (Mio)

Isradipine Placebo

400 "

C lO0 ..i

t:~ E

300 -

~ ~

200 -

lO0

6'o

12;

Time (Min)

6'0

12;

18'0

Time (Min) =

¢ HCTZ Placebo

Figure. Effects of isradipine versus placebo: on glucose levels (A); on insulin levels (B); during a n oral glucose tolerance test (n = 11), compared with effects of hydrochlorothiazide (HCTZ) versus placebo on glucose (C); and insulin levels (D) during oral glucose tolerance test (n = 6). All patients were type II diabetics and h a d slightly elevated blood pressure. *P < 0.05. t P < 0.005. (Reproduced, with permission of the American H e a r t Association, Inc., from Klauser et al. 12)

therapy when compared with placebo. Patients of African descent or origin, as a subset of the diabetic hypertensive population, may have a higher risk of comorbidities (eg, renal failure, myocardial infarction, cerebrovascular accident). 1s-22 DISCUSSION

According to reliable scientific data (Framingham Report), the impact of coexisting diabetes and hypertension on excess morbidity and mortality is 769

ANTtHYPERTENSIVE THERAPY WITH ISRADIPINE

substantial. The existence of these two disorders significantly increases the risk and progression of cardiac and peripheral vascular disease, stroke, retinopathy, and nephropathy (Table IV). 5 The goal of successful antihypertensive therapy for diabetic patients who also have hypertension is twofold: blood pressure normalization and metabolic control. 5 Seventy-five to 80% of diabetics eventually have extensive multiorgan involvement and/or complications. 2~ Hypertension may represent only one of several medical problems for physicians to treat, but it is one in which treatment has a profound preventative capacity in terms of morbidity and mortality. The ideal antihypertensive agent must reduce blood pressure while having a neutral (or beneficial) effect on the critical factors such as glucose control, lipid metabolism, and neuropathy, which, when aggravated, can worsen the prognosis for diabetics.

Table IV. End-organ damage and medical complications of coexisting hypertension and diabetes. (Adapted, with permission, from Houston. 5) Cardiovascular CHD and sequelae (angina, MI) CHF and cardiomyopathy Peripheral vascular disease Generalized atherosclerosis Cerebrovascular Transient ischemic attack Cerebrovascular accident Neurologic CNS Peripheral nervous system (impotence, autonomic dysfunction, postural hypotension, peripheral neuropathy) Kidneys Albuminuria/proteinuria Arteriolosclerosis and atherosclerosis with renal ischemia Chronic renal insufficiency Glomerular nephritis (especially membranous) Glomerulopathy (Kimmelstiel-Wilson syndrome) Glomerulosclerosis Intrarenal hypertension and glomerular hyperfiltration Papillary necrosis Pyelonephritis and UTIs Eyes Retinopathy and blindness Other Metabolism Hyperlipoproteinemia Fluid and electrolyte disorders Hyper- or hypokalemia Diabetic ketoacidosis Hyper- or hypoglycemia Hyper- or hypomagnesemia Hyperosmolar state Hyper- or hypophosphatemia Osmotic diuresls and intravascular volume depletion CHD = coronary heart disease; MI = myocardial infarction; CHF = congestive heart failure; CNS = central nervous system; UTI = urinary tract infection, 770

A. O. MARCUS

Conventional antihypertensive drugs, notably thiazide diuretics and beta-blockers (which the practitioner may prescribe out of habit), should be used with caution in diabetic patients and (consistent with the American Diabetes Association guidelines) are not first-line therapy for diabetics. 2 4 - 2 6 Long-term t r e a t m e n t with these older agents is associated with a substantially increased risk of complications related to diabetes mellitus 27-29 as a result of glucose, electrolyte, insulin, and neuropathic disturbances. Furthermore, diuretics have been shown to accelerate diabetic nephropathy 3째 and have been associated with increased mortality in certain hypertensive as well as diabetic patient populations. 31-33 A review of the m a n y clinical trials with the calcium channel blocker isradipine in types I and II diabetic patients demonstrates its usefulness as an appropriate agent for the frequently coexisting diseases of diabetes and hypertension. A majority of patients with hypertension and diabetes, who were treated with isradipine as monotherapy at dosages of 1.25 to 10 mg BID, achieved reductions of 10 mmHg or greater in diastolic blood pressure. 14-17 These clinical study results are in agreement with studies performed in nondiabetic patients. 34-3s A distinctive and repeatedly verified pharmacodynamic feature of isradipine is its ability to effectively control blood pressure by reducing peripheral resistance with minimal or no effect on heart rate, cardiac conduction, or contractility. 39'4째 The lack of a significant effect on heart rate is important because of the frequent occurrence of dysrhythmias secondary to diabetic neuropathies in diabetics of both types. According to all studies to date, isradipine is well tolerated in diabetic patients. Among the studies reviewed, the most frequently reported adverse reactions were headache, dizziness, and flushing, which occurred in a dose-dependent manner in a small number of patients. 14'15'17 These reactions, common to all calcium channel blockers, were reported as mild and transient and related to vasodilation. Edema, which m a y be a troublesome and frequent side effect of dihydropyridines, was not observed. Furthermore, in nondiabetic patients, the reported incidence of edema with isradipine is low. At dosages up to 20 mg/day, the incidence of edema is 7.2%, 41 while at dosages of 5 mg/day or less, the incidence of edema decreases to 2.4%. 42 This incidence of edema contrasts sharply with those seen with nifedipine (10% to 30%) and with felodipine (14% to 36%). 43,44 Most important is the finding that isradipine appears to have no adverse effects on the diabetic state. In accordance with the Hippocratic Oath and the credo of "do no harm," isradipine produces desired results on critical parameters used to gauge success in diabetes and hypertension t r e a t m e n t (Table V). The double-blind, crossover design employed in these trials is essential, because glucose control tends to improve in any group of diabetic patients studied intensively as a result of the "study effect." The beneficial effects of isradipine on serum lipids in diabetic patients have also 771

ANTIHYPERTENSIVE THERAPY WITH ISRADIPINE

Table V. Effects of isradipine on related parameters for diabetic patients with hypertension.

Parameter

Desired Effect

Effect of Isradipine

Reference

Serum glucose levels HbAlc Insulin sensitivity Serum potassium levels Known interaction with oral hypoglycemics Serum lipids Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

0 / ,], 0/$ 0 / I' 0

0 / ,], 0/ 0 0

12,14-17 12-17 12 12

12 13,15,16

0/$ 0 / ,], 0 / 1' 0 / ~,

0 0 0 / 1' 0

0 = no significant effect; $ = statistically significant decrease; ~' = statistically significant increase; HbAlc = glycosylated hemoglobin Ale; LDL = low density lipoprotems; HDL = high density lipoproteins.

been observed and reported in studies with nondiabetic hypertensive patients. 45-47 Currently under investigation is the effect of isradipine on the progression of atherosclerosis, which is common in diabetic patients and is accelerated by hypertension in the presence of hypercholesterolemia.5 Preliminary data in both animals and humans suggest that calcium channel blockers may prevent or reduce the process of atherosclerosis, theoretically by altering lipid metabolism, decreasing platelet aggregation and cell necrosis, and inhibiting vascular smooth-muscle cell proliferation. 9 Isradipine demonstrated, at necropsy, reduced arterial cholesterol accumulation in cholesterol-fed rabbits at dosages approximating those used in humans. 4s Similar studies with other calcium channel blockers examining arterial atheroma formation required much higher doses than those used in humans to achieve an effect on atherogenesis.4s This potential usefulness of isradipine as a therapy to prevent progression of atherosclerosis is being investigated in the Multicenter Isradipine Diuretic Atherosclerotic Study. 49 The results are expected to confirm whether or not the antiatherogenic properties observed with isradipine in animal models also have clinical significance. The Importance of Renal Function in Diabetes Mellitus and the Effect

of lsradipine Hypertension, diabetes, and renal function are closely interrelated. According to the American Diabetes Association, diabetes and hypertension represent the two leading causes of end-stage renal disease in the United States. 5째 Long-term data on hypertensive patients treated with diuretics, reserpine, hydralazine, or methyldopa have shown an unexpected decline in renal function despite achieving acceptable blood pressure control. ~1 772

A. O. MARCUS

Treatment with isradipine has been demonstrated to protect renal function while controlling blood pressure. In numerous clinical trials 4째'52-~7 of nondiabetic patients with normal or impaired renal function, isradipine significantly increased renal plasma flow and significantly decreased renal vascular resistance while maintaining or improving glomerular filtration rate and filtration fraction. It has been suggested 5s that, based on these beneficial effects on renal hemodynamics, isradipine use m a y reverse or prevent the pathophysiological progression of hypertensive renal disease. Proteinuria is a well-known marker of nephropathy in diabetic patients. 59 Each calcium channel blocker affects the rate of urinary protein excretion differently. 6째-~s To date, there are no reports of increases in proteinuria associated with isradipine administration. In a study of 26 patients with essential hypertension, Schmieder et a169 found that isradipine significantly (P < 0.05 versus baseline) reduced proteinuria and microalbuminuria after 7 weeks of therapy in patients with elevated pretreatment values. A large study evaluating the effect of isradipine on proteinuria in diabetic hypertensives is currently ongoing at our clinic; preliminary results show a stabilization or improvement in proteinuria in these patients. Another distinguishing characteristic of calcium channel blockers is their natriuretic activity. All three classes of calcium channel blockers have been shown to induce at least some degree of natriuresis and diuresis following acute administration, although these effects are most pronounced with the dihydropyridines. 7째-73 Like other calcium channel blockers, isradipine produces acute diuresis and natriuresis both in normal subjects and in patients with essential hypertension. 74-76 Isradipine is presently the only calcium channel blocker that does not demonstrate tachyphylaxis in regard to this natriuresis. Isradipine has documented long-term natriuretic effects, as reflected by increased sodium clearance for as long as 2 years, providing hypertensive patients with a sustained negative sodium balance. 54'55'~7 For diabetic patients, in whom a positive sodium balance is a common problem, the long-term natriuretic effects of isradipine may help to reduce sodium retention. Specific studies to establish the natriuretic effects of isradipine in diabetic patients will be necessary to prove this effect in this specific disease state. CONCLUSIONS

A review of the available data favors the efficacy and safety of isradipine in the treatment of diabetic patients with hypertension. In the majority of patients studied, monotherapy with isradipine at recommended therapeutic dosages achieved satisfactory blood pressure control with minimal adverse reactions such as edema or significant alteration of heart rate. 773

ANTIHYPERTENSIVETHERAPYWITHISRADIPINE

Isradipine had no adverse effect on glycemic control or serum lipids in patients with insulin-dependent or non-insulin-dependent diabetes mellitus, and, in some cases, therapy with isradipine had a beneficial effect on glucose and lipid levels. In nondiabetic patients, isradipine has been shown to facilitate renal function, which may represent an additional advantage of using the drug in diabetic patients, for whom end-stage renal disease is a common consequence. The findings of beneficial metabolic effects with isradipine deserve special attention and will require further investigation. Well-controlled studies comparing isradipine with other antihypertensive agents in diabetic patients should also be considered.

Acknowledgment This study was supported by a research grant from Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey. References: 1. Shea S, Cook EF, Kannel WB, et al. Treatment of hypertension and its effect on cardiovascular risk factors: Data from the Framingham Heart Study. Circulation 1985; 71:2230. 2. Materson BJ. Hypertension and concomitant disease: Guidelines for treatment. Drug Ther 1985; 15:177-188. 3. Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988; 11:821-827. 4. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992; 19:403418. 5. Houston MC. Treatment of hypertension in diabetes mellitus. Am Heart J 1989; 118: 819-829. 6. Reaven PD, Barrett-Connor EL, Browner DK. Abnormal glucose tolerance and hypertension. Diabetes Care 1990; 13:119-125. 7. The Working Group on Hypertension in Diabetes. Statement on hypertension in diabetes mellitus. Arch Intern Med 1987; 147:830-842. 8. Viberti G. Etiology and prognostic significance of albuminuria in diabetes. Diabetes Care 1988; 11:840-845. 9. Savage S, Miller LA, Schrier RW. The future of calcium channel blocker therapy in diabetes mellitus. J Cardiovasc Pharmacol 1991; 18(Suppl 1):$19-$24. 10. Fitton A, Benfield P. Isradipine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1990; 40:31-74. 11. Freedman DD, Waters DD. 'Second generation' dihydropyridine calcium antagonists greater vascular selectivity and some unique applications. Drugs 1987; 34:578-598. 12. Klauser R, Prager R, Gaube S, et al. Metabolic effects of isradipine versus hydrochlorothiazide in diabetes mellitus. Hypertension 1991; 17:15-21. 774

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