Medications Monotherapy

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Different classes of medications are beneficial in the management of hypertension in patients with diabetes, including ACE inhibitors and angiotensin-receptor blockers (ARBs). The ALLHAT trial showed benefits of chlorthalidone therapy in the hypertensive and diabetic subset (8).

In the vast majority of hypertensive individuals, more than one medication is needed to achieve control (see Table 1). This is truly important in the diabetic patient, where lower systolic and diastolic blood pressures are important. Clearly, there is strong evidence that pharmacological therapy for hypertensive diabetic patients can provide substantial improvements in cardiovascular and microvascular outcomes.

The a-blocker arm of the ALLHAT trial was terminated after a subanalysis showed that a-blockers were substantially less effective than diuretic therapy in reducing congestive heart failure.

Clearly, the data indicates that patients with diabetes should be treated to a diastolic blood pressure of less than 80 mmHg. Patients with a systolic blood pressure of greater than 130 mmHg and less than 139 mmHg can try therapeutic lifestyle changes and behavior therapy for a maximum of 3 months, but must be treated pharmacologically if not successful after this short trial period.

Individuals with systolic blood pressures greater than 140 mmHg or diastolic blood pressures greater than 90 mmHg should be started on medication therapy. This therapy should be with ACE inhibitors, ARBs, or diuretics. In hypertensive individuals who have existing microalbuminuria or clinical evidence of nephropathy, ARBs and ACE inhibitors should be given unless there is some contraindication to their use.

For individuals who are 55 years of age or older, either with or without hypertension, ramipril at doses titrated up to 10 mg is the agent of choice in view of the outstanding data from the Heart Outcomes Prevention Evaluation (HOPE) trial (9).

An important therapeutic decision in managing the hypertensive patient with diabetes is the role of P-blockers, and at what point in therapy they should be used. Clearly, for patients who have had a recent myocardial infarction, P-blockers should be added to the regimen.

In a study of diabetic patients with unstable angina, P-blockers improved the 3-month mortality from 8.6 to 2.5% and the 6-month mortality from 16.8 to 8.6%. Cardiac mortality was reduced by 42% and cardiac events declined from 14 to 7.8% after 3 years of P-blocker use in diabetic subjects (10).

P-blockers have several beneficial effects on the cardiovasculature in the myocardium. When the heart rate decreases, diastolic filling time is prolonged, thereby increasing the blood flow to the myocardial tissue. By decreasing heart rate and blood pressure, P-blockers are responsible for reducing cardiac workload. These agents can also increase vagal tone, lessening the likelihood of arrhythmia and having an antiatherogenic effect by decreasing arterial sheer stress, improving endothelial function, decreasing inflammation within the atheromatous plaques, and inhibiting platelet aggregation.

P-blockers are also effective in decreasing the hepatic production and myocardial use of free fatty acids, increasing myocardial glucose utilization. The subsequent decrease in myocardial oxygen consumption decreases the frequency of myocardial ischemia and results in fewer cardiac arrhythmias. P-blockers also lower levels of C-reactive protein and P-blockers have been shown to both prevent and reverse myocardial remodeling (11).

Third-generation P-blockers, such as carvedilol, enhance vasodilation and maintain cardiac output, resulting in better outcomes in patients with congestive failure. Additionally, the third-generation P-blockers, such as carvedilol, reduce insulin resistance, which is not the case for the first-generation P-blockers (propranolol and timolol) or the second-generation P-blockers (metoprolol and bisoprolol) (12).

Carvedilol has improved left ventricular ejection fractions and decreased mortality rates in both diabetic and nondiabetic patients with congestive heart failure. In a doubleblind, randomized trial, the effects of the ACE inhibitor, perindopril (Aceon) on blood pressure and endothelial function were compared with carvedilol in 26 diabetic patients with hypertension. Both perindopril and carvedilol significantly reduced mean blood pressure and increased leg blood flow to the same extent.

Interestingly, carvedilol reduced platelet aggregation significantly but this effect was not seen with perindopril. In other controlled trial, the metabolic and cardiovascular effects of carvedilol and atenolol in 45 hypertensive patients with type 2 diabetes were evaluated. Mean fasting glucose, insulin, and hemoglobin A1-C concentrations decreased during carvedilol treatment and increased during atenolol treatment (p < 0.01 between the two groups) (12).

The Appropriate Blood Pressure Control in Type II Diabetes (ABCD) (13) trial was primarily designed to evaluate renal end points with intensive hypertension control in patients with type 2 diabetes. In this study, 470 patients with hypertension and diabetes were assigned to one of two treatment goals, a target diastolic blood pressure of 80-89 mmHg or of 75 mmHg. In the intensive hypertension control group, a mean blood pressure level of 132/78 mmHg was achieved compared with 138/86 mmHg in the moderate hypertension control group. After 5 years of follow-up, the groups did not differ in progression of normal albuminuria or microalbuminuria, diabetic retinopathy, or neuropathy. However, total mortality was 5.5% in the intensively controlled group and 10.7% in the moderately controlled group.

Various studies have evaluated the effects of specific classes of drugs in the management of hypertension in patients with diabetes. Some studies compared ACE inhibitors with CCBs.

In a substudy of the ABCD trial (14), 470 hypertensive patients with diabetes were randomly assigned to treatment with either nisoldipine or enalapril. Equivalent blood pressures were achieved, but the nisoldipine group had a substantially higher rate of myocardial infarction.

The Fosinopril vs. Amlodipine Cardiovascular Events Trial (FACET) was an open label study that randomized 380 patients with type 2 diabetes to receive either fosinopril or amlodipine. At the conclusion of the study, systolic blood pressure control was better in the amlodipine group, and diastolic pressures were similar. Fosinopril had significantly fewer combined cardiovascular events, despite having higher systolic blood pressures, although total mortality and changes in albumin secretions did not differ (15).

In the Swedish Trial in Old Patients with Hypertension (STOP II), three drug groups were evaluated: CCBs, ACE inhibitors, and P-blockers plus diuretics. In a post hoc analysis of patients in the group with type 2 diabetes, blood pressure was equal in the treatment groups and cardiovascular events and total mortality were not changed. Interestingly, as seen in the ABCD trial, risk for myocardial infarction was lower in patients treated with the ACE inhibitors than with the CCBs (16).

The ALLHAT trial showed that in a prespecified subgroup analysis of 12,000 patients with type 2 diabetes, there was no significant difference between treatment with ACE inhibitors, CCBs, or thiazide diuretics in the primary outcomes of nonfatal myocardial infarction plus coronary heart disease death or all-cause mortality. However, the risk for heart failure was lowest in the diuretic group.

In comparison to the STOP II and ALLHAT trials, two studies compared traditional P-blocker or diuretic base therapy with ACE inhibitors. The Captopril Prevention Project trial (CAPP) (17) randomly assigned patients with hypertension to treatment with P-blockers or diuretics and captopril, with target diastolic blood pressure being less than 90 mmHg. In this hypertensive group, 572 patients had diabetes. Although blood pressure control was similar in both groups, in the captopril group, the risk for myocardial infarction, all-cause mortality, and cardiovascular events was lower. The UKPDS trial also included a subanalysis in which patients in the intensive control group with blood pressures less than 150/85 mmHg were randomly assigned to atenolol or captopril. In contrast to the Captopril Prevention Project trial, there were no differences in any of the aggregated or individual macrovascular or microvascular events between the two groups (12).

In addition to ALLHAT and STOP II, two other studies directly compared traditional treatment with P-blockers or diuretics to CCBs. The Nordic Diltiazem Trial (NORDIL) (18) compared treatment with P-blockers or diuretics to diltiazem. Blood pressure was similarly reduced in both groups, but in the subgroup analysis of 727 patients with type 2 diabetes, no differences were seen in total mortality or combined cardiovascular end points. The International Nifedipine Study Intervention as a Goal in Hypertensive Treatment Trial (INSIGHT) (19) compared treatment with thiazide diuretics and a long-acting nifedipine. Once again, blood pressure reductions were similar in both groups but in the subanalysis of 1302 patients with diabetes, there was no difference in the risk for total mortality or cardiovascular end points.

ARBs and other drugs for treating hypertension and diabetes have been compared in two trials. The Irbesartan Diabetic Nephropathy Trial (IDNT) randomly assigned 1715 patients with diabetic nephropathy and hypertension into three groups: placebo, amlodipine, and irbesartan. Irbesartan was more effective than amlodipine or the placebo in preventing the primary end point of doubling serum creatinine, death, or a development of end-stage renal disease. No differences were seen between placebo and amlodipine in any of the outcomes or between any of the groups in the secondary outcomes (20).

The Losartan Intervention for End Point Reduction Trial (LIFE) randomly assigned patients with left ventricular hypertrophy and hypertension to an angiotensin II-receptor blocker (losartan) or a P-blocker (atenolol). In the subset of 1195 people with diabetes, the losartan group had substantially lower risks for cardiovascular end points and total mortality and a lower risk for microalbuminuria (21 ).

The effects of many of these agents in controlling some of the risk factors associated with hypertension can be understood when we look at the characteristics of people with hypertension and diabetes. These characteristics include decreased plasma renin activity, increased peripheral vascular resistance, increased salt sensitivity, decreased barore-ceptor sensitivity, an increased tendency to orthostatic hypotension and blood pressure variability, and increased body weight and abdominal girth.

Along with the dyslipidemia associated with diabetes, the metabolic syndrome, and insulin resistance, come vascular hypertrophy, accelerated atherogenesis, excessive angio-tensin II production, sodium retention, increased sympathetic outflow, and increased mortality and morbidity. The importance in treating hypertension in the diabetic patient cannot be minimized. End-organ damage and medical complications are plentiful when we look at this patient population. Cardiovascular complications include congestive heart failure and its sequelae, cardiomyopathies, peripheral vascular disease, and generalized arteriosclerotic vascular disease. Patients are prone to cerebral vascular infarctions, ischemic events, hemorrhages, and carotid and intracerebral arteriosclerotic vascular disease.

Neurological manifestations include peripheral nervous system abnormalities of impotence, autonomic dysfunction, peripheral neuropathy, and postural hypotension; central nervous system disturbances include behavioral changes, memory loss, hallucinations, nightmares, depressions, and insomnia.

Ophthalmologically, patients have an increased risk of retinopathy and blindness; nephrologically, patients are prone to albuminuria, proteinuria, and atherosclerosis of the renal arteries with subsequent renal ischemia, renal insufficiency, glomerulonephritis (especially membranous), Kimmelstiel-Wilson glomerulopathy, glomerulosclerosis, intrarenal hypertension and glomerulohyperfiltration, papillary necrosis, pyelonephritis, and frequent urinary tract infections.

To determine the risks and the benefits of the various agents it is important to look at the metabolic variables associated with each type of treatment.

Thiazide diuretics will increase glucose intolerance, hypokalemia, hypomagnesemia, and total cholesterol and triglycerides (but relatively neutral for high-density lipoprotein [HDL] levels). Thiazide diuretics act as vasodilators, with data confirming their ability to reduce left ventricular hypertrophy.

The P-blockers without intrinsic sympathomimetic activity except third-generation P-blockers (carvedilol), will tend to increase triglycerides and glucose intolerance, decrease HDL, and have a neutral effect on magnesium, cholesterol, and potassium, although occasionally may aggravate hyperkalemia.

Calcium-channel blockers are relatively neutral in terms of metabolic variables, but the phenylalkylamines (verapamil) and the benzothiazepines (diltiazem) can cause slowing of the heart rate in individuals prone to bradyarrhythmia. The phenylalkylamines are negatively inotropic, whereas the benzothiazepines are negatively inotropic only if the ejection fraction is decreased before therapy is initiated.

The ACE inhibitors are likewise neutral to the parameters suggested, except for a slight tendency to cause hyperkalemia. This is most often seen when ACE inhibitors are combined with ^-blockers, ARB, or aldosterone antagonists, or when a diabetic patient has renal insufficiency (22).

Although a-blockers tend to raise HDL, lower total cholesterol, and be relatively neutral for other metabolic variables, they should not used as first-line therapy in diabetic patients because of the unfavorable outcomes in the ALLHAT trial. a-Blockers are better used as adjuvant therapy, particularly in patients who have some prostatic outlet obstruction problems.

Because of the inability to achieve hypertensive control with a single agent, the primary care physician should be aware of the importance of fixed-dose combinations in treating hypertension. Data from the Third National Health and Nutrition Examination Survey (23) demonstrates that only 11% of people with diabetes and hypertension achieved the blood pressure goal of less than 130/85 mmHg.

Initial therapy with fixed-dose combinations can achieve the recommended blood pressure goal in patients with type 2 diabetes faster than conventional monotherapy. The physician should understand that strategical use of early and intensive antihypertensive therapy with combination agents can be an important adjunct in achieving patient goals and can aid in compliance.

In the UKPDS trial, more than one-half of the participants required two or more drugs to achieve their blood pressure goals, with 29% needing three or more medications to maintain the target blood pressure after 9 years of follow-up (24). Growing evidence now supports the use of fixed-dose combination therapy in mixed patient populations, demonstrating that they are more effective than commonly used monotherapy and are better tolerated. These trials include the use of a diuretic with a ^-blocker or an ACE inhibitor or an ACE inhibitor plus CCB combination.

The Study of Hypertension and the Efficacy of Lotrel in Diabetes (SHIELD) trial was a 12-week randomized double-blind, parallel-group, multicentered study. This trial followed a maximum 3-week placebo run-in with 214 participants recruited from 22 centers around the United States. The use of 5-10 mg/day of amlodipine plus benazepril (Lotrel) was compared with 10 mg/day of enalapril. From baseline to week 12, combination therapy produced a 20.5 mmHg decrease in systolic blood pressure and a 13.9 mmHg decrease in diastolic blood pressure compared with a 14.5/9.6 mmHg decrease with enalapril alone, which was statistically significant (25).

The SHIELD trial provided support for the use of these fixed-dose combinations, including ACE inhibitors and CCBs, in the management of diabetic hypertensive patients. In this trial, the cumulative percentage of patients achieving treatment success was significantly greater in the combined therapy group than in the enalapril-alone group, even when patients receiving hydrochlorothiazide add-on therapy were excluded from the combination group but not the ACE-inhibitor group. The rates of adverse events were similar in each group. The SHIELD trial provided important evidence that this fixed-dose combination can successfully treat diabetic hypertensive patients without influencing the glycemic or lipid control.

The Fogari trial published in the American Journal of Hypertension in 2002 (26) demonstrated superior blood pressure lowering and significant lowering of urinary albumin excretion with the ACE inhibitor plus CCB combination compared with monotherapy. This 4-year trial showed that a combination of fosinopril and amlodipine was superior to each agent alone in reducing blood pressure and urinary microalbumin. Additionally, the decreases in urinary albumin excretion were significantly greater in the combination group compared with either monotherapy as the patients were followed for up to 4 years.

These superior reductions in urinary albumin excretion may be related to the renal protective effects of the ACE inhibitors and a synergistic combined effect of the ACE inhibitor and dihydropyridines. Additionally, a greater percentage of patients who initially received combination therapy maintained their blood pressure treatment goal compared with the conventional treatment group. This was maintained regardless of whether the blood pressure target was 130/85 mmHg or 130/80 mmHg (27).

The Fogari study (28) supports the growing concept that one pill containing two different blood pressure-lowering agents achieves blood pressure goals in a larger percentage of patients than one pill with a single agent. This lends a great deal of merit to the use of fixed-dose combinations in the diabetic patient who is already looking at the distinct possibility of multipharmacy to control other risk factors.

The level of blood pressure reduction that optimizes cardiovascular risk reduction continues to be controversial. The Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (29) recommends a target blood pressure of less than 130/85 mmHg for individuals with concomitant hypertension and diabetes, and the National Kidney Foundation 2000 Guidelines (30) and The American Diabetes Association (ADA) 2002 Guidelines (31) for the treatment of hypertension and diabetes recommend an even lower target blood pressure of 130/80 mmHg.

There is also an increased risk for cardiovascular events and mortality in diabetic patients with systolic blood pressures greater than 120 mmHg. When both hypertension and diabetes coexist, the risk of nephropathy and arteriosclerotic cardiovascular disease are markedly increased. Therefore, the primary therapeutic objective in the hypertensive diabetic patient is to reduce the risk of renal and cardiovascular complications without adversely affecting glycemic and lipid controls.

Fixed-dose combinations make sense in diabetic patients not only because of the effects on blood pressure and target organ disease but also because of the efficient use of different mechanisms of action in reducing cardiovascular risk that is accomplished with the use of ^-blockers and diuretics, ACE inhibitors or ARB with diuretics, or ACE inhibitors and CCBs.

Additionally, by using combination therapy, lower doses of each component drug are often used, reducing adverse events. This can be seen in the combination of CCBs containing dihydropyridine and the ACE inhibitors, which tend to attenuate venous dilation and subsequent edema associated with dihydropyridine use. Reduction of adverse events is also seen with synergistic hypertension control when diuretics are added to ACE inhibitors or ARBs, because the diuretics attenuate the hyperkalemia risk. The ALLHAT trial also used component classes of antihypertensive agents that were used in both the Systolic Hypertension in Europe (32) and the Hypertension Optimal Treatment (HOT) (3) trials. Additionally, the STOP II trial showed that CCB were as effective as diuretics, ^-blockers, and ACE inhibitors in reducing morbidity and mortality in hypertensive patients with diabetes (16).

The cardiovascular benefits of the CCBs seem to be derived from their blood pressure-lowering effect. CCBs are more efficacious for lowering blood pressure than ACE inhibitors in some patient populations. Although the short-acting CCBs increase the risk of cardiovascular events, long-acting CCBs are safe and effective in reducing cardiovascular outcomes (especially stroke) in diabetic and nondiabetic patients with hypertension (33).

However, the dihydropyridine CCBs should be avoided as solo therapy in patients with macroalbuminuria equal to or greater than 300 mg of albumin per gram of creatinine unless these individuals are being treated with an ACE inhibitor or an ARB.

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