Controversy no longer exists regarding the beneficial effects of aggressive blood pressure control in individuals with diabetes. Tightly controlling blood pressure has been shown to effectively delay the development and progression of microvascular diabetic complications, including nephropathy and retinopathy. Moreover, extensive data from a number of studies have demonstrated that reduction of cardiovascular risk from such treatment is greater in the diabetic population than in the nondiabetic population.

Much controversy, however, still rages surrounding the best approach for treatment, in part stemming from recent reports of increased cardiovascular events in diabetic populations treated with calcium channel blockers (CCBs), as well as from the lingering belief that diuretic treatment is associated with adverse effects in diabetic individuals. This article focuses on evidence from randomized trials supporting the critical importance of blood pressure control in diabetic individuals, evaluates the strength of the data surrounding the reported negative effects of CCBs and effects of other classes of drugs, and presents a rationale for choosing a pharmaceutical approach.

Goals of Hypertensive Treatment: Cardiovascular Benefits
Hypertensive treatment should not only decrease blood pressure, it should reduce the risk of macrovascular and microvascular complications. But how low is beneficial and still safe? Until recently, much scientific debate surrounded this issue. Today, all such discussion should be put to rest by the results of a number of trials, including the Systolic Hypertension in the Elderly Program (SHEP), Systolic Hypertension in Europe study (Syst-Eur), and the Hypertension Optimal Treatment (HOT) trial.

The SHEP¹ was a randomized, double-masked, placebo-controlled study designed to assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular event rates in older type 2 diabetic and nondiabetic patients who had isolated systolic hypertension (ISH). The study included 4,736 men and women aged 60 years or older, 583 with type 2 diabetes, who were followed prospectively for 5 years. ISH was defined as systolic blood pressure (sBP) >160 mm Hg and diastolic blood pressure (dBP) <90 mm Hg.

The active treatment group received chlorthalidone (12.5­25 mg/d), and, if needed, either low-dose atenolol or reserpine was added for blood pressure control. Of note, only 46% of patients were controlled with the diuretic alone. The placebo-treated group could also receive, if needed, any antihypertensive treatment prescribed by their own physicians. Over time, sBP and dBP were lower for diabetic patients on active treatment by 9.8 and 2.2 mm Hg on average, respectively, attaining levels of approximately 145/70 mm Hg.

The results from the active treatment diabetic group demonstrated reductions in rates for all major cardiovascular events (34%), for nonfatal and fatal stroke (22%), for nonfatal and fatal myocardial infarction (MI) (56%), and for all-cause mortality (26%).¹ Moreover, there was no evidence from this study that the use of a relatively low-dose diuretic was associated with increased mortality. These results strongly suggest that such an approach can be safely used for treatment of systolic hypertension in an elderly diabetic population, and that dBP levels much lower than the goals we traditionally aim for are safe and beneficial.

The Syst-Eur study confirmed the finding that antihypertensive treatment could reduce risk of cardiovascular complications in elderly patients with isolated hypertension.² This study used a long-acting dihydropiridine CCB, nitrendipine, versus placebo as first-line treatment. Enalapril or hydrochlorothiazide (12.5–25 mg/day), or matching placebo, was added or substituted as needed. Four hundred ninety-two (10.5%) subjects had diabetes. Average follow-up was 2 years, and the treatment group achieved a blood pressure average of approximately 153/78 versus 162/82 mm Hg in the placebo group.

Figure 1.  Reductions in overall mortality, CV mortality, fatal and nonfatal strokes, and all CV events i the Syst-Eur study 3-5 in: subjects with type 2 diabetes ( ) and nondiabetic subjects () on antihypertensive Tx compared with placebo (n=492 for  diabetic subjects, 4,695 for nondiabetic subjects.)

Post hoc analysis of the results^3-5 in the diabetic subjects showed reductions in the treated group in overall mortality of 55%, in cardiovascular mortality of 76%, in fatal and nonfatal stroke of 73%, and in all cardiovascular events of 69%. Comparison of the reductions in the same parameters in the nondiabetic subjects are shown in Figure 1, demonstrating a particular benefit of lowering sBP in the diabetic group.

The third study that assessed the association between major cardiovascular events and level of blood pressure control was the HOT trial.⁶ This study included 18,790 subjects, aged 50–80, who were randomized to three dBP goals: <90, <85, and <80 mm Hg, and were followed for an average of 3.8 years. Of these, 1,501 (7.9%) had diabetes.

Utilizing a "stepped care" approach to treatment, patients started first with the dihydropyridine CCB felodipine at 5 mg/day and sequentially added an angiotensin-converting enzyme inhibitor (ACEI) or a -blocker, then doubled the dose of felodipine, then doubled the ACEI or -blocker, and lastly, added a diuretic, as needed, in order to achieve the blood pressure targets. The actual blood pressures achieved in each group were: 144/85 (<90 mm Hg group), 141/83 (<85 mm Hg group), and 140/81 (<80 mm Hg group), with considerable overlap between groups. Forty-one percent of patients required the addition of an ACEI and 28% a -blocker to achieve blood pressure targets.

Results demonstrated a clear benefit of lowering blood pressure in the diabetic subjects and no evidence of a negative effect at the lowest levels ("J-curve"). In all patients, there was a decline in cardiovascular mortality (P = 0.005 for trend), but in the <80 mm Hg group compared with the <90 mm Hg group it was reduced by 67% (P = 0.016). Major cardiovascular events including silent MI were reduced by 36% (P = 0.045). These significant results support an aggressive approach to lowering blood pressure to 140/80 mm Hg or less in diabetic individuals.

Results of the United Kingdom Prospective Diabetes Study (UKPDS)^7-9 also demonstrate the cardiovascular benefits of tight blood pressure control in a large type 2 diabetic population. Antihypertensive treatment was added in 1988 to this trial of intensive glycemic management because a large percentage of the diabetic subjects had high blood pressure at enrollment. The study included 1,148 subjects with blood pressures of >160/90 mm Hg who were randomized to a tight (<150/80 mm Hg) versus a less tight (<180/105 mm Hg) control policy, the former accomplished with either captopril (25­50 mg twice daily) or atenolol (50­100 mg/day). As needed, furosemide and/or nifedipine could be added to attain the blood pressure goals.

The average actual blood pressures of each of the two groups over a mean follow-up of 8.4 years were 144/82 and 154/87 mm Hg, respectively. Both drugs were equally effective at controlling blood pressure, but 29% of patients required three or more drugs. The beneficial results of tight blood pressure control demonstrated in this trial are summarized in Table 1.

Together the results of these studies provide convincing evidence for aggressively controlling blood pressure in diabetic individuals and demonstrate two important overall findings: 1) even small decreases in blood pressure can have a big impact on cardiovascular risk, and 2) the lower the better. That this second point applies to the development of diabetic microvascular complications is supported by a number of studies described below.

Goals of Hypertensive Treatment: Microvascular Benefits
The renal effects of good hypertensive control in patients with diabetes are well established. In both type 1 and type 2 diabetes, a number of studies have shown that lowering systemic blood pressure slows the rate of decline in renal function and improves survival.

In a now-classic study, Parving initially observed a significant decrease in glomerular filtration rate (GFR) accompanying an increase in blood pressure and albumin excretion in 18 type 1 diabetes patients.¹⁰ After initiating effective antihypertensive treatment with -blockers, diuretics, hydralazine, and later, ACEIs, he followed these patients and 13 untreated control subjects for as long as an additional 3 years. He had demonstrated that blood pressure control decreased the albumin excretion rate by 50% and the rate of decline in GFR from approximately 0.9 ml/min/month to 0.1­0.29 ml/min/month.^11,12

Studies have also confirmed that lowering blood pressure in hypertensive type 2 diabetic patients will decrease the progression of microalbuminuria and the rate of decline in renal function, regardless of pharmaceutical choice. In one 3-year study, the observed fall in GFR in 44 hypertensive diabetic individuals, 18 with microalbuminuria, randomized to receive either an ACEI or a slow-release dihydropyridine CCB to lower blood pressure to a target of <140/85 mm Hg, was significantly and inversely related to the decrease in mean blood pressure (P < 0.0001).¹³

Numerous studies have shown that lowering blood pressure even in "normotensive" diabetic individuals has clear renal benefits. In a double-masked, double-dummy study, 92 patients with sBP <140 and dBP <90 mm Hg, type 1 diabetes, and microalbuminuria were randomized to treatment with an ACEI, long-acting dihydropyridine CCB, or placebo. Clear benefits were seen in both active treatment groups in delaying the progression to macroalbuminuria over 3 years.¹⁴ Comparable results were observed in the North American Microalbuminuria Study (NAMS) comparing captopril with placebo over 2 years in a similar population.¹⁵ Finally, a 7-year study in 94 type 2 diabetes patients who were "normotensive" (<140/90 mm Hg) but microalbuminuria demonstrated stabilization of renal function in the treated group and progression to proteinuria in the placebo group.¹⁶ As clinical proteinuria strongly predicts progression to renal failure, these studies support the benefit of lowering blood pressure even below conventional levels in diabetic individuals.

Some evidence also supports the effect of good blood pressure control to prevent the development and progression of retinopathy. Most recently, the UKPDS results demonstrated a 34% reduction in 2-step progression of retinopathy and a 47% reduction in risk of decline in visual acuity in the tightly controlled blood pressure group compared with the group with less tight control.⁷

Results of these studies provide more evidence for aggressively controlling blood pressure in diabetic individuals below levels that have traditionally been considered ideal for effective prevention of microvascular complications.

Is There an Ideal Antihypertensive Drug for Use in Diabetes?
Recent attention increasingly has focused on which antihypertensive drug is best to prescribe for diabetic patients. Some studies have claimed beneficial microvascular and cardioprotective effects specific to those agents (e.g., ACEIs) beyond what would be expected from lowering blood pressure per se. Of concern are some reports that have raised issues regarding potential negative effects of other drugs (e.g., CCBs), particularly on cardiovascular risk. In that the primary cause of death in diabetic individuals is cardiovascular disease (CVD), the potential impact of a given drug on this risk must be carefully assessed. Antihypertensive agents that improve (or do not worsen) insulin resistance, dyslipidemia, glycemic control, and/or nephropathy are also preferable. Diabetic individuals are more likely to have sexual dysfunction, hypoglycemia, and orthostatic hypotension, so consideration should be given to choosing a medication that will not worsen any of these conditions.

Low-dose diuretics have been shown in a number of clinical studies to be effective in diabetic patients, without significant negative effects on glycemic control or lipid profiles. The SHEP study discussed above, for example, which compared active treatment with chlorothalidone with placebo, demonstrated no evidence of increased mortality from the use of a relatively low-dose diuretic, and a benefit with regard to reduction in cardiovascular mortality.¹ Results from the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS), which used low-dose hydrochlorothiazide as one of its treatment arms in diabetic and nondiabetic subjects, showed no treatment group differences in the primary endpoint, the rate of progression of carotid artery intimal-medial thickness, over 3 years.¹⁷

Concern is often raised about the use of -blockers in diabetic patients because of concerns of hypoglycemia, potential adverse effects on glucose and lipid control, and cardiovascular risk. Compelling evidence to the contrary comes from the UKPDS, which compared the -blocker atenolol with the ACEI captopril. Both drugs were equally effective at controlling blood pressure, and no difference in cardiovascular endpoints, including incidence of MI, stroke, or congestive heart failure, was seen between groups. Moreover, no difference in the incidence of hypoglycemia was observed. However, after 8 years of the study, 81% of the atenolol group versus 71% of the captopril group required an additional glucose-lowering drug to control glycemia.¹⁸ Those subjects on atenolol gained more weight and showed a slightly greater increase in glycated hemoglobin concentrations, but neither of these affected the clinical endpoint outcomes.

In summary, the results of the SHEP, Syst-Eur, HOT, MIDAS, and UKPDS studies all support the safety and efficacy of the use of low-dose diuretics and -blockers in diabetic individuals. These results suggest importantly that blood pressure reduction in itself may be a more critical factor in preventing diabetic complications than is the agent(s) used.

Do CCBs Have Potential Detrimental Effects in Diabetic Patients?
Recently, much debate is ongoing in the scientific literature concerning the results of a number of studies that have suggested that CCBs might be associated with increased cardiovascular events in diabetic individuals. The earliest concerns were raised by the Established Populations for Epidemiologic Studies of the Elderly (EPESE) and MIDAS trials. EPESE examined all-cause mortality in 906 older people with hypertension, 19.2% (342) of whom had diabetes, comparing clinical outcome results in those using -blockers, verapamil, diltiazem, short-acting nifedipine, or ACEIs. Results showed that the use of nifedipine was associated with decreased survival in this population.¹⁹

It has been suggested that the negative effects seen in this study are likely related to the pharmacokinetics of short-acting CCBs,^20,21 and this seems likely. The MIDAS results, showing more angina and cardiovascular events in the CCB group versus a group on diuretics, further suggest that these concerns might spill over to the use of intermediate-acting CCBs.^17,22,23 An "increased susceptibility" hypothesis, i.e., that poor glycemic control may lower the risk threshold for cardiovascular events in those individuals on CCBs, has also been suggested.^22,24,25

Two recent studies comparing long-acting dihydropyridine CCBs with other treatment choices, the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) and the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial, deserve careful examination. FACET was an open-label, randomized, prospective trial designed to assess treatment-related differences in serum lipids and glycemic control in hypertensive patients with type 2 diabetes.²⁶ Prospectively designed cardiovascular events were secondary outcomes. The study included 380 patients who were randomized to initial treatment with fosinopril or amlodipine. If blood pressure was not adequately controlled, the other drug was added, so that by study end, 30.7% of the fosinopril group was also taking amlodipine, and 26.2% of the amlodipine group was also taking fosinopril, with analysis done by intention-to-treat. -Blockers were being taken by 10.5% of the fosinopril and 9.5% of the amlodipine group, and diuretics by 29% and 34.5% of each group, respectively.

Goals for sBP and dBP were met by an equal percentage of each treatment group, but the sBP was 4 mm Hg lower in the amlodipine group. Results after 3.5 years demonstrated a 50% lower incidence of major cardiovascular events in the group assigned to fosinopril, including acute MI, stroke, and hospitalized angina combined, despite no differences in serum lipids or glycemic control.

These results, the authors suggested, could either be due to a specific beneficial effect of ACEIs in diabetic patients or to a detrimental effect of CCBs. The former is more plausible, since the lowest risk by post hoc analysis was seen in the group of patients (approximately 30%) who were on both drugs at study end.²⁷ There were no significant differences between the study groups for individual cardiovascular events, and all-cause mortality was the same in both drug groups. Only when grouped together did any of the events reach statistical significance.

With only 380 diabetic subjects included, the study was not powered to compare the effects of the two drugs on cardiovascular events, which were secondary outcomes of the study. Further criticisms of this study include its open-label design and the fact that events were documented by asking patients if such events occurred. It has also been suggested that the study conclusions were flawed in that no information was provided about potential baseline differences between groups in terms of cardiovascular risk factors such as family history, left ventricular hypertrophy, or autonomic neuropathy. Further, the mean urinary albumin excretion rate was significantly higher at entry in the amlodipine group, suggesting that this group may have had increased baseline risk for cardiovascular disease development given the predictive power for cardiovascular morbidity of this finding.²⁸ These data also point out the flaws inherently associated with using surrogate endpoints (e.g., lipids, glucose, blood pressure) instead of actual clinical outcomes.

The ABCD trial^29,30 was a prospective, randomized study designed to test the primary hypothesis that intensive blood pressure control (target dBP 75 mm Hg) would slow or prevent the progression of microvascular and cardiovascular events in type 2 diabetic subjects compared with moderate blood pressure control (target dBP 80­89 mm Hg). A secondary hypothesis was that the long-acting dihydropyridine CCB nisoldipine would have equivalent effects to the ACEI enalapril.

The study included 950 subjects who were followed for 5 years, 470 with hypertension defined as baseline dBP >90 mm Hg. The design of the study allowed for the addition of a second agent, either hydrochlorothiazide or metoprolol, to be added as an open-label drug if the single agent did not adequately control blood pressure.

Results in the hypertensive subgroup showed similar blood pressure control and no differences in lipids or glucose control, but analysis of secondary endpoint data, i.e., incidence of fatal and nonfatal MI, revealed a significantly higher incidence in the nisoldipine group, such that this arm of the study was stopped by the Data Safety Monitoring Group. No such difference was seen in the normotensive subgroup.

The question again arises, are the results due to a beneficial effect of ACEIs in diabetic patients or a detrimental effect of CCBs? One flaw in the conclusion that CCBs are detrimental lies in the fact that the study was not designed or powered to test the effect of one drug versus the other on cardiovascular outcomes, as this was a secondary study endpoint only. Also, more patients in the ACEI group were on -blockers and diuretics, possibly affording a benefit from the combination of therapies or from individual benefits of each of these classes of drugs on cardiovascular morbidity. And, more patients in the CCB group discontinued the study drug. No data were given about microalbuminuria or about aspirin use at baseline. Finally, for ethical reasons, neither FACET nor ABCD included a placebo arm, but this disallows a conclusion that CCBs were harmful.

A valid interpretation of the results of these studies is that the combination of ACEI plus dihydropyridine CCB provides the best outcome for patients with type 2 diabetes and hypertension. And, in fact, evidence from other studies that included dihydropyridine CCBs, including post hoc analyses of the Syst-Eur^4,5 and the HOT⁶ trials, suggests that there was no detrimental effect from CCB use in the diabetic subjects in either of these studies. The Syst-Eur results, in fact, suggested a particular benefit in diabetic subjects from first-line treatment with the dihydropyridine CCB nitrendipine. Furthermore, when the results in the CCB-treated patients in the FACET and ABCD trials are put into the perspective of a comparison of MI rates in similar populations with type 2 diabetes in other published trials (randomized and historical), it suggests that the rate of MIs is not significantly different (Figure 2).³⁰

Do ACE Inhibitors Have Specific Beneficial Effects on Microvascular Disease?
A number of clinical studies have examined the hypothesis that ACEIs afford beneficial effects on microvascular diabetic complications, particularly nephropathy, when compared to other agents. In a 3-year, randomized, double-masked trial in 409 type 1 diabetic patients with hypertension, proteinuria, and mild renal insufficiency, captopril treatment was shown to decrease the creatinine doubling time by 48% and to reduce the combined endpoints of death, dialysis, and renal transplantation by 50% when compared with placebo treatment, despite similar blood pressure control in both groups.³¹

Four studies comparing ACEIs and long-acting dihydropyridine CCBs are described. The Melbourne Diabetic Nephropathy Study (MDNS) randomized hypertensive type 1 and type 2 patients to treatment with either perindopril or nifedipine, titrated to blood pressure control, and found no difference in the rate of decline of GFR between groups over 1 year.³² Similar results were reported in another study in 44 patients with type 2 diabetes on either cilazapril or amlodipine.¹³ Another study in 52 type 2 diabetic patients with hypertension and nephropathy followed for 5 years on atenolol, lisinopril, verapamil, or diltiazem found that the ACEIs and the CCBs equally delayed the decline in creatinine clearance compared with the -blocker.³³ In contrast, however, another study reported lesser decline in GFR with nisoldipine compared with lisinopril in 49 hypertensive type 1 diabetic subjects followed for 1 year.³⁴

The recent UKPDS results demonstrated that captopril and atenolol were equally effective in reducing microvascular endpoints, including the progression of retinopathy and development of proteinuria.¹⁸

Thus, the potential of specific benefits of ACEIs to delay development of nephropathy is supported in part, but not in total, by clinical studies. A specific benefit may be afforded in some diabetic patients from the use of ACEIs, but the critical point is that blood pressure should be aggressively controlled, and this can appropriately be accomplished by a variety of strategies, in most cases requiring combinations of drugs. Data on effects of angiotensin-II receptor antagonists (AIIRAs) in nephropathy³⁵ and of ACEIs in retinopathy³⁶ are emerging and beginning to suggest benefits. We await the results of the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Losartan Renal Protection Study (RENAAL), which are examining the effects of AIIRAs on progression of nephropathy in type 2 diabetes.

Perspective and Recommendations
Aggressive blood pressure lowering is clearly beneficial in diabetic patients with hypertension. An exact goal remains ill-defined, but several national expert consensus panels, including that of the American Diabetes Association,³⁷ have recommended that the goal of blood pressure reduction should be <130/85 mm Hg. Current recommendations from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)³⁸ are consistent with this, and furthermore support the use of either an ACEI or dihydropyridine CCB as first-line treatment in diabetes. Blood pressure reduction in itself appears to be the most critical factor in preventing diabetic complications, rather than the specific agent(s) used.

The future results of the ALLHAT study are awaited with anticipation, as new information may come from this head-to-head comparison of a dihydropyridine CCB, a diuretic, an ACEI, and an -blocker as initial treatment in diabetic as well as nondiabetic patients.³⁹

Cost considerations would suggest that using diuretics, -blockers, and captopril would be wise choices, and the rationale for each drug's efficacy is established. However, aggressive goals are unlikely to be achieved with monotherapy in most patients, as demonstrated in many studies, so combinations will usually be required to attain the best control with the fewest side effects. In fact, the average number of drugs needed to attain blood pressure control in multiple clinical studies is 3.4.⁴⁰

Therefore, based on careful examination of the current data from available studies, my approach today to management of hypertension is initial treatment with an ACEI, followed by a dihydropyridine CCB, then a low-dose diuretic and/or -blocker added as needed to achieve the crucial goal of tight blood pressure control.

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Jennifer B. Marks, MD, CDE, is an associate professor of medicine in the Division of Endocrinology at the University of Miami School of Medicine, in Florida.

Note of disclosure: Dr. Marks has received honoraria from Smith Kline Beecham, Bristol Myers Squibb, Pfizer, Hoechst Marion Roussel, Roche, and Schering and has received grant support from Smith Kline Beecham and Pfizer. These companies manufacture drugs for the treatment of hypertension.

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