Pharmacologic Prevention of Microvascular and Macrovascular Complications in Diabetes Mellitus

Implications of the Results of Recent Clinical Trials in Type 2 Diabetes

Nikhil Tandon; Mohammed K. Ali; K.M. Venkat Narayan

Disclosures

Am J Cardiovasc Drugs. 2012;12(1):7-22. 

In This Article

3. Blood Pressure Lowering

Early studies evaluating the effects of various antihypertensive agents on CV outcomes systematically chose to exclude patients with diabetes from their analysis. The first major BP target trial in people with diabetes was the UKPDS (Table III).

3.1 UKPDS Blood Pressure-lowering Study

Epidemiologic data from the UKPDS BP-lowering study suggested that each 10 mmHg reduction in mean systolic BP was associated with the following risk reductions: 12% in diabetes-related complications, 15% for deaths related to diabetes, 11% for MI, and 13% for microvascular complications.[2] Furthermore, there was no inflection point or threshold of systolic BP for any of these complications, suggesting that BP represents a continuum of risk and there is no specific target that must be achieved. The clinical trial analysis from UKPDS demonstrated that tight BP control (144/82 mmHg) compared with less tight control (154/87) was associated with the following risk reductions: 24% in diabetes-related endpoints, 32% in diabetes-related deaths, 44% in strokes, and 37% in microvascular endpoints.[43] However, unlike the persistence of benefit seen even 10 years after trial completion in the intensive glucose-lowering arm, the benefits of better BP control disappeared with the loss of between-group differences in BP, which occurred within 2 years of trial cessation.[44]

3.2 ADVANCE and ACCORD: BP-lowering Studies

Among the recent studies, both ADVANCE and ACCORD employed BP-lowering interventions in addition to the glucose-lowering strategies ( Table III ). ADVANCE assessed the effects of routine administration of an ACE inhibitor-diuretic (perindopril-indapamide) combination on a composite end-point of major micro- and macrovascular events.[42] The BP difference between patients assigned to intensive BP control and standard BP control was 5.6/2.2 mmHg. As a result, active therapy was associated with a 9% reduction in combined major micro- and macrovascular endpoints (95% CI 0.83, 1.0; p = 0.04), 18% reduction in death from CVD (95% CI 0.68, 0.98; p = 0.03), and 14% reduction in all-cause mortality (95% CI 0.75, 0.98; p = 0.03). However, while separate reductions in macro- and microvascular events were also observed, these were not independently significant. Significant reduction was observed in coronary events (14%; 95% CI 0.76, 0.98; p = 0.02), but unlike that reported in several other BP-lowering studies,[45,46] there was no difference in total cerebrovascular events. Among microvascular complications, active therapy was associated with a 21% reduction in all renal events (95% CI 0.73, 0.85; p < 0.0001) and 21% reduction in new-onset microalbuminuria (95% CI 0.73, 0.86; p < 0.001), but no difference in incidence or progression of retinopathy or neuropathy.[23,42]

ACCORD employed a different strategy, with randomization to two groups after initial assignment to glucose control arms: intensive BP control arm (target systolic BP <120 mmHg) and standard BP control arm (systolic BP <140 mmHg).[41] While the pre-specified BP targets were met (mean systolic BP in intensive and standard arms: 119.3 mmHg and 133.5 mmHg, respectively), there was no difference in the annual rate of the primary outcome. There was a significant excess of serious adverse events in the group randomized to intensive BP control (serious adverse events were reported in 3.3% participants in the intensive BP control group and in 1.3% participants of the standard BP control group, respectively; p < 0.001). These data indicate that there may be no advantage in targeting a systolic BP target <120 mmHg. The study lost power, reflected in the wide CIs observed, since the event rate in the standard control arm was 50% less than anticipated. Unlike ADVANCE, the risk of stroke was significantly reduced in the intensive control arms. There was also no benefit of intensive BP control on progression of retinopathy.[26]

This raises the question of a differential application of the 'lower the better' rule to different organ systems. The benefit seen in renal outcomes in the active BP-lowering arm of ADVANCE, taken together with the benefit in stroke outcome seen in ACCORD and other studies, prompts one to suggest that perhaps the brain and kidney continue to benefit at BPs lower than those required for coronary artery disease benefit. The clinical implication of this conclusion would be relevant in a patient or population at high risk for cerebrovascular disease, who may still be considered for targeting BP <120 mmHg.

However, a question that is often raised is whether there are specific advantages of using one drug category over another to achieve macrovascular benefits. A recent meta-analysis reports that with the exception of benefit seen with β-adrenoceptor antagonist (β-blocker) therapy post-MI and minor additional effects seen with calcium channel antagonists in stroke prevention, there are no advantages of any particular drug/group of drugs in reducing coronary events or stroke.[47]

3.3 Conclusions

The UKPDS BP-lowering study demonstrated benefits from tighter BP control compared with less tight control.[43] ADVANCE[14] and ACCORD[41] used different strategies and assessed the effects of BP levels lower than the levels achieved in UKPDS.[43] In ADVANCE, the mean BP at randomization was 145/81 mmHg, with BP <140/90 mmHg in more than 40% subjects. These BP values at trial commencement were significantly better than what was achieved in the tight BP arm in UKPDS over 9 years' follow-up (144/82 mmHg). Through the study, patients in the intervention arm had systolic and diastolic BP values ranging from 133 to 136 mmHg and 73 to 76 mmHg, respectively. This intervention was associated with a significant reduction in the primary endpoint (composite of micro- and macrovascular outcomes), with clear benefit in all-cause mortality, CV mortality, and new onset microalbuminuria. In contrast, ACCORD compared systolic BP <120 mmHg (intervention arm) with BP <140 mmHg (standard arm) and showed no difference in outcomes between these groups.

These data suggest that while bringing systolic BP levels below 140 mmHg is beneficial, not only is there no incremental benefit in reducing systolic BP <120 mmHg, there is an added likelihood of an increase in incidence of adverse effects.

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