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

Abstract and Introduction

Abstract

Observational epidemiologic data indicate that lower blood glucose levels, blood pressure (BP), and lipid parameters are associated with a lower incidence of micro- and macrovascular complications in people with diabetes. While no threshold for this effect is discernible in these observational studies, intervention studies do not mirror this finding. The earliest glycemia target study in type 2 diabetes mellitus, UKPDS, demonstrated unequivocal benefits of tight glucose control on microvascular complications, but needed a prolonged follow-up to demonstrate a benefit on macrovascular outcomes and mortality. Recently, three major studies, ACCORD, ADVANCE, and VADT, evaluated the impact of attaining euglycemia (ACCORD) or near-euglycemia (ADVANCE, VADT) in older patients with diabetes and high cardiovascular (CV) risk. None of these studies, either individually or on pooled analysis, demonstrated any reduction in all-cause or CV mortality, although the meta-analyses revealed 15–17% reductions in the incidence of non-fatal myocardial infarction in those exposed to tight glucose control. A higher mortality was observed in the intensive glucose control arm of ACCORD, resulting in the premature termination of the glucose-lowering component of this study. Also, the occurrence of hypoglycemic episodes (total and major) was significantly higher in the intensive glucose control arm.
ADVANCE and ACCORD also had BP-lowering components. While data from ADVANCE demonstrated a benefit of routine use of a combination of perindopril and indapamide, with a decline in all-cause mortality, CV mortality, and new-onset microalbuminuria, reducing systolic BP to <120 mmHg in ACCORD did not result in any incremental benefits over a systolic BP <140 mmHg.
A residual CV risk observed in people with diabetes even after low-density lipoprotein (LDL) cholesterol lowering has led to trials evaluating additional therapy with fibric acid derivatives to reduce triglyceride levels. The lipid-lowering arm of ACCORD failed to demonstrate any benefit of add-on therapy with fibric acid derivatives to LDL-lowering treatment with HMG-CoA reductase inhibitors (statins) on vascular outcomes in patients with diabetes. However, data from earlier studies, and also from the subgroup analysis of ACCORD, indicate a probable benefit of adding treatment with fibric acid derivatives to individuals with persistently elevated triglyceride levels despite statin therapy.
The most compelling evidence comes from studies assessing the impact of multiple risk factors – glucose, BP, and cholesterol. Studies like the Steno study unequivocally demonstrate the benefit of aggressive control of all three parameters on vascular outcomes in patients with diabetes.
In conclusion, attempts to achieve euglycemia in older patients with type 2 diabetes with co-morbidities are not associated with any survival benefit, but may reduce the occurrence of non-fatal CV events. There is a significant risk of major hypoglycemia with this approach, thereby probably limiting its utility to younger patients with new-onset disease. Similarly, lowering systolic BP below 120 mmHg in high CV risk people with diabetes is associated with significant excess adverse events, limiting the utility of such an intervention. However, a clear benefit, which is also cost effective, is observed with strategies for multiple risk-factor control, which should be universally adopted in clinical practice.

1. Introduction

Observational epidemiologic data indicate that lower blood glucose levels, lower blood pressure (BP), and lower levels of cholesterol and its atherogenic sub-fractions are each associated with diminished risk of both microvascular and macrovascular complications in people with diabetes mellitus.[1–6] Furthermore, these relationships exhibit no defined thresholds – suggesting that 'lower is better'. There have therefore been several attempts to confirm these relationships through clinical trials, which have either targeted lowering of individual risk factors, namely glucose levels, BP, and cholesterol levels, or concurrently used multiple interventions to lower all these parameters. In contrast to the epidemiologic data, the results of these clinical trials, especially those evaluating relationships between achievement of aggressive risk factor targets and macrovascular disease, have not always been consistent with the hypothesis 'lower is better'.[7] This review will discuss the results of recent clinical trials and analyses of extensions of earlier trials to help define clinical strategies for micro- and macrovascular risk lowering in patients with diabetes. Most of the studies, and thereby discussion, are based on glucose level lowering and its implications. However, recent trial evidence on BP, cholesterol level, and multiple risk-factor lowering will also be presented and discussed.

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