Implications of recent clinical trials targeting glycemia to reduce cardiovascular risk: insights on prevention of cardiovascular disease in insulin resistant syndromes

People with type 2 diabetes mellitus experience higher risk for cardiovascular disease (CVD) than persons without diabetes. The risk, however, has declined over the years as the recommendations for both primary and secondary prevention of cardiovascular (CV) events have been strengthened primarily through LDL lowering with statins and the adoption of lower targets for blood pressure (BP) in the management of hypertension. Updated results of two studies, DCCT/EDIC in type 1 diabetes and UKPDS in type 2 diabetes, have revealed that a treatment-directed lower HbA1c can reduce CV events but that this benefit takes longer than that observed in trials in which the CV benefit of LDL and BP has been tested. In both DCCT/EDIC and UKPDS, the mean HbA1c was lower than the HbA1c in the conventionally treated cohort. In each trial, statistically significant reduction in CV endpoints was not observed during the randomized period of the trial, but CV benefits did become evident in the follow-up phases of both trials during which the HbA1cs of the randomized groups had converged. The term “legacy effect” or “metabolic memory” has been used to describe this phenomenon.

Recent blockbuster trials evaluating the effect of LDL and BP lowering on CV events have demonstrated significant results in trial durations usually less than 5 years. The time course of CV benefit related to glycemic control in the two trials discussed above raise important considerations regarding the durations of clinical trials that aim to evaluate the effect of pharmacologic lowering of glycemia in general and establish an optimal glycemic target to reduce CVD in particular. Another strategy aimed at reducing the risk for CVD in type 2 diabetes would be to strengthen CV prevention in pre-diabetes. We know that pre-diabetes, defined as impaired fasting glucose, impaired glucose tolerance, or metabolic syndrome, is associated with elevated CV risk. Even though such individuals have dysglycemia, targeting glycemia with glucose lowering drugs is unlikely to have a significant effect on removing CV risk in these patients and would be impractical in practice, particularly as hypoglycemia could be a major limiting factor as glycemia is brought to normal levels. We suspect there could be a CV benefit, but such a trial would require a very large sample size and at least 10 years of observation. The fact that there is no macrovascular benefit with lowering HbA1c in patients with type 2 diabetes below the currently recommended level of 7.0% (ACCORD, ADVANCE, VADT) logically reduces enthusiasm for targeting glycemia in pre-diabetes. To reduce cardiometabolic risk in pre-diabetic individuals, the recent American Association of Clinical Endocrinologists conference on pre-diabetes suggested these persons receive a “diabetes-like” CV prevention strategy, with administration of statins regardless of LDL levels and lowering of the BP target to 130/80 mmHg. This strategy would not only reduce CV risk in this group but very likely provide a “carry-over” benefit even after such individuals convert to type 2 diabetes.