Effect of Intensive Glucose Lowering Treatment on All Cause Mortality, Cardiovascular Death, and Microvascular Events in Type 2 Diabetes: Meta-Analysis of Randomized Controlled Trials

Study Questions:

What is the rate of all-cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes?

Methods:

This was a meta-analysis of randomized controlled trials. Trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥18 years) with type 2 diabetes were included in the analysis. Primary endpoints were all-cause mortality and death from cardiovascular causes. Secondary endpoints were severe hypoglycemia and macrovascular and microvascular events. Statistical heterogeneity between trials was assessed with χ2, τ2, and I2 statistics. A fixed-effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score.

Results:

A total of 13 studies were included. Of 34,533 patients, 18,315 received intensive glucose lowering treatment and 16,218 received standard treatment. Intensive treatment did not significantly affect all-cause mortality (risk ratio [RR], 1.04; 99% confidence interval [CI], 0.91-1.19) or cardiovascular death (RR, 1.11; 99% CI, 0.86-1.43). Intensive therapy was, however, associated with reductions in the risk of nonfatal myocardial infarction (RR, 0.85; 99% CI, 0.74-0.96; p < 0.001), and microalbuminuria (RR, 0.90; 99% CI, 0.85-0.96; p < 0.001), but a more than twofold increase in the risk of severe hypoglycemia (RR, 2.33; 99% CI, 21.62-3.36; p < 0.001). Over a treatment period of 5 years, 117-150 patients would need to be treated to avoid one myocardial infarction and 32-142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycemia would occur for every 15-52 patients. In analysis restricted to high-quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions, but resulted in a 47% increase in risk of congestive heart failure (p < 0.001).

Conclusions:

The authors concluded that the overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all-cause mortality and deaths from cardiovascular causes.

Perspective:

This meta-analysis of data from 13 randomized controlled trials showed no benefit of intensive glucose lowering treatment on all-cause mortality or death from cardiovascular causes in adults with type 2 diabetes. Furthermore, a 19% increase in all-cause mortality and a 43% increase in death from cardiovascular causes could not be ruled out. Intensive treatment was also associated with a significant twofold increased risk of severe hypoglycemia. Additional high-quality randomized trials assessing morbidity and mortality outcomes are warranted to establish the best approach for glucose lowering in people with type 2 diabetes. For now, intensive glucose lowering treatment of type 2 diabetes should not be considered routinely, and therapeutic escalation should be limited.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Risk, Myocardial Infarction, Diabetes Mellitus, Type 2, Heart Failure, Cardiovascular Diseases, Hypoglycemia, Glucose


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