Fewer Major Adverse Cardiovascular Events With New Antihyperglycemic Drugs With Lower Hypoglycemic Risk

Variety of pills and capsules
Variety of pills and capsules
Investigators proposed that reduction in MACE may be proportional to the magnitude of HbA1c reduction seen with newer antihyperglycemic agents.

Newer antihyperglycemic agents with a reduced risk of causing hypoglycemia may significantly reduce the risk for major adverse cardiovascular events (MACE) in individuals with type 2 diabetes (T2D), according to research published in Diabetes, Obesity and Metabolism.

Researchers conducted a systematic review of 10 randomized control trials including 92,400 individuals with T2D to compare the relative efficacy and safety of newer antihyperglycemic drugs with lower hypoglycemia risk.

They assessed the effects of newer antihyperglycemic drugs on blood glucose control and overall risk for MACE in individuals with T2D, with an end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Study results found, within an average of 2.6 years, a total of 9773 MACE. Compared with individuals given placebo, individuals treated with antihyperglycemic agents were found to have a 0.42% lower mean HbA1c concentration and a significantly lower risk for MACE after adjusting for confounding variables in the meta-regression analysis, such as age, sex, baseline HbA1c, duration of follow-up, difference in systolic blood pressure, difference in body weight, and risk for difference in hypoglycemia (β value, -0.39 to -0.55; P <.02).

The researchers found that even a 1% reduction in HbA1c caused a 30% MACE risk reduction (95% CI, 17%-40%) and a 40% stroke risk reduction (95% CI, 15%-57%). There was an observed proportional risk reduction between HbA1c reduction and both MACE and stroke (P =.0005 and P =.0044, respectively).

When comparing the differences in achieved HbA1c reductions, there was greater risk reduction in trials demonstrating a ≥0.5% difference (relative risk reduction [RRR], 13%; 95% CI, 6%-20%; P =.0008) compared with trials with a 0.3% to 0.5% difference (11%; 95% CI, 4%-17%; P =.002); no benefit was seen in those with a <0.3% difference (0%; 95% CI, −7% to 6%; P =.90).

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Overall, there was an 8% risk reduction of MACE in individuals receiving antihyperglycemic treatment compared with placebo (95% CI, 3% to 13%; P=.002). When compared with conventional antihyperglycemic agents, no relationship was observed between achieved HbA1c difference and MACE risk after meta-regression analysis.

The researchers also assessed the efficacy of the 4 classes of oral antidiabetic agents: dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and thiazolidinediones.  Compared with placebo, the latter 3 classes were significantly associated with decreased risk for MACE (P =.048, P =.002, P =.02, respectively); no treatment effect was demonstrated with dipeptidyl peptidase-4 inhibitors.

The researchers concluded that newer antihyperglycemic medications with lower hypoglycemic hazard were associated with significantly reduced risk for MACE when compared with placebo, with a linear reduction relationship between HbA1c and MACE. Therefore, clinicians should consider the use of these antihyperglycemic drugs when treating individuals with T2D.


Huang C-J, Want W-T, Sung S-H, et al. Blood glucose reduction by diabetic drugs with minimal hypoglycemia risk for cardiovascular outcomes: evidence from meta-regression analysis of randomized controlled trials [published online May 2, 2018]. Diabetes Obes Metab. doi: 10.1111/dom.13342