A Review of CV Benefit With Antihyperglycemic Medications

Ahmed HM, Khraishah H, Cho L.
Cardioprotective anti-hyperglycaemic medications: a review of clinical trials. Eur Heart J 2017;Dec 9:[Epub ahead of print].

The following are 10 key points from this review, which is intended to provide clinicians with a practical guide to understanding cardiovascular (CV) benefits of antihyperglycemic medications, including sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor (GLP-1-R) agonists, based on recent clinical trials:

  1. Recent randomized controlled clinical trials in patients with type 2 diabetes found a decrease in CV events on SGLT-2 inhibitors (empagliflozin, canagliflozin) and GLP-1-R agonists (liraglutide, semaglutide). The US Food and Drug Administration recently approved empagliflozin in patients with type 2 diabetes and pre-existing CV disease to reduce risk of CV death.
  2. SGLT-2 inhibitors increase urinary excretion of glucose in renal tubules, leading to improvement in glycemic control without increased risk for hypoglycemia because they do not increase insulin secretion. Hemoglobin A1C is lowered by 0.5-0.7%. Blood pressure, weight, and triglycerides are also reduced.
  3. Metabolic effects of SGLT-2 inhibitors include weight loss, improved insulin sensitivity, and negative energy balance. The negative energy balance promotes ketone bodies to be utilized by cardiac myocytes, which are more efficient as energy sources.
  4. All-cause mortality was significantly decreased (32%), as was hospitalization from heart failure (35%) and CV mortality (38%), with empagliflozin compared with control in patients with type 2 diabetes at high CV risk in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients).
  5. Compared with placebo in patients with type 2 diabetes with high CV risk, canagliflozin was found to decrease primary endpoints of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. However, there was not a significant difference for individual endpoints of the primary endpoint or all-cause mortality in CANVAS (Canagliflozin Cardiovascular Assessment Study).
  6. GLP-1-R agonists increase insulin secretion by pancreatic beta cells and inhibits glucagon secretion. Hypoglycemia is unlikely because insulin secretion is not effected when glucose is ≤81 mg/dL. Hemoglobin A1C, weight, low-density lipoprotein, and blood pressure are all lowered with GLP1-R agonists. Major side effects include gastrointestinal issues and pruritus at the injection site.
  7. Patients with type 2 diabetes and high CV risk were studied on liraglutide or placebo in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial. Primary outcome composite (CV death, non-fatal MI, or non-fatal stroke) was reduced with liraglutide (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.78-0.97; p < 0.01). Also reduced were death from CV causes (HR 0.78; 95% CI, 0.66-0.93; p = 0.007) and from any cause (HR 0.85; 95% CI, 0.74-0.97; p = 0.02).
  8. In clinical trials for lixisenatide and CV risk, no CV benefit was found. CV trials for dapagliflozin are ongoing.
  9. Patients who would benefit from these agents with positive trial outcomes have 1) type 2 diabetes; 2) history of MI, coronary revascularization, stroke, cerebrovascular disease, or peripheral arterial disease; and 3) glomerular filtration rate > 30 mL/min/1.73m2.
  10. The CV benefits seen with these medications may not be class specific. Further studies are ongoing to determine if the effects are drug- or class-specific.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Acute Coronary Syndrome, Metabolic Syndrome X, Dyslipidemias, Heart Failure, Primary Prevention, Secondary Prevention

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