Diabetes Drugs and Cardioprotection: A Summary for Primary Care

Current cardioprotection standards. In section 10 of the 2021 Standards of Medical Care in Diabetes titled Cardiovascular Disease and Risk Management, the ADA recommends an SGLT2i or GLP-1 RA with demonstrated CVD benefit as part of the comprehensive CV risk reduction or glucose-lowering regimen—or both—for patients with T2D who have established ASCVD or established kidney disease.

Reduce major events risk. The ADA recommends an SGLT2i with demonstrated CV benefit to reduce the risk of major adverse CV events and heart failure hospitalization in patients with T2D and established ASCVD, multiple ASCVD risk factors, or diabetic kidney disease. Also, a GLP-1 RA to reduce the risk of major adverse CV events in patients with T2D and established ASCVD or multiple risk factors for ASCVD.

HFrEF recommendation. An SGLT2i with proven benefit in the population of patients with T2D and established HFrEF is recommended to reduce risk of worsening heart failure and CV death.

Growing body of evidence. Numerous trials have reported statistically significant reductions in CV events for the FDA-approved SGLT2is empagliflozin, canagliflozin, and dapagliflozin and GLP-1 RAs liraglutide, albiglutide, semaglutide, and dulaglutide. Meta-analyses suggest they reduce major adverse ASCVD event risk to a comparable degree in patients with T2D and established ASCVD.

Empagliflozin breakthrough for heart failure. EMPEROR-Preserved phase 3 trial results established the SGLT2i empagliflozin as the first and only therapy to significantly reduce the risk of the composite of CV death or hospitalization for heart failure in adults, with or without T2D, who have HFrEF. When added to earlier results, they demonstrate efficacy in all forms of heart failure regardless of ejection fraction.

Canagliflozin consistent across age and sex groups. The SGLT2i canagliflozin, known to reduce the risk of kidney and CV events in patients with T2D and CKD, did so with consistent effects and no differences in safety outcomes across subgroups defined by age and sex in findings from the randomized, placebo-controlled CREDENCE trial.

Combination SGLT2i /SGLT1i. Building on the evidence of a new class of drugs, the SCORED and SOLOIST trials evaluated the benefits of a combination drug that inhibits both SGLT2 and SGLT1 in patients with kidney failure or heart failure. Sotagliflozin showed significant benefits in reducing heart failure, heart attack, and stroke in patients with T2D with CKD or heart failure.

Efpeglenatide for CV or kidney disease. In the AMPLITUDE-O trial, weekly subcutaneous injections of the GLP-1 RA efpeglenatide (4 mg or 6 mg) significantly reduced the first occurrence of heart attack, stroke, or death and reduced progression of kidney disease in patients with T2D who had a history of CVD or current kidney disease plus at least 1 other CV risk factor.

Tirzepatide for weight loss. The novel dual glucose-dependent insulinotropic polypeptide and GLP-1 RA tirzepatide showed robust improvements in glycemic control and body weight, without increased risk of hypoglycemia, in patients with T2D in the double-blind, randomized, phase 3 SURPASS-1 trial. The safety profile was consistent with GLP-1 RA, indicating a potential monotherapy use for T2D treatment.

Dapagliflozin and COVID-19. In the first-of-its-kind trial, DARE-19 explored the use of SGLT2i for patients hospitalized with COVID-19 who have hypertension, CVD, heart failure, T2D, or CKD. Numerically fewer patients treated with dapagliflozin experienced organ failure or death, but treatment did not achieve statistically significant reduction in organ failure or death or significantly improve clinical recovery.