Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar

Abstract

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.

Keywords: cardiovascular outcomes trials; diabetes drugs; type 2 diabetes.

FIGURE 1. Physiologic Mechanisms of Novel Pharmacologic Agents for Diabetes

Both SGLT2i and GLPRA have effects on multiple organs in the body, modulating not only glycemic control but lipogenesis, satiety, smooth muscle tone, and renal filtration. From top to bottom, the pancreas, pancreatic islet cells, liver, skeletal muscle adipocytes, heart, vasculature, kidneys, central nervous system, and gastrointestinal track are affected by these molecules. Up and down arrows denote whether a process is increased or decreased by each medication. Directional arrows denote the proposed effects of modulations in these processes. GLPRA = glucagon-like peptide 1 receptor agonist; FA = ■■■; FFA = ■■■; NAFLD = ■■■; Na/H = ■■■; SGLT2i = sodium glucose cotransporter 2 inhibitor; SNS = ■■■; TG = ■■■.

FIGURE 2. Selecting Pharmacologic Therapy for Patients With Type 2 Diabetes

The evidence base for selecting pharmacologic therapy for patients with type 2 diabetes depends on presence of risk factors, comorbid heart failure, atherosclerotic disease, and renal disease. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; CVOT = cardiovascular outcome trial; DDP4i = dipeptidyl peptidase 4 inhibitor; HF = heart failure; RF = ■■■; TZD = ■■■; other abbreviations as in Figure 1.

FIGURE 3. Algorithm Choosing Pharmacologic Therapy for Type 2 Diabetes

In patients with type 2 diabetes on metformin with hemoglobin a1c above goal, second-line therapy depends on cost limitations, comorbid disease, and desire for weight loss. Abbreviations as in Figures 1 and 2.

FIGURE 4. Timeline of Pharmacologic Agents Used in Type 2 Diabetes

Timeline delineating the dates of discovery, U.S. Food and Drug Administration (FDA) approval and, if applicable, cardiovascular outcome trial publication for biguanides, sulfonylureas, TZDs, DPP4is, GLP1RAs, and SGLTis. Adapted with permission from Mudaliar (72) and Drucker et al. (103). HHF =; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study; other abbreviations as in Figures 1 and 2.

CENTRAL ILLUSTRATION. Diversity of Physiologic Effects of SGLT2i and GLP1RA

Increasing evidence supports the role of both SGLT2i and GLP1RA in reducing major adverse cardiac events and progression of renal disease while increasing weight loss and reducing blood pressure. SGLT2i accomplish this primarily via hemodynamic effects, whereas GLP1RAs have stronger anti-atherogenic effects.GLP1RA = glucagon-like peptide 1 receptor agonist; MACE = major adverse cardiac events; SGLT21 = sodium glucose cotransporter 2 inhibitor.