Endocrinol Metab.  2022 Jun;37(3):415-429. 10.3803/EnM.2022.304.

Extra-Glycemic Effects of Anti-Diabetic Medications: Two Birds with One Stone?

• Rhee EJ

• KMID: 2531385
• DOI: http://doi.org/10.3803/EnM.2022.304

Abstract

The world is suffering from a rapid increase in the number of people with diabetes due to the increased prevalence of obesity and lengthened life span. Since the development of insulin thanks to the efforts of Prof. Banting and Dr. Best in 1922, for which they won the Nobel Prize, remarkable developments in anti-diabetic medications have dramatically lengthened the lifespan of patients with diabetes. However, the control rate of hyperglycemia in patients with diabetes remains unsatisfactory, since glycemic control requires both medication and lifestyle modifications to slow the deterioration of pancreatic beta-cell function and prevent diabetic complications. From the initial “triumvirate” to the “ominous octet,” and now the “egregious eleven,” the number of organs recognized as being involved in hyperglycemia and diabetes has increased with the development of anti-diabetic medications. Recent unexpected results from outcome trials of anti-diabetic medications have enabled anti-diabetic medications to be indicated for the prevention of chronic kidney disease and heart failure, even in patients without diabetes. In this review, I would like to summarize the extra-glycemic effects of anti-diabetic medications.

Keyword

Diabetes mellitus; Medication therapy management; Cardiovascular diseases; Heart failure; Diabetic nephropathies; Stroke; Osteoporosis

Figure

• 

  Fig. 1. Cardiovascular outcome trials of anti-diabetic drugs according to the mean duration of the trial and relative risk reduction of major adverse cardiovascular events. The numbers in boxes are hazard ratios and 95% confidence intervals of major adverse cardiovascular events, defined as the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. PIONEER-6, Peptide Innovation for Early Diabetes Treatment 6; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53; EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58; VERTIS-CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; CAROLINA, Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Type 2 Diabetes; HARMONY, Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; CANVAS, Canagliflozin Cardiovascular Assessment Study; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; REWIND, Dulaglutide and cardiovascular outcomes in type 2 diabetes; DPP-4, dipeptidylpeptidase-4; SGLT2, sodium-glucose cotransporter type 2; GLP-1, glucagon-like peptide-1. aComparator is another anti-diabetic medication; bIncludes primary prevention population.

• 

  Fig. 2. Extra-glycemic effects of anti-diabetic medications. GLP-1RA, glucagon-like peptide receptor agonist; DPP-4, dipeptidyl peptidase 4; SGLT2, sodium-glucose cotransporter 2; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TZD, thiazolidinedione.

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