Type 2 diabetes is a cardiorenal metabolic disorder that involves both the microvasculature and the macrovasculature. Hyperglycemia is the major factor responsible for the microvascular complications (i.e., eye, kidney, and nerve damage), whereas insulin resistance and its associated components (e.g., hypertension, dyslipidemia, visceral adiposity, procoagulant state, and endothelial dysfunction) are the major risk factors for the macrovascular complications (i.e., myocardial infarction and stroke). Further, heart failure has become increasingly recognized as an important cause of cardiovascular mortality in people with type 2 diabetes. Thus, antidiabetic medications that provide protection against both the microvascular and macrovascular complications are desirable. Because the etiologies of hyperglycemia and cardiovascular disease in type 2 diabetes are distinct and multifactorial, effective treatment will require multiple agents used in combination.
The seminal studies (1,2) by myself and my colleagues with phlorizin (a combined sodium–glucose cotransporter 2 [SGLT2]/sodium–glucose cotransporter 1 inhibitor) demonstrated the efficacy of inhibiting renal tubular glucose absorption as an effective means of improving glycemic control in type 2 diabetes and led to the development of the SGLT2 inhibitor class of antidiabetic medications. Importantly, recent cardiovascular and renal outcomes trials have demonstrated that SGLT2 inhibitors exert beneficial effects on both the cardiovascular and renal systems.
It now is well established that SGLT2 inhibitors have documented efficacy to 1) improve glycemic control by promoting glucosuria and secondarily enhancing β-cell function and insulin sensitivity, 2) retard the progression of diabetic kidney disease, 3) decrease cardiovascular mortality and myocardial infarction in high-risk individuals, 4) prevent heart failure, and 5) be used in combination with all other antidiabetic agents. Because of these pleotropic benefits on both microvascular and macrovascular complications, SGLT2 inhibitors should be given consideration as first-line therapy in all type 2 diabetes patients, including those with 1) established cardiovascular and renal disease, 2) risk factors for cardiovascular disease but without an established event, and 3) newly diagnosed type 2 diabetes, as well as those early in the natural history of their disease.
Glucagon-like peptide 1 (GLP-1) receptor agonists amplify glucose-stimulated insulin secretion by the β-cell, but only under conditions of hyperglycemia; therefore, they do not cause hypoglycemia. Agents in the GLP-1 receptor agonist class work by improving β-cell glucose sensitivity; this beneficial effect on β-cell function can be observed within 8 hours after a single injection of a GLP-1 receptor agonist (3) and persists for at least 3 years (4). In the α-cell, GLP-1 receptor agonists suppress glucagon secretion, leading to correction of postmeal hyperglycemia in individuals with type 2 diabetes. Thus, these agents produce a rapid and durable reduction in A1C, with a low risk of hypoglycemia.
GLP-1 receptor agonists also exert multiple nonglycemic actions, which contribute to improved metabolic control in people with type 2 diabetes. These include 1) delayed gastric emptying, which slows the absorption of ingested glucose; 2) appetite suppression, which promotes weight loss, secondarily leading to enhanced insulin sensitivity; 3) reduction of hepatic and visceral fat content; and 4) lowering of systolic blood pressure and pulmonary capillary wedge pressure and improvement in endothelial function.
Recent cardiovascular outcome trials have demonstrated that GLP-1 receptor agonists reduce major adverse cardiovascular events in people with type 2 diabetes and, like the SGLT2 inhibitors, should be considered as first-line therapy. Combination therapy with an SGLT2 inhibitor and a GLP-1 receptor agonist is an especially attractive intervention that addresses multiple metabolic and cardiorenal problems that are present in the great majority of type 2 diabetes patients (5).
In this Diabetes Spectrum From Research to Practice section, world-renowned clinical investigators review the cardiovascular and renal outcome trials with SGLT2 inhibitors and incretin-based therapies, as well as the thiazolidinedione pioglitazone (6), and provide their perspective on the effective use of these agents in patients with type 2 diabetes.
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Duality of Interest
R.A.D. has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk and has received research support from AstraZeneca, Boehringer Ingelheim, Janssen, and Merck. He also serves on speaker’s bureaus for AstraZeneca and Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.
