Pharmacological treatment of hyperglycemia in type 2 diabetes
Simeon I. Taylor, Zhinous Shahidzadeh Yazdi, Amber L. Beitelshees
Simeon I. Taylor, Zhinous Shahidzadeh Yazdi, Amber L. Beitelshees
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Review Series

Pharmacological treatment of hyperglycemia in type 2 diabetes

Abstract

Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA’s recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.

Authors

Simeon I. Taylor, Zhinous Shahidzadeh Yazdi, Amber L. Beitelshees

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Figure 1

Mechanisms of action for drugs approved for glycemic control in patients with T2D.

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Mechanisms of action for drugs approved for glycemic control in patients...
Seven classes of FDA-approved T2D drugs are widely used: Biguanides. Several hypotheses have been proposed for metformin’s mechanism of action: (i) activation of AMPK (102, 103); (ii) inhibition of hepatic adenylyl cyclase (104); (iii) inhibition of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) (105); (iv) increasing levels of GDF15 (106, 107); and (v) alteration of intracellular protein-bound iron levels (108). Metformin decreases hepatic glucose production (109). Its action may be exerted in the gut independent of absorption into the circulation (110). Sulfonylureas bind to sulfonylurea receptor-1 (SUR-1) in pancreatic β cells, leading to closure of the ATP-inhibitable K+ channel Kir6.1, thereby initiating electrophysiological changes that trigger insulin secretion (111). Thiazolidinediones (TZDs) activate PPARγ, an adipose tissue transcription factor (112). TZDs promote triglyceride storage in adipose tissue while decreasing deposition of triglycerides in liver and muscle, thereby increasing insulin sensitivity (113, 114). GLP1RAs bind to the GLP1 receptor on pancreatic β cells, augmenting glucose-stimulated insulin secretion. GLP1RAs also delay gastric emptying, decrease glucagon levels, and decrease food intake (115). DPP4is protect GLP1 from degradation, thereby potentiating endogenous GLP1 activity. SGLT2is promote glucosuria and natriuresis by inhibiting proximal tubular glucose reabsorption. Glucosuria decreases HbA1c levels and promotes weight loss. Natriuresis decreases blood pressure, and may also protect against congestive heart failure (41). Insulin binds to its receptor in liver, skeletal muscle, and adipose tissue, triggering intracellular signaling pathways that mediate the various biological actions of insulin — including increased glucose transport into skeletal muscle and adipocytes, regulation of several key metabolic enzymes, and regulation of gene expression (116). Five other classes of approved drugs are less widely used: meglitinides, α-glucosidase inhibitors, amylinomimetics, bile acid sequestrants, and bromocriptine (a D2/D3 dopaminergic agonist).