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
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e142243. https://doi.org/10.1172/JCI142243.
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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 3

Algorithm to guide selection of HbA1c-lowering drugs for T2D patients.

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Algorithm to guide selection of HbA1c-lowering drugs for T2D patients. D...
DP-0: lifestyle modification. Although lifestyle modification may sufficiently improve glucose levels to avoid the need for drugs, pharmacotherapy and lifestyle modification are most often initiated simultaneously. DP-1: which drug(s) to initiate. As recommended by the ADA/EASD, metformin should ordinarily serve as the foundation for pharmacotherapy. Nevertheless, the fact that patients will often benefit from intensive therapy early in the natural history of T2D (60) favors the ADA/EASD guidelines’ option to initiate two drugs simultaneously. DPP4is and GLP1RAs have favorable safety profiles without increasing risk of serious hypoglycemia in this setting. Driving to lower HbA1c levels diminishes risk of microvascular complications (12). Although addition of a second drug increases cost, this will become less of an issue after DPP4is become generic. DP-2: which third drug to add? Many patients experience secondary failure, requiring intensification of therapy. Achievement of ambitious HbA1c targets favors the objective of minimizing risk of microvascular complications (12, 60). SGLT2is are an attractive component of three-drug regimens (e.g., metformin+DPP4i+SGLT2i or metformin+GLP1RA+SGLT2i), especially because of lowering of blood pressure, weight loss, renoprotection, and reported cardiovascular benefits. The “all-oral” three-drug option is available as convenient fixed-dose combination tablets (metformin+DPP4i+SGLT2i), which will be more affordable when DPP4is and SGLT2is become generic. We deprioritize pioglitazone despite its attractive efficacy profile (117) because of safety concerns with TZDs (17). If secondary failure occurs in patients receiving metformin+DPP4i, the regimen can be intensified by substitution of a GLP1RA in place of a DPP4i. DP-3: whether to initiate insulin. Insulin is often the best option for patients experiencing secondary failure on a three-drug regimen. Nevertheless, some patients may be manageable with a four-drug regimen that does not include hypoglycemia-inducing drugs such as insulin. Metformin+DPP4i+SGLT2i+pioglitazone and metformin+GLP1RA+SGLT2i+pioglitazone stand out as the most attractive among these regimens.