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Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Key Points

  • Greater understanding of the complex and multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) has informed the development of several new classes of glucose-lowering therapies

  • Metformin remains the first-line pharmacotherapy for patients with T2DM, whereas the use of other well-established agents, such as sulfonylureas, meglitinides, pioglitazone and α-glucosidase inhibitors, varies in different regions

  • Agents that enhance incretin activity (DPP-4 inhibitors), supplement endogenous GLP-1 (GLP-1 receptor agonists) or increase urinary glucose elimination (SGLT2 inhibitors) have low risk of hypoglycaemia and can assist weight control

  • Treatment with two or three agents with different modes of action can be required as T2DM advances, and insulin therapy is required if other agents are unable to maintain adequate glycaemic control

  • Glycaemic targets and the choice of glucose-lowering agents should be customized to meet the needs and circumstances of individual patients, which could be facilitated by future developments in pharmacogenomics

  • Although the balance of benefits and risks for different agents varies between individual patients, early, effective and sustained glycaemic control delays the onset and reduces the severity of hyperglycaemia-related complications

Abstract

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

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Figure 1: Sites of action of glucose-lowering agents.
Figure 2: Intracellular actions of metformin.
Figure 3: Sulfonylureas, meglitinides and glucagon-like peptide 1 receptor agonists (GLP-1RAs) act on pancreatic β cells to increase nutrient-induced insulin secretion.

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All authors researched data for the article, made substantial contributions to discussions of content and contributed to writing the article, as well as reviewing and editing the manuscript before submission.

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Correspondence to Abd A. Tahrani.

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Competing interests

A.A.T. is a clinician scientist supported by the National Institute for Health Research (NIHR) in the UK. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. A.A.T. has received honoraria for lectures and advisory work or support for attending conferences from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk and Sanofi-Aventis. A.A.T. received investigator-led grant support from the Novo Nordisk Research Foundation. A.H.B. has received honoraria for lectures and advisory work from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, MSD, Novartis, Novo Nordisk, Sanofi-Aventis and Takeda. C.J.B. has undertaken ad-hoc consultancy for AstraZeneca, Bristol-Myers Squibb, Elcelyx, Eli Lilly, Janssen, Lexicon, MSD, Novo Nordisk, Roche, Sanofi-Aventis and Takeda. C.J.B. has delivered continuing medical education programmes sponsored by AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and MSD, and received travel or accommodation reimbursement from AstraZeneca and Bristol-Myers Squibb.

Supplementary information

Supplementary information S1 (table)

Sulfonylurea pharmacokinetics (PDF 150 kb)

Supplementary information S2 (box)

Pancreatic and extrapancreatic effects of glucagon-like peptide 1 (PDF 143 kb)

Supplementary information S3 (table)

Summary of the pharmacokinetic properties of currently available dipeptidyl peptidase 4 (DPP-4) inhibitors (PDF 245 kb)

Supplementary information S4 (table)

Summary of the pharmacokinetic properties of available GLP-1RAs (PDF 219 kb)

Supplementary information S5 (table)

Summary of the effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on glycaemic parameters185,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264 (PDF 202 kb)

Supplementary information S6 (box)

Summary of the effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on weight, waist circumference and systolic blood pressure185,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270 (PDF 226 kb)

Supplementary information S7 (box)

Pharmacokinetics of sodium/glucose cotransporter 2 (SGLT2) inhibitors289 (PDF 160 kb)

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Tahrani, A., Barnett, A. & Bailey, C. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 12, 566–592 (2016). https://doi.org/10.1038/nrendo.2016.86

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