SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choos in ga second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyper-glycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.
Original languageEnglish
Pages (from-to)1543-1556
Number of pages14
JournalDiabetes Care
Volume41
Issue number8
DOIs
Publication statusPublished - 2018

Cite this

@article{d08fdab17d214ad9886eb05f4487b474,
title = "SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management",
abstract = "The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choos in ga second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyper-glycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.",
keywords = "Animals, Blood Glucose/drug effects, Diabetes Mellitus, Type 2/drug therapy, Dipeptidyl-Peptidase IV Inhibitors/administration & dosage, Drug Therapy, Combination, Humans, Hypoglycemic Agents/administration & dosage, Insulin/administration & dosage, Metformin/administration & dosage, Signal Transduction/drug effects, Sodium-Glucose Transporter 2/antagonists & inhibitors, Sulfonylurea Compounds/administration & dosage, Thiazolidinediones/administration & dosage, Treatment Outcome",
author = "{van Baar}, {Micha{\"e}l J. B.} and {van Ruiten}, {Charlotte C.} and Muskiet, {Marcel H. A.} and {van Bloemendaal}, Liselotte and IJzerman, {Richard G.} and {van Raalte}, {Dani{\"e}l H.}",
note = "{\circledC} 2018 by the American Diabetes Association.",
year = "2018",
doi = "10.2337/dc18-0588",
language = "English",
volume = "41",
pages = "1543--1556",
journal = "Diabetes Care",
issn = "0149-5992",
publisher = "American Diabetes Association Inc.",
number = "8",

}

TY - JOUR

T1 - SGLT2 Inhibitors in Combination Therapy

T2 - From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

AU - van Baar, Michaël J. B.

AU - van Ruiten, Charlotte C.

AU - Muskiet, Marcel H. A.

AU - van Bloemendaal, Liselotte

AU - IJzerman, Richard G.

AU - van Raalte, Daniël H.

N1 - © 2018 by the American Diabetes Association.

PY - 2018

Y1 - 2018

N2 - The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choos in ga second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyper-glycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.

AB - The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choos in ga second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyper-glycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.

KW - Animals

KW - Blood Glucose/drug effects

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Dipeptidyl-Peptidase IV Inhibitors/administration & dosage

KW - Drug Therapy, Combination

KW - Humans

KW - Hypoglycemic Agents/administration & dosage

KW - Insulin/administration & dosage

KW - Metformin/administration & dosage

KW - Signal Transduction/drug effects

KW - Sodium-Glucose Transporter 2/antagonists & inhibitors

KW - Sulfonylurea Compounds/administration & dosage

KW - Thiazolidinediones/administration & dosage

KW - Treatment Outcome

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85053563266&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30030256

U2 - 10.2337/dc18-0588

DO - 10.2337/dc18-0588

M3 - Review article

VL - 41

SP - 1543

EP - 1556

JO - Diabetes Care

JF - Diabetes Care

SN - 0149-5992

IS - 8

ER -