Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data

Ann Pharmacother. 2019 Dec;53(12):1227-1237. doi: 10.1177/1060028019859323. Epub 2019 Jun 21.

Abstract

Objective: To review phase 3 trials of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes mellitus (T1DM) patients. Data Sources: A literature search of Ovid MEDLINE databases (1946 through May 17, 2019) limited to English-language human clinical trials was conducted using the following terms: sodium-glucose transporter 2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, ipragliflozin, or remogliflozin combined with type 1 diabetes mellitus. Results were verified via Google Scholar and clinicaltrials.gov. Study Selection and Data Extraction: Articles were included if they were phase 3 trials in adults with T1DM. Data Synthesis: Phase 3 trials are available for dapagliflozin, empagliflozin, and sotagliflozin. All 3 drugs demonstrated statistically significant reductions in hemoglobin A1C, weight, and total daily insulin dose without an increased risk of hypoglycemia in up to 52 weeks of therapy. The incidence of diabetic ketoacidosis (DKA) was higher in patients on a SGLT inhibitor at all doses, with the exception of empagliflozin 2.5 mg (0.8% vs 1.2% with placebo). Relevance to Patient Care and Clinical Practice: SGLT inhibitors are potential adjuncts to insulin in T1DM patients, providing clinically meaningful benefits. Regulatory bodies have either approved or are reviewing these agents for use in T1DM. Clinicians should be familiar with the DKA risk associated with SGLT inhibitors and utilize DKA risk-mitigation strategies. Empagliflozin 2.5 mg warrants additional investigation given its efficacy without an increased incidence of DKA. Conclusions: Phase 3 trial data of SGLT inhibitors provide evidence for sustained efficacy in T1DM patients. Appropriate patient selection for therapy and routine monitoring are essential to minimize associated risks.

Keywords: canagliflozin; dapagliflozin; empagliflozin; ertugliflozin; ipragliflozin; remogliflozin; sodium-glucose transporter 2 inhibitors; sotagliflozin; type 1 diabetes mellitus.

Publication types

  • Review

MeSH terms

  • Blood Glucose / analysis
  • Clinical Trials, Phase III as Topic
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetic Ketoacidosis / prevention & control
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypoglycemia / prevention & control
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / administration & dosage
  • Insulin / therapeutic use
  • Molecular Targeted Therapy
  • Sodium-Glucose Transporter 2 / metabolism*
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors