Empagliflozin and the Preservation of Beta-cell Function in Women with Recent Gestational Diabetes (EMPA post-GDM)

Double-blind, parallel arm, randomized controlled trial, in which non-lactating women with recent GDM who are between 6 to 36 months postpartum to be randomized to either empagliflozin 10 mg daily or matching placebo. The duration of treatment will be 48-weeks. Beta-cell function will be assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), measured on oral glucose tolerance test (OGTT) at baseline, 24-weeks, 48-weeks, and after a 4-week washout.

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Placebo oral capsule

Detailed Description

Gestational diabetes mellitus (GDM), defined as glucose intolerance of varying severity with first onset and recognition in pregnancy, identifies a population of women who are at high risk for the future development of type 2 diabetes (T2DM). This risk of T2DM is mediated by the progressive deterioration of insulin secretion by the pancreatic beta-cells in the years after delivery, a pathologic process that current anti-diabetic therapies have not been shown to modify. Importantly, since very mild glycemia has deleterious but reversible effects on insulin secretion ("glucotoxicity"), the beta-cell dysfunction of women with recent GDM should have a prominent reversible component that potentially could be mitigated through the elimination of glucotoxicity. In this context, the sodium glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin is a novel anti-diabetic therapy that specifically alleviates glucotoxicity and thus may be able to preserve beta-cell function. Coupled with its capacity to induce weight loss with low risk of hypoglycemia, empagliflozin could be an ideal therapy for diabetes prevention in women with recent GDM. Specifically, by eliminating glucotoxicity, SGLT-2 inhibition could enable the preservation of beta-cell function and thereby prevent the development of incident T2DM in this high-risk population. Thus, a double-blind, parallel arm, randomized controlled trial, in which non-lactating women with recent GDM who are between 6 to 36 months postpartum to be randomized to either empagliflozin 10 mg daily or matching placebo is proposed. The duration of treatment will be 48-weeks. Beta-cell function will be assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), measured on oral glucose tolerance test (OGTT) at baseline, 24-weeks, 48-weeks, and after a 4-week washout.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • Leadership Sinai Centre foe Diabetes - Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women with recent gestational diabetes who are between 6-36 months postpartum inclusive and no longer breastfeeding
• Age 20 - 50 years inclusive
• Negative pregnancy test at recruitment

Exclusion Criteria:

• Current breastfeeding
• Current diabetes or treatment with any anti-diabetic medication
• Involvement in any other clinical study requiring drug therapy
• Hypersensitivity to empagliflozin or the formulations of this product
• Any history of diabetic ketoacidosis
• History of recurrent urinary infection (i.e. more than 2 episodes over the past year).
• Renal dysfunction as evidenced by estimated glomerular filtration rate < 45 ml/min by Modification of Diet in Renal Disease (MDRD) formula
• Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, or previous liver transplant) or transaminases >2.5X the upper limit of normal
• Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy within the previous 5 years (with the exception of basal cell skin cancer)
• Pregnancy or unwillingness to use reliable contraception. Women should not be planning pregnancy for the duration of the study or the first 3 months after the study. Reliable contraception includes the following: birth control pill, intra-uterine device, abstinence, tubal ligation, partner vasectomy, or condoms with spermicide.
• Any other factor likely to limit adherence to the study, in the opinion of the investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin; Empagliflozin 10 mg PO daily	Drug: Empagliflozin 10 MG; Empagliflozin 10 mg PO daily
Placebo Comparator: Placebo; Matched placebo PO daily	Drug: Placebo oral capsule; Placebo PO daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted ISSI-2 at 48-weeks	The primary outcome will be measured by ISSI-2. ISSI-2 is a validated OGTT-derived measure of beta-cell function analogous to the disposition index obtained from the intravenous glucose tolerance test. ISSI-2 is defined as the product of (i) insulin secretion measured by the ratio of the area-under-the-insulin-curve (AUCins) to the area-under-the-glucose curve (AUCgluc) and (ii) insulin sensitivity measured by the Matsuda index.	48-weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose tolerance status at 48-weeks	Prevalence of dysglycemia on the OGTT at this visit.	48-weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted ΔISR0-120/Δgluc0-120 × Matsuda index at 48 weeks	and insulinogenic index/HOMA-IR.	48-weeks
Baseline-adjusted insulinogenic index/HOMA-IR at 48-weeks	Beta-cell function assessed by ΔISR0-120/Δgluc0-120 × Matsuda index at 48-weeks	48-weeks
Body mass index at 48-weeks		48-weeks
Insulin sensitivity at 48 weeks.	Insulin sensitivity will be measured by Matsuda index on OGTT	48-weeks
Central abdominal fat mass at 48 weeks	Central abdominal fat mass will be measured by DXA assessment at L2-L4	48-weeks
Quality of life at 48 weeks	Quality of life will be assessed annually by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36).	48-weeks

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Caroline kramer, MD PhD, Mount Sinai Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): December 31, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: July 7, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 12, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: gestational diabetes, SGLT-2 inhibitor, empagliflozin
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Pregnancy Complications; Glucose Metabolism Disorders; Diabetes, Gestational; Diabetes Mellitus; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Empagliflozin
• Other Study ID Numbers: 16-0226-A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No