Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women

NCT02338193 | Completed Phase 3 Results

• 1 other identifier: RP-14-012
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

Brief Summary

Women with a history of gestational diabetes (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). Compared with the general population, these women are more likely to be overweight or obese. Moreover, weight gain after GDM is significantly associated with T2DM, independent of baseline body weight. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of β-cell compensation for insulin resistance. Taken together, our findings and other studies support increased abdominal fat as the strongest factor associated with declining B-cell compensation for insulin resistance in prior GDM women at high risk for T2DM. Dapagliflozin is a novel highly selective SGLT2 inhibitor that improves glycemic control by reducing renal glucose reabsorption leading to urinary glucose excretion. Its efficacy and safety has been studied in multiple randomized controlled trials including an add-on to metformin compared with a placebo. To the extent that glucotoxicity contributes to the demise in β-cell function in subjects with impaired glucose, SGLT2 inhibitors also may prove useful in the treatment of "prediabetes." An additional secondary benefit of SGLT2 inhibition is the elimination of calories in the form of glucose. The loss of glucose with attendant caloric loss contributes to weight loss; in addition, improvements in β cell function have been seen. Weight loss seen with SGLT2 inhibitors is similar to that seen with glucagon-like peptide 1 analogs, and may be more acceptable because they are oral agents. A consistent finding in all dapagliflozin studies has been a reduction in blood pressure. The investigators hypothesize that combination dapagliflozin -metformin treatment over a 24-week period will have a greater positive impact on body weight, anthropometric measurements and glycemic and cardiometabolic parameters than dapagliflozin or metformin monotherapy in overweight/obese at-risk women with a history of GDM.

Conditions

Diabetes Prevention in Women After GDM Who Are at High-risk

Keywords

GDM; T2DM; prediabetes

Outcome Measures

Primary Outcomes (1)

• Change in Body Weight

  Change in absolute body weight with combination therapy compared to monotherapy from baseline to week 24

  Change from baseline (time 0) to study end (24 weeks)

Secondary Outcomes (15)

• Change in Percent Body Weight

  Change from baseline (time 0) to study end (24 weeks)

• Body Mass Index (BMI)

  24 weeks of treatment

• Waist Circumference (WC)

  24 weeks of treatment

• Waist- to -Hip Ratio (WHR; Measure of Central Adiposity)

  24 weeks of treatment

• Waist-to-height Ratio (WHtR)

  24 weeks of treatment

Study Arms (3)

DAPA/MET Extended Release (XR)

EXPERIMENTAL

Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks

Drug: DAPA/MET XR

Dapaglifloxin

ACTIVE COMPARATOR

Dapagliflozin- 10 mg once daily before first meal for 24 weeks

Drug: DAPA

Metformin XR

ACTIVE COMPARATOR

Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the morning (AM), 1000 mg in the evening ( PM) for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks

Drug: MET XR

Interventions

DAPA/MET XR DRUG

final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks

Also known as: Xigduo 5mg/1000 mg

DAPA/MET Extended Release (XR)

DAPA DRUG

10 mg dapagliflozin QD for 20-24 weeks

Also known as: Farxiga 10 mg

Dapaglifloxin

MET XR DRUG

1000 mg Metformin XR BID for 20-24 weeks

Also known as: Glucophage XR 500 mg

Metformin XR

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Overweight/obese (BMI \>25) females 18 years to 45 years of age, who experienced gestational diabetes (GDM) during recent (within 12 months) pregnancy
• postpartum metabolic abnormalities determined by a 75 g oral glucose tolerance test (Inclusive of prior GDM women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) postpartum)
• Completed lactation
• Using adequate contraception during study period unless sterilized
• Written consent for participation in the study

You may not qualify if:

• Cholestasis during the past pregnancy
• Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology), gallstones, abnormal liver function tests or renal impairment (elevated serum creatinine levels or abnormal creatinine clearance
• Presence of significant systemic disease, heart problems including congestive heart failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2)
• Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR \<60)
• Significantly elevated triglyceride levels (fasting triglyceride \> 400 mg %)
• Untreated or poorly controlled hypertension (sitting blood pressure \>160/95mm Hg)
• Prior history of a malignant disease requiring chemotherapy
• Known hypersensitivity or contraindications to use of insulin sensitizers such as metformin or thiazolidinediones
• History of hypersensitivity reaction to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions)
• Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors or weight loss medications (prescription or OTC)
• Uncontrolled thyroid disease (documented normal TSH) or hyperprolactinemia
• Liver enzymes (serum alanine aminotransferase \[ALT\] and/or aspartate aminotransferase \[AST\] ) levels exceeding more than twice normal lab values
• Use of drugs known to exacerbate glucose tolerance
• History of diabetes or prior use of medications to treat diabetes except GDM
• Currently lactating

Sponsors & Collaborators

• Woman's: lead
• AstraZeneca: collaborator

Study Sites (1)

Woman's Hospital

Baton Rouge, Louisiana, 70815, United States

Location

Related Publications (1)

• Elkind-Hirsch KE, Seidemann E, Harris R. A randomized trial of dapagliflozin and metformin, alone and combined, in overweight women after gestational diabetes mellitus. Am J Obstet Gynecol MFM. 2020 Aug;2(3):100139. doi: 10.1016/j.ajogmf.2020.100139. Epub 2020 May 16.

  PMID: 33345876 DERIVED

MeSH Terms

Conditions

Prediabetic State

Interventions

dapagliflozin; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

Important limitations were the small number completed patients per drug group and only 24 weeks of therapy. Surrogate measures were for central adiposity; use of dual-energy x-ray absorptiometry to measure body composition would increase accuracy

Results Point of Contact

• Title: Dr Karen Elkind-Hirsch, Director of Research
• Organization: Woman's Hospital

karen.elkind-hirsch@womans.org

225 231-5278

Study Officials

• Karen E Elkind-Hirsch, PhD

  Woman's Hospital, Louisiana

  PRINCIPAL INVESTIGATOR

• Renee Harris, MD

  Woman's Hospital, Louisiana

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Research

Study Record Dates

• First Submitted: January 7, 2015
• First Posted: January 14, 2015
• Study Start: September 22, 2015
• Primary Completion: February 13, 2019
• Study Completion: March 13, 2019
• Last Updated: June 11, 2019
• Results First Posted: April 30, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)