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

• Status: Completed
• Trial end date: 2019-03-13
• Target enrollment: 0
• Participant gender: Female

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Woman's
• Collaborator: AstraZeneca
• Treatments: Dapagliflozin; Metformin

Criteria

Inclusion Criteria:

• • 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

Exclusion Criteria:

• 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

• Eating disorders (anorexia, bulimia) or gastrointestinal disorders

• Suspected pregnancy (documented negative serum pregnancy test within 72 hours before first dose of study drug), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months

• Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or significant intake of alcohol or history of alcoholism

• Patient not willing to use adequate contraception during study period and up to 4 weeks after last dose of study drug (unless sterilized).

• Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables

• Inability or refusal to comply with protocol

• Not currently participating or having participated in an experimental drug study in previous three months