Effect of Dapagliflozin in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin - Effect of Dapagliflozin in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin

Jun 24, 2010
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb and AstraZeneca
Date Published:
01/01/2010
Date Updated:
06/24/2010
Original Posted Date:
06/24/2010
References

Description:

Several newer agents have emerged as alternatives/adjuncts to metformin in patients with type 2 diabetes in the past few years. The current trial was a phase III trial that sought to study the safety and efficacy of three different doses of dapagliflozin (a sodium-glucose cotransporter [SGLT]-2 inhibitor), as compared with placebo in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

Hypothesis:

Dapagliflozin would be safe and efficacious compared with placebo in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Number of screened applicants: 915
  • Number of enrollees: 546
  • Duration of follow-up: 24 weeks
  • Age 18-77 years; mean age 53.9 years
  • Percentage female: 47%
  • Type 2 diabetes
  • HbA1c between 7% and 10%
  • C-peptide concentration ≥0.34 nmol/L
  • Body mass index ≤45 kg/m2
  • Stable dose of metformin (at least 1500 mg) for 8 weeks prior to enrollment

Exclusions:

  • Serum creatinine ≥1.5 mg/dl (men) or 1.4 mg/dl (women)
  • Urine albumin/creatinine ratio more than 203.4 mg/mmol
  • Alanine aminotransferase/aspartate aminotransferase >3 x upper limit of normal (ULN)
  • Creatine kinase >3 x ULN
  • Symptoms of poorly controlled diabetes
  • Clinically significant renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic disease
  • Cardiovascular event within 6 months
  • New York Heart Association class III/IV symptomatic congestive heart failure
  • Systolic blood pressure ≥180 mm Hg, diastolic blood pressure ≥110 mm Hg

Primary Endpoints:

  • Change from baseline in HbA1c % at week 24

Secondary Endpoints:

  • Changes in fasting plasma glucose concentration and total body weight at week 24
  • Change in fasting plasma glucose concentration at week 1
  • Proportion of patients achieving a therapeutic glycemic response (HbA1c <7% at week 24)
  • Change in HbA1c % at week 24 for patients with a baseline HbA1c of ≥9%

Drug/Procedures Used:

After a run-in phase, patients were randomly assigned in a 1:1:1:1 ratio to double-blinded groups of once-daily dapagliflozin 2.5 mg, 5 mg, or 10 mg, or matching placebo orally before the morning meal for 24 weeks. All patients also received open-label metformin at their pre-randomization doses.

Principal Findings:

A total of 546 patients were randomized, 137 to dapagliflozin 2.5 mg once daily, 137 to dapagliflozin 5 mg once daily, 135 to dapagliflozin 10 mg once daily, and 137 to matching placebo. The mean baseline hemoglobin A1c (HbA1c) was about 8%, with a mean fasting blood glucose of about 160-170 mg/dl. The mean metformin dose during the trial was about 1800 mg daily.

Mean change from baseline at week 24 in HbA1c was –0.3% in the placebo arm compared with –0.67% in the dapagliflozin 2.5 mg arm (p = 0.0002), –0.7% in the dapagliflozin 5 mg arm (p < 0.0001), and –0.84% in the dapagliflozin 10 mg arm (p < 0.0001). Similar changes were noted in the fasting plasma glucose levels at 24 weeks, and were in fact noted as early as 1 week after enrollment. Total body weight was reduced from baseline by 0.9 kg in the placebo arm, as compared with 2.2 kg in the dapagliflozin 2.5 mg arm (p < 0.0001), 3.0 kg in the dapagliflozin 5 mg arm (p < 0.0001), and 2.9 kg in the dapagliflozin 10 mg arm (p < 0.0001). Waist circumference also decreased a mean –1.7 cm, –2.7 cm, and –2.5 cm in the dapagliflozin 2.5 mg, 5 mg, and 10 mg groups, respectively, compared with –1.3 cm in the placebo group. Proportion of patients with adequate glycemic control (HbA1c <7%) was significantly lower in the placebo arm (25.9%), as compared with the dapagliflozin 5 mg arm (37.5%, p = 0.03) and dapagliflozin 10 mg arm (40.6%, p = 0.006), but not the dapagliflozin 2.5 mg arm (33%, p = 0.17).

There were no deaths in any of the arms. Adverse events leading to discontinuation were numerically lower in the dapagliflozin groups than in the placebo group. The incidence of hypoglycemia was infrequent, and similar between the four arms. Signs, symptoms, and other reports suggestive of urinary tract infections (of concern due to mechanism of action of dapagliflozin resulting in enhanced glycosuria) were reported in similar proportions of patients in all groups, including the placebo group. Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (8-13%) than in the placebo group (5%), with the increased rate occurring in both men and women. No alterations of measures of mean renal function, including serum creatinine concentration, were noted.

Interpretation:

Dapagliflozin is a new medication for the treatment of type 2 diabetes that works by inhibiting the SGLT-2 transporter in the proximal renal tubule, thus preventing glucose reabsorption, and promoting glycosuria. It is therefore considered an insulin-independent agent.

The results of this phase 3 trial suggest that the addition of dapagliflozin results in a greater improvement in glycemic control (measured by HbA1c) compared with placebo, in a dose-dependent manner, in patients who are not adequately controlled on metformin alone. This may thus be another valuable addition to the armamentarium of antidiabetic medications, although the reduction in HbA1c is modest (0.7-0.8%). Further studies into this class of medications, including those with longer follow-up, and powered for cardiovascular endpoints, are awaited.

References:

Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.

Keywords: Insulin, Follow-Up Studies, Urinary Tract Infections, Glycosuria, Sodium, Diabetes Mellitus, Type 2, Body Weight, C-Peptide, Creatinine, Glucosides, Hypoglycemia, Glucose, Glycated Hemoglobin A, Waist Circumference, Body Mass Index, Metformin, Blood Glucose, Hypoglycemic Agents, Kidney Tubules, Proximal, Breakfast, Fasting


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