Impact of LX4211, a Dual Inhibitor of Sodium Glucose Transporter 1 and 2, on Cardiovascular Risk Factors in Type 2 Diabetes - Impact of LX4211

Description:

The goal of this dose-ranging trial was to evaluate treatment with LX4211, a dual inhibitor of sodium glucose transporter 1 and 2, among poorly controlled type 2 diabetic patients compared with placebo.

These transporters are responsible for gastrointestinal glucose absorption and renal glucose reabsorption, respectively.

Hypothesis:

The aim of this study was to evaluate the efficacy and safety of LX4211.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel

Patient Populations:

  • Patients 18-75 years of age with type 2 diabetes on metformin therapy
  • HbA1c 7-10.5%
  • Body mass index ≤45 kg/m2

    Number of enrollees: 299
    Duration of follow-up: 12 weeks
    Mean patient age: 56 years
    Percentage female: 42%

Primary Endpoints:

  • Change in HbA1c from baseline to week 12

Secondary Endpoints:

  • Percentage of patients reaching target HbA1c ≤7%
  • Fasting plasma glucose change from baseline to week 12
  • Change in body weight
  • Change in blood pressure
  • Change in urinary glucose
  • Safety profile

Drug/Procedures Used:

Patients with poorly controlled diabetes on metformin monotherapy were randomized to 12 weeks of LX4211: 75 mg daily (n = 59), 200 mg daily (n = 60), 200 mg twice daily (n = 60), 400 mg daily (n = 60), versus placebo (n = 60).

Principal Findings:

Overall, 299 patients were randomized. The mean age was 56 years, 42% were women, mean body mass index was 33 kg/m2, mean glycated hemoglobin (HbA1c) was 8.0%, mean blood pressure was 126/80 mm Hg, mean low-density lipoprotein (LDL) cholesterol was 101 mg/dl, and mean high-density lipoprotein (HDL) cholesterol was 45 mg/dl.

Compared with placebo, there was a significant decrease in HbA1c at 12 weeks in all LX4211 groups; however, this was most pronounced in the 200 mg twice daily dose and 400 mg daily dose. At 12 weeks, there was a significant increase in urinary glucose excretion among all the LX4211 groups, except for the 75 g daily group.

There was a significant reduction in body weight at 12 weeks in the 200 mg daily, 200 mg twice daily, and 400 mg daily groups compared with placebo (p < 0.05). There was a nonsignificant reduction in weight loss in the 75 mg daily group compared with placebo.

There was a significant reduction in systolic blood pressure at 12 weeks in the 200 mg twice daily and 400 mg daily groups compared with placebo (p < 0.05). There was a nonsignificant reduction in systolic blood pressure in the 200 mg daily group compared with placebo.

There was a small increase in HDL cholesterol in the 75 mg, 200 mg twice daily, and 400 mg daily groups (p < 0.05). There was no change in LDL cholesterol.

Study drug discontinuation due to adverse event:
- 75 mg daily: 1.8%
- 200 mg daily: 1.7%
- 200 mg twice daily: 0
- 400 mg daily: 1.7%
- Placebo: 1.7%

Total genital infections:
- 75 mg daily: 0
- 200 mg daily: 8.3%
- 200 mg twice daily: 5.0%
- 400 mg daily: 8.3%
- Placebo: 0%

Interpretation:

Among poorly controlled diabetic patients on metformin monotherapy, LX4211 reduced important components of metabolic risk. This agent was associated with reductions in HbA1c, body weight, and systolic blood pressure, and an increase in HDL cholesterol. The short-term side effect profile appeared favorable. Based on these data, longer-term studies powered for clinical events appear warranted.

References:

Presented by Dr. Julio Rosenstock at the American Heart Association Scientific Sessions, Los Angeles, CA, November 6, 2012.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Hemoglobin A, Glycosylated, Cholesterol, Sodium-Glucose Transporter 1, Follow-Up Studies, Body Mass Index, Weight Loss, Metformin, Diabetes Mellitus, Type 2, Lipoproteins, Blood Pressure, Hypoglycemic Agents, Glucose


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