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ADA 2013: Dapagliflozin Update

Durability of Dapagliflozin vs. Glipizide as Add-On Therapies in T2DM Inadequately Controlled on Metformin: 4-Year Data

 

The efficacy, tolerability and safety of dapagliflozin was studied compared to glipizide over a period of 4 years. Dapagliflozin is a novel medication that is a highly selective inhibitor of SLGLT2 and reduces blood glucose independently of insulin by increasing excretion of glucose through the urine. In a randomized, double-blind, active controlled study, the researchers compared dapagliflozin to glipizide as add-on medications to metformin. The primary endpoints of focus were changes in HbA1c, weight and systolic blood pressure (SBP) at 52 weeks. Data was collected up to 208 weeks as part of the extension period. Safety and Tolerability were determined by the incidence of adverse events (side effects, hypoglycemia, UTI)….

After 52 weeks, dapagliflozin was reported to be non-inferior to glipizide regarding change in HbA1c. Dapagliflozin did show better sustained reduction of HbA1c compared to glipizide after 52 weeks and up to 208 weeks. Dapagliflozin showed sustained weight loss over 4 years whereas glipizide had shown sustained weight gain. The SBP was also found to be consistently lower in patients taking dapagliflozin. In regards to safety and tolerability, glipizide use resulted in 10 times the incidence of hypoglycemia during the first year compared to dapagliflozin. Genital infections and UTI were more frequent with the use of dapagliflozin.

 

Dapagliflozin as Part of Triple Combination Therapy Helps Reduce HbA1c and Body Weight in Patients with Type 2 Diabetes

The aim of the analysis was to determine the efficacy of dapagliflozin (SGLT2 inhibitor) as part of a triple combination therapy to achieve HbA1c goals in patients with type 2 diabetes. Researchers performed a subgroup analysis on four 24-week studies with patients receiving either placebo or dapagliflozin as an addition to: sitagliptin + metformin; sulfonylurea + metformin; or insulin + metformin. The researched focused on the outcomes of change in HbA1c, body weight, and safety.

In each of the four studies, HbA1c was significantly reduced with the addition of dapagliflozin compared to placebo after 26 weeks (-0.4% to -0.6%). Body weight was significantly reduced from baseline in each study following the administration of dapagliflozin compared to placebo (-1.9kg to -2.2kg). The overall frequency of adverse events across the four studies was consistent, reporting more frequent genital and urinary tract infections with the administration of dapagliflozin. Researchers concluded that dapagliflozin was effective in improving glycemic control in a mechanism that is independent of insulin, disease severity, and residual beta cell function.

 

Exploring the Potential of Dapagliflozin in Type 1 Diabetes: Phase 2a Pilot Study

The study examined the short-term safety profile, pharmacokinetic and pharmacodynamic parameters of dapagliflozin use in patients with type 1 diabetes as an addition to insulin. Seventy Patients, age 18-65, with T1DM treated with insulin > 12months were enrolled in a 2-week randomized parallel-group, placebo-controlled phase 2a pilot study. The primary objective of the study was to assess safety and tolerability of dapagliflozin after 2 weeks. Secondary objectives included change from baseline to Day 7 in 7-point glucose monitoring profiles. Exploratory objectives included change in baseline of: total daily insulin dosing, fasting plasma glucose, 24hr urine glucose output, body weight, and fluid intake/output.

The authors reported no effects of dapagliflozin on urine output, total fluid intake or changes from baseline in body weight or BMI. The steady-state PK parameters were similar to the reported use of dapagliflozin in patients with T2DM. Reductions in total daily dosing of insulin were seen with the use of dapagliflozin. No difference was reported in mean daily plasma glucose as determined by the 7-point glucose monitoring between placebo and dapagliflozin. Hypoglycemia was observed in all treatment groups but overall there were no marked laboratory abnormalities of clinical concern reported. Authors concluded that dapagliflozin was well tolerated in this T1DM population; however due to the small sample size of the study, further research is needed to determine if the use of this medication is beneficial in T1DM.

 

Dapagliflozin as Monotherapy in Drug-Naïve Asian Patients with T2DM Inadequately Controlled on Diet and Exercise

This study presents a Phase III, 24 week, double-blind with a single-blind placebo lead-in period over 40 sites in several Asian nations. The safety and efficacy of dapagliflozin monotherapy was determined in drug naive Asian patients with inadequately controlled T2DM. Patients were randomized to placebo, dapagliflozin 5mg or dapagliflozin 10mg once daily before the first meal. Patients received metformin rescue therapy if glycemic targets were not met. Primary endpoint of focus was the mean change from baseline in HbA1c. Secondary endpoints included: change in fasting plasma glucose (FPG), change in 2-hr postprandial glucose (PPG), change in total body weight, proportion achieving therapeutic response (HbA1c <7%). Adverse events were also reported.

At week 24, the authors reported significantly lower HbA1c in both dapagliflozin treated groups compared to placebo (-0.75% 5mg and -0.82% 10mg). Dapagliflozin 5 and 10mg produced significant reduction in FPG versus placebo (-27.7mg/dL and -40.4mg/dL respectively). Significant difference in reduction of PPG of dapagliflozin 5 and 10mg versus placebo was noted as well (-46.8mg/dL and -54.9mg/dL respectively). In 42.6% patients taking dapagliflozin 5mg and 49.8% patients taking 10mg an HbA1c < 7.0% versus placebo (21.3%) was achieved. The total body weight reduction was also reported to be significantly less for both 5 and 10mg of dapagliflozin compared to placebo. Dapagliflozin was well tolerated, hypoglycemia was uncommon and no cases led to discontinuation of therapy. Genital and urinary tract infections were reported in all treatment groups, however more were prevalent with treatment of dapagliflozin.

 

Efficacy and Safety of Dapagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise

To determine safety and efficacy of dapagliflozin, researchers conducted a Phase III multicenter, randomized, double-blind, placebo-controlled 24-week parallel group study with 3-week follow-up in 261 Japanese patients with T2DM inadequately controlled by diet and exercise. Patients were randomized to receive placebo, dapagliflozin 5mg or dapagliflozin 10mg once daily. Primary endpoint of the study was the change in HbA1c. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight. Safety endpoints were based on reported outcomes of adverse events, laboratory values, blood pressure, eGFR, etc.

After 24 weeks, the authors reported significant reductions in HbA1c levels for dapagliflozin treatment arms (-0.4% 5mg; -0.5% 10mg) compared to placebo (-0.1%). A greater proportion of patients receiving either dose of dapagliflozin achieved a therapeutic response defined by HbA1c <7.0% compared to placebo. Regarding secondary endpoints, significant reductions of FPG and total body weight were observed in both dapagliflozin treatment groups compared to placebo. Two subjects treated with dapagliflozin 10mg discontinued the medication due to reduce eGFR. Medication was discontinued due to renal impairment in 2, 3, and 2 patients of dapagliflozin 5mg, 10mg and placebo respectively. There were no reports of abnormalities in BUN, urea or creatinine in all treatment groups. The authors concluded that once daily dapagliflozin in the Japanese population showed similar safety and efficacy comparable to the international population.

 

Dapagliflozin Effects on the Lipid Profile of Patients with Type 2 Diabetes Mellitus

Dapagliflozin has been shown to reduce hyperglycemia in patients with T2DM and have beneficial effects towards cardiovascular risk factors by reducing total body weight, blood pressure and uric acid. Researchers analyzed the lipid profile reported as exploratory endpoints of 3731 patients in 12 phase 2b/3 double-blind controlled trials receiving dapagliflozin 5 or 10 mg or placebo for up to 24-weeks.

The results of the pooled analysis demonstrated changes from baseline in HDL-C were +6.5% and +5.5% for dapagliflozin 5 and 10 mg, respectively and +3.8% for placebo. Changes in LDL-C were +0.6% and +2.7% for dapagliflozin 5 and 10 mg, respectively, and −1.9% for placebo. Total cholesterol was reported as +1.1% and +1.4% for dapagliflozin 5 and 10 mg, respectively, and −0.4% for placebo. The authors concluded that though dapagliflozin was associated with small mean changes in fasting lipid parameters, the changes were not clinically significant.

Compiled by:
 
David Joffe, BSPharm, CDE, Editor
Cale Courtney Doctor of Pharmacy Candidate , University of Florida College of Pharmacy

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