Elise Hardy

Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4 inhibitor with or without metformin. RESEARCH DESIGN AND METHODS In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study with a 24-week blinded extension period, 432 patients were randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/day) ± metformin (≥1,500 mg/day). RESULTS Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL (9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL (9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean HbA1c levels (–0.5% [–4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]). Dapagliflozin reduced body weight versus placebo (–2.1 and –0.3 kg) and reduced HbA1c levels in patients with baseline values ≥8.0% (–0.8% [8.7 mmol/mol] and 0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (–24.1 mg/dL [–1.3 mmol/L] and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified by background therapy. Glycemic and weight benefits observed at week 24 were maintained through week 48. Changes from baseline in systolic blood pressure at week 8 were not significantly different between treatment groups. Over 48 weeks, fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycemic targets compared with placebo. Adverse events were balanced between groups, and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%). CONCLUSIONS These results suggest that in patients with type 2 diabetes, inadequately controlled on sitagliptin with or without metformin, add-on treatment with dapagliflozin provides additional clinical benefit and is well tolerated.

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial

BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin. METHODS DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged ≥18 years) with type 2 diabetes and inadequate glycaemic control (HbA1c 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA1c (<9·0% vs ≥9·0% [<75 mmol/mol vs ≥75 mmol/mol]). The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA1c less than 7·0% (<53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396. FINDINGS Between Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA1c 9·3% [SD 1·1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA1c was -2·0% (95% CI -2·1 to -1·8) in the exenatide plus dapagliflozin group, -1·6% (-1·8 to -1·4) in the exenatide group, and -1·4% (-1·6 to -1·2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone (-0·4% [95% CI -0·6 to -0·1]; p=0·004) or dapagliflozin alone (-0·6% [-0·8 to -0·3]; p<0·001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7·0% (<53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p≤0·025). Adverse events were recorded in 131 (57%) of 231 patients in the exenatide plus dapagliflozin group, 124 (54%) of 230 patients in the exenatide group, and 121 (52%) of 233 patients in the dapagliflozin group. The most common adverse events (≥5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported. INTERPRETATION Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (eg, AWARD-10; NCT02597049) will further inform the use of these drug classes in combination. FUNDING AstraZeneca.

Effects of Dapagliflozin on Cardiovascular Risk Factors

Abstract People with diabetes are more likely to develop a cardiovascular (CV) disease compared with those without diabetes. Although effective glycemic control has been the focus of the management of type 2 diabetes mellitus (T2DM), it is also important to control other CV risk factors to improve outcomes in these patients. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, lowers glucose levels in patients with T2DM by increasing urinary glucose excretion. Dapagliflozin therapy has been shown to impact a number of CV risk factors. Dapagliflozin improved glycemia with a low intrinsic propensity to cause hypoglycemia. Caloric loss associated with dapagliflozin-induced glucosuria also led to body weight reduction. Small changes from baseline in mean lipid parameters and reductions in serum uric acid levels were observed in patients taking dapagliflozin. Blood pressure reductions were also noted, consistent with modest drug-induced diuresis and weight loss.

Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes

Dapagliflozin, a sodium‐glucose cotransporter 2 (SGLT‐2) inhibitor, has been shown to lower glycated hemoglobin (HbA1c), weight, blood pressure and serum uric acid in clinical trials. Plasma lipids were also evaluated as exploratory variables. The goal of this study was to estimate the long‐term cardiovascular (CV) and microvascular outcomes of dapagliflozin added to the standard of care (SOC) versus SOC using simulation methodology.

Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION)

To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control.

Association of Weight Loss and Medication Adherence Among Adults With Type 2 Diabetes Mellitus: SHIELD (Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes)

Background Adherence to prescribed diabetes medications is suboptimal, which can lead to poor glycemic control and diabetic complications. Treatment-related weight gain is a side effect of some oral antidiabetic agents and insulin, which may negatively affect adherence to therapy. Objective This study investigated whether adults with type 2 diabetes mellitus (T2DM) who lost weight had better medication adherence than those who gained weight. Methods Weight change over 1 year (2007 to 2008) was assessed among respondents in the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD). Weight loss of >1.0%, ≥3%, and ≥5% of weight was compared with weight gain of ≥1.0%. Medication adherence was assessed using the Morisky 4-item questionnaire for medication-taking behavior, with lower scores representing better adherence. Results There were 746 T2DM respondents who lost >1.0%, 483 who lost ≥3%, 310 who lost ≥5%, and 670 who gained ≥1.0% of weight. Each weight-loss group had significantly lower Morisky scores than the weight-gain group; mean scores of 0.389 versus 0.473 (P = 0.050) for the >1.0% weight-loss group, 0.365 versus 0.473 (P = 0.026) for the ≥3% weight-loss group, and 0.334 versus 0.473 (P = 0.014) for the ≥5% weight-loss group. Significantly fewer respondents who lost weight had received insulin, sulfonylurea, or thiazolidinedione therapy (57%) compared with respondents who gained weight (64%) (P = 0.002). Demographics, exercise habits, and dieting were similar between weight-loss and weight-gain groups. Conclusions T2DM respondents with weight loss had significantly better medication adherence and were less likely to be on treatment regimens that increase weight than T2DM respondents with weight gain. These findings suggest that strategies that lead to weight loss, including use of diabetes medications associated with weight loss, may improve medication adherence.

Exenatide versus Insulin Lispro Added to Basal Insulin in a Subgroup of Korean Patients with Type 2 Diabetes Mellitus.

Background The prevalence of type 2 diabetes mellitus (T2DM) and obesity is increasing in Korea. Clinical studies in patients with T2DM have shown that combining the glucagon-like peptide-1 receptor agonist exenatide twice daily with basal insulin is an effective glucose-lowering strategy. However, these studies were predominantly conducted in non-Asian populations. Methods We conducted a subgroup analysis of data from a multinational, 30-week, randomized, open-label trial to compare the effects of exenatide twice daily (n=10) or three times daily mealtime insulin lispro (n=13) among Korean patients with T2DM inadequately controlled (glycosylated hemoglobin [HbA1c] >7.0%) on metformin plus optimized insulin glargine. Results Exenatide twice daily and insulin lispro both reduced HbA1c (mean −1.5% and −1.0%, respectively; P<0.01 vs. baseline). Fasting glucose and weight numerically decreased with exenatide twice daily (−0.7 mmol/L and −0.7 kg, respectively) and numerically increased with insulin lispro (0.9 mmol/L and 1.0 kg, respectively). Minor hypoglycemia occurred in four patients receiving exenatide twice daily and three patients receiving insulin lispro. Gastrointestinal adverse events were the most common with exenatide twice daily treatment. Conclusion This analysis found treatment with exenatide twice daily improved glycemic control without weight gain in Korean patients with T2DM unable to achieve glycemic control on metformin plus basal insulin.

Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time

Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium‐glucose cotransporter‐2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials.

Upper and/or lower gastrointestinal adverse events with glucagon-like peptide-1 receptor agonists: Incidence and consequences

To characterize gastrointestinal adverse events (AEs) with different glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs).

Upper and/or lower gastrointestinal adverse events with GLP-1 receptor agonists: incidences and consequences.

To characterize gastrointestinal adverse events (AEs) with different glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs).