Safety and tolerability of dapagliflozin,saxagliptin and metformin in combination: Post‐hoc analysis of concomitant add‐on versus sequential add‐on to metformin and of triple versus dual therapy with metformin

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post‐hoc analysis of 3 randomized trials of sequential or concomitant add‐on of dapagliflozin and saxagliptin to metformin. In the concomitant add‐on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add‐on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add‐on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add‐on regimens. Urinary tract infections were more common with sequential than with concomitant add‐on therapy; genital infections were reported only with sequential add‐on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add‐on, were similar to dual therapy with either agent added to metformin.     

Comparing the effects of 12 months aerobic exercise and resistance training on glucose metabolism among prediabetes phenotype: A explorative randomized controlled trial

AimsThe pathophysiology of each phenotype of prediabetes is unique that promotes different levels of diabetes and cardiovascular disease risks. Exercise guidelines for individuals with prediabetes including both aerobic and resistance training could improve metabolic control, but its effects on different prediabetes subtypes are unclear. The aim of this explorative randomized controlled trial was to evaluate the effects of aerobic training (AT) or resistance training (RT) on glucose metabolism and lipid profile by different prediabetes subtypes with.MethodsA randomized controlled trial in which 128 individuals with isolated impaired fasting glucose (i-IFG; n = 39), isolated impaired glucose tolerance (i-IGT; n = 29), combined glucose tolerance (CGI; n = 27) and isolated elevated HbA_1c (n = 33) were randomly assigned to the control group, AT group and RT group, respectively. Supervised exercise training, including AT and RT were completed at moderate intensity for 60 min per day, three non-consecutive days per week for 12 months. The primary outcome was improvement in glucose metabolism. Secondary outcomes included measure of lipid profile and if these effects were moderated by the prediabetes phenotype.ResultsOf the initial 128 participants, 118 finished the study, but all participants were included in the intention-to-treat analyses. The improvement in 2 h postprandial plasma glucose (2 hPG) between group difference (AT vs. RT) at 12 months was 0.87 (95% CI, -1.59 to-0.16; p < 0.05). Compared with RT group, AT significantly decreased the 2hPG in participants with i-IGT at 12 months (-1.66, 95% CI -3.04 to -0.28; p < 0.05).ConclusionsAT program conferred benefits in improving 2 h PG and HbA_1c compared with RT for prediabetes. These findings may moderate by prediabetes phenotype, and AT appeared more effective in i-IGT. A future trial with large sample size and long time follow up of prediabetes phenotype groups are needed.     

Effects of exenatide once weekly plus dapagliflozin,exenatide once weekly alone,or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION‐8 randomized controlled trial

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION‐8 trial. Potential treatment‐by‐subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least‐squares mean reductions ranged from ?8.4 to ?26.1 mmol/mol (?0.77% to ?2.39%) for HbA1c and from ?2.07 to ?4.55 kg for body weight. Potential treatment‐by‐subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m² (least‐squares mean reductions of ?23.6 vs ?19.0 mmol/mol [?2.16% vs ?1.74%], ?17.3 vs ?12.0 mmol/mol [?1.58% vs ?1.10%], and ?17.7 vs ?16.9 mmol/mol [?1.62% vs ?1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment‐by‐subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range ?2.56 to ?3.98 kg vs ?0.56 to ?2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.     

Correction of hypomagnesemia by dapagliflozin in patients with type 2 diabetes: A post hoc analysis of 10 randomized,placebo-controlled trials

AimsHypomagnesemia (serum magnesium [Mg] <0.74 mmol/L [<1.8 mg/dL]) is commonly observed in patients with type 2 diabetes (T2D). This study investigated the effect of treatment with dapagliflozin 10 mg on Mg concentrations in patients with T2D.MethodsIn this post hoc analysis, we used pooled data from 10 placebo-controlled studies of dapagliflozin over 24 weeks of treatment in patients with T2D. We evaluated the change in Mg in patients receiving dapagliflozin vs. placebo overall, and in subgroups with baseline hypomagnesemia and normal/hypermagnesemia (≥0.74 mmol/L [≥1.8 mg/dL]). We determined the proportion of patients with baseline hypomagnesemia who achieved Mg ≥0.74 mmol/L (≥1.8 mg/dL).ResultsA total of 4398 patients with T2D were included. The mean change from baseline to week 24 in Mg was significantly larger with dapagliflozin vs. placebo; difference, 0.06 mmol/L (95% confidence interval [CI]: 0.05, 0.06). The proportion of patients with Mg within the population reference range after 24 weeks of treatment was significantly higher with dapagliflozin vs. placebo; difference, 47.8% (95% CI: 41.4, 53.9). The proportion of patients displaying hypermagnesemia did not increase with dapagliflozin treatment.ConclusionsTreatment with dapagliflozin 10 mg resulted in correction of Mg concentrations in patients with T2D and hypomagnesemia.