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Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.
Lalau, JD, Al-Salameh, A, Hadjadj, S, Goronflot, T, Wiernsperger, N, Pichelin, M, Allix, I, Amadou, C, Bourron, O, Duriez, T, et al
Diabetes & metabolism. 2021;(5):101216
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Abstract
AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P < 0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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iGlarLixi reduces residual hyperglycemia in Japanese patients with type 2 diabetes uncontrolled on basal insulin: A post-hoc analysis of the LixiLan JP-L trial.
Yabe, D, Iizuka, K, Baxter, M, Watanabe, D, Kaneto, H
Journal of diabetes investigation. 2021;(11):1992-2001
Abstract
INTRODUCTION Treatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia. MATERIALS AND METHODS Outcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia. RESULTS Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (-0.72% difference between groups; P < 0.0001). CONCLUSIONS New data from this post-hoc analysis of the JP-L trial show that treatment with the fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin vs similar doses of iGlar alone.
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Do sodium-glucose cotransporter 2 inhibitors lead to fracture risk? A pharmacovigilance real-world study.
Zhao, B, Shen, J, Zhao, J, Pan, H
Journal of diabetes investigation. 2021;(8):1400-1407
Abstract
AIMS/INTRODUCTION Given the mechanism of action of sodium-glucose cotransporter 2 inhibitors (SGLT2is), these drugs can also reduce bone density and increase fracture risk. We aimed to identify and characterize fracture-related adverse events that are associated with SGLT2is. MATERIALS AND METHODS In this observational, retrospective, pharmacovigilance, real-world study, we used disproportionality and Bayesian analyses to compare fracture-related adverse event reporting in patients who received SGLT2is from the first quarter in 2004 to the fourth quarter in 2019 in the Food and Drug Administration Adverse Event Reporting System. We also compared the effect on combined therapy with SGLT2is and other glucose-lowering medications (GLMs), and compared their onset times and outcomes. RESULTS A total of 317 SGLT2is-associated fractures were identified. Affected patients tended to be aged >45 years (68.76%) and were more often male than female (58.04% vs 34.07%). SGLT2is-associated fracture is most commonly reported with canagliflozin (51.10%), dapagliflozin (24.60%) and empagliflozin (23.66%). SGLT2is or SGLT2is combined with GLMs do not show an association with fracture risk under disproportionality and Bayesian analyses. SGLT2i-associated fractures result in hospitalization in 66.64% of patients and death in 9.38% of patients. GLMs show an increased hospitalization rate compared with SGLT2is (69.72% vs 55.14%, P < 0.0001) and GLMs plus SGLT2is (69.72% vs 61.20%, P = 0.0197). CONCLUSIONS Based on the Food and Drug Administration Adverse Event Reporting System database, no association is noted between fracture risk and SGLT2is, or SGLT2is combined with GLMs. Long-term follow up and high-quality studies need to further verify and explore the relationship between SGLT2is and fractures.
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Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin.
Miya, A, Nakamura, A, Cho, KY, Kawata, S, Nomoto, H, Nagai, S, Sugawara, H, Taneda, S, Tsuchida, K, Omori, K, et al
Journal of diabetes investigation. 2021;(8):1395-1399
Abstract
AIMS/INTRODUCTION To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion. MATERIALS AND METHODS A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median. RESULTS ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 ± 28.3 vs -20.0 ± 24.6, respectively; P = 0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P < 0.01). CONCLUSIONS COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.
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Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial.
Pastor-Villaescusa, B, Plaza-Díaz, J, Egea-Zorrilla, A, Leis, R, Bueno, G, Hoyos, R, Vázquez-Cobela, R, Latorre, M, Cañete, MD, Caballero-Villarraso, J, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111117
Abstract
BACKGROUND Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. METHODS The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. RESULTS Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumption. CONCLUSION Further studies with a large sample size controlled by lifestyle patterns are required in obese children and adolescents to clarify whether metformin might trigger gut microbiota alterations. TRIAL REGISTRATION Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.
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Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study.
Cho, KY, Nomoto, H, Nakamura, A, Kawata, S, Sugawara, H, Takeuchi, J, Nagai, S, Omori, K, Tsuchida, K, Miya, A, et al
Journal of diabetes investigation. 2021;(8):1417-1424
Abstract
AIMS/INTRODUCTION We recently reported the beneficial effect of the combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. MATERIALS AND METHODS The CALMER study was a multicenter, open-label, prospective, randomized, parallel-group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. RESULTS All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2-82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (-14.8% vs -7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). CONCLUSIONS Sodium-glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase-4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.
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Efficacy and safety of trelagliptin in Japanese patients with type 2 diabetes with severe renal impairment or end-stage renal disease: Results from a randomized, phase 3 study.
Kaku, K, Ishida, K, Shimizu, K, Achira, M, Umeda, Y
Journal of diabetes investigation. 2020;(2):373-381
Abstract
INTRODUCTION To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.
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Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus.
Ejiri, K, Miyoshi, T, Kihara, H, Hata, Y, Nagano, T, Takaishi, A, Toda, H, Nanba, S, Nakamura, Y, Akagi, S, et al
Journal of the American Heart Association. 2020;(16):e015103
Abstract
Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.
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Comparison of Group Medical Visits Combined With Intensive Weight Management vs Group Medical Visits Alone for Glycemia in Patients With Type 2 Diabetes: A Noninferiority Randomized Clinical Trial.
Yancy, WS, Crowley, MJ, Dar, MS, Coffman, CJ, Jeffreys, AS, Maciejewski, ML, Voils, CI, Bradley, AB, Edelman, D
JAMA internal medicine. 2020;(1):70-79
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Abstract
IMPORTANCE Traditionally, group medical visits (GMVs) for persons with diabetes improved glycemia by intensifying medications, which infrequently led to weight loss. Incorporating GMVs with intensive dietary change could enable weight loss and improve glycemia while decreasing medication intensity. OBJECTIVE To examine whether a program of GMVs combined with intensive weight management (WM) is noninferior to GMVs alone for change in glycated hemoglobin (HbA1c) level at 48 weeks (prespecified margin of 0.5%) and superior to GMVs alone for hypoglycemic events, diabetes medication intensity, and weight loss. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial identified via the electronic medical record 2814 outpatients with type 2 diabetes, uncontrolled HbA1c, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 27 or higher from Veterans Affairs Medical Center clinics in Durham and Greenville, North Carolina. Between January 12, 2015, and May 30, 2017, 263 outpatients started the intervention. INTERVENTIONS Participants randomized to the GMV group (n = 136) received counseling about diabetes-related topics with medication optimization every 4 weeks for 16 weeks, then every 8 weeks (9 visits). Participants randomized to the WM/GMV group (n = 127) received low-carbohydrate diet counseling with baseline medication reduction and subsequent medication optimization every 2 weeks for 16 weeks followed by an abbreviated GMV intervention every 8 weeks (13 visits). MAIN OUTCOMES AND MEASURES Outcomes included HbA1c level, hypoglycemic events, diabetes medication effect score, and weight at 48 weeks analyzed using hierarchical generalized mixed models to account for clustering within group sessions. RESULTS Among 263 participants (mean [SD] age, 60.7 [8.2] years; 235 [89.4%] men; 143 [54.4%] black), baseline HbA1c level was 9.1% (1.3%) and BMI was 35.3 (5.1). At 48 weeks, HbA1c level was improved in both study arms (8.2% in the WM/GMV arm and 8.3% in the GMV arm; mean difference, -0.1%; 95% CI, -0.5% to 0.2%; upper 95% CI, <0.5% threshold; P = .44). The WM/GMV arm had lower diabetes medication use (mean difference in medication effect score, -0.5; 95% CI, -0.6 to -0.3; P < .001) and greater weight loss (mean difference, -3.7 kg; 95% CI, -5.5 to -1.9 kg; P < .001) than did the GMV arm at 48 weeks and approximately 50% fewer hypoglycemic events (incidence rate ratio, 0.49; 95% CI, 0.27 to 0.71; P < .001) during the 48-week period. CONCLUSIONS AND RELEVANCE In GMVs for diabetes, addition of WM using a low-carbohydrate diet was noninferior for lowering HbA1c levels compared with conventional medication management and showed advantages in other clinically important outcomes. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01973972.
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Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study.
Kinoshita, T, Shimoda, M, Nakashima, K, Fushimi, Y, Hirata, Y, Tanabe, A, Tatsumi, F, Hirukawa, H, Sanada, J, Kohara, K, et al
Journal of diabetes investigation. 2020;(6):1612-1622
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. MATERIALS AND METHODS We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography. RESULTS There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable. CONCLUSIONS The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.