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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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Impact of Hyperglycemia on Long-Term Outcome in Patients With ST-Segment Elevation Myocardial Infarction.
Kojima, T, Hikoso, S, Nakatani, D, Suna, S, Dohi, T, Mizuno, H, Okada, K, Kitamura, T, Kida, H, Oeun, B, et al
The American journal of cardiology. 2020;(6):851-859
Abstract
In patients with ST-segment elevation myocardial infarction (STEMI), the association between stress-induced hyperglycemia (SIH) and long-term outcomes, as well as the effects of baseline diabetic status on this association remain elusive. To clarify the association between SIH and long-term outcomes, and the effects of baseline diabetic status on this association, we studied 6,287 STEMI patients who were discharged alive. SIH was estimated using the stress hyperglycemia ratio (SHR), which is defined as [(admission glucose (mg/dl))/(28.7 × HbA1c (%) - 46.7)]. End points were all-cause death and admission for heart failure (HF). We compared prognosis between patients in the highest SHR quartile and those in other quartiles of the nondiabetic and diabetic population. Over a follow-up of 5 years (median 1,522 days), 464 (7.4%) and 401 (6.4%) cases of all-cause death and HF admission were observed. In the nondiabetic population, the highest SHR quartile (Q4) group was significantly associated with worse long-term outcomes (adjusted hazard ratio [HR] (95% confidence interval [CI]), all-cause death; 1.45 (1.06 to 1.98), p = 0.021, HF admission; 1.48 (1.04 to 2.10), p = 0.031). However, in the diabetic population, SHR Q4 group was not significantly associated with worse long-term outcomes (adjusted HR (95% CI), all-cause death; 1.00 (0.68 - 1.48), p = 0.996, HF admission; 1.31 (0.90 to 1.89), p = 0.154). In conclusion, in STEMI patients discharged alive, high SHR was significantly associated with worse long-term prognosis in the nondiabetic population. In contrast, high SHR was not significantly associated with worse long-term prognosis in the diabetic population.
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Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data.
Gabriel, R, Boukichou Abdelkader, N, Acosta, T, Gilis-Januszewska, A, Gómez-Huelgas, R, Makrilakis, K, Kamenov, Z, Paulweber, B, Satman, I, Djordjevic, P, et al
PloS one. 2020;(4):e0231196
Abstract
OBJECTIVES To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. METHODS Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. PARTICIPANTS Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. INTERVENTION Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. RESULTS One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. CONCLUSIONS ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. REGISTRATION - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.
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Mediation of the association of smoking and microvascular complications by glycemic control in type 1 diabetes.
Braffett, BH, Rice, MM, Young, HA, Lachin, JM
PloS one. 2019;(1):e0210367
Abstract
Studies have demonstrated the adverse effects of smoking on the risk of microvascular complications; however, few have also examined the potential mediating effects of glycemic control. Using data from the Diabetes Control and Complications Trial (DCCT 1983-1993), we describe the acute and long-term risks of smoking on glycemic control and microvascular complications in a well-characterized cohort of participants with type 1 diabetes. The DCCT recorded self-reported smoking behaviors, glycemic exposure based on HbA1c, and complications status. Generalized linear mixed models were used to assess whether time-dependent measurements of smoking predict HbA1c levels. Cox proportional hazard models were used to assess time-dependent smoking exposures as predictors of retinopathy and nephropathy. During a mean of 6.5 years of follow-up, current smokers had consistently higher HbA1c values and were at a higher risk of retinopathy and nephropathy compared with former and never smokers. These risk differences were attenuated after adjusting for HbA1c suggesting that the negative association of smoking on glycemic control is partially responsible for the adverse association of smoking on the risk of complications in type 1 diabetes. These findings support the potential for a beneficial effect of smoking cessation on complications in type 1 diabetes.
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Efficacy and safety of MYL-1501D vs insulin glargine in patients with type 1 diabetes after 52 weeks: Results of the INSTRIDE 1 phase III study.
Blevins, TC, Barve, A, Sun, B, Ankersen, M
Diabetes, obesity & metabolism. 2018;(8):1944-1950
Abstract
AIM: To test the safety and efficacy of MYL-1501D, a proposed insulin glargine biosimilar, in patients with type 1 diabetes mellitus (T1DM). METHODS The safety and efficacy of MYL-1501D and reference insulin glargine were evaluated in INSTRIDE 1, a 52-week, open-label, randomized, phase III study in patients with T1DM. The primary objective was to determine whether once-daily MYL-1501D was non-inferior to once-daily insulin glargine when administered in combination with mealtime insulin lispro based on change in glycated haemoglobin (HbA1c) from baseline to week 24. Secondary endpoints were changes in fasting plasma glucose, insulin dose, self-monitored blood glucose and immunogenicity from baseline, and occurrences of hypoglycaemic, nocturnal hypoglycaemic and adverse events up to week 52. RESULTS Overall, 558 patients were randomized 1:1 to MYL-1501D or reference insulin glargine in combination with thrice-daily mealtime insulin lispro for 52 weeks. The mean change in HbA1c from baseline to week 24 was 0.14% (standard error [SE] 0.054; 95% confidence interval [CI] 0.033, 0.244) for MYL-1501D and 0.11% (SE 0.054; 95% CI 0.007, 0.220) for reference insulin glargine. MYL-1501D had a safety profile similar to that of reference insulin glargine and was well tolerated in patients with T1DM up to week 52. CONCLUSIONS The upper 95% CI limit for mean change in HbA1c at week 24 indicated that MYL-1501D was non-inferior to reference insulin glargine. There were no clinically meaningful differences between groups in incidence of overall and nocturnal hypoglycaemia, local or systemic reactions, safety or immunogenicity.
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Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes.
Seino, Y, Terauchi, Y, Osonoi, T, Yabe, D, Abe, N, Nishida, T, Zacho, J, Kaneko, S
Diabetes, obesity & metabolism. 2018;(2):378-388
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AIMS: To assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D). METHODS In this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks. RESULTS Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin -1.13%, 95% confidence interval [CI] -1.32; -0.94, and -1.44%, 95% CI -1.63; -1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD -2.22 kg, 95% CI -3.02; -1.42 and -3.88 kg, 95% CI -4.70; -3.07; both P < .0001). CONCLUSIONS In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon-like peptide-1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin.
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Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial.
Pratley, RE, Eldor, R, Raji, A, Golm, G, Huyck, SB, Qiu, Y, Sunga, S, Johnson, J, Terra, SG, Mancuso, JP, et al
Diabetes, obesity & metabolism. 2018;(5):1111-1120
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AIM: To evaluate the efficacy and safety of ertugliflozin and sitagliptin co-administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. METHODS In this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. RESULTS At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (-1.5%) and E15/S100 (-1.5%) than with individual agents (-1.0%, -1.1% and -1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin-treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups. CONCLUSIONS In patients with uncontrolled type 2 diabetes while using metformin, co-administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.
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Metformin extended-release versus immediate-release: An international, randomized, double-blind, head-to-head trial in pharmacotherapy-naïve patients with type 2 diabetes.
Aggarwal, N, Singla, A, Mathieu, C, Montanya, E, Pfeiffer, AFH, Johnsson, E, Zhao, J, Iqbal, N, Bailey, C
Diabetes, obesity & metabolism. 2018;(2):463-467
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This international, randomized, double-blind trial (NCT01864174) compared the efficacy and safety of metformin extended-release (XR) and immediate-release (IR) in patients with type 2 diabetes. After a 4-week placebo lead-in, pharmacotherapy-naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once-daily metformin XR 2000 mg or twice-daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: -0.93% vs -0.96%; -21.1 vs -20.6 mg/dL (-1.2 vs -1.1 mmol/L); -24.7 vs -27.1 mg/dL (-1.4 vs -1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once-daily dosing.
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Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.
Guja, C, Frías, JP, Somogyi, A, Jabbour, S, Wang, H, Hardy, E, Rosenstock, J
Diabetes, obesity & metabolism. 2018;(7):1602-1614
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AIMS: To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin. METHODS This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose. RESULTS Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events. CONCLUSIONS Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.
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Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4).
Home, PD, Bergenstal, RM, Bolli, GB, Ziemen, M, Rojeski, M, Espinasse, M, Riddle, MC
Diabetes, obesity & metabolism. 2018;(1):121-128
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AIMS: Insulin glargine 300 U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla-100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM). METHODS EDITION 4 was a 6-month, multicentre, randomized, open-label phase 3 study. People with T1DM who completed the 6 months continued randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6 months. RESULTS Among 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, -0.13 to 0.17]) %-units [0.2 (-1.5 to 1.9) mmol/mol]), to a mean of 7.86 %-units (62.4 mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12 months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning group than in the Gla-300 evening group (difference, -0.25 [-0.47 to -0.04] %-units [-2.7 (-5.2 to -0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla-300 than with Gla-100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups. CONCLUSIONS In T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day.