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    Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. Montvida Olga,Shaw Jonathan,Atherton John J,Stringer Frances,Paul Sanjoy K Diabetes care OJBECTIVE:To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS:Patients with type 2 diabetes aged 18-80 years, who initiated any ADD, were selected ( = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, = 357,482); the third-line therapy choices were further explored. RESULTS:From 2005 to 2016, first-line use increased for metformin (60-77%) and decreased for sulfonylureas (20-8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60-46%), it remained the most popular second ADD choice. Use increased for insulin (7-17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4-21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, < 0.05). CONCLUSIONS:Most patients initiate second-line therapy at elevated HbA levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas. 10.2337/dc17-1414
    Pioglitazone versus sulfonylureas: cardiovascular outcomes with older diabetes drugs. Fonseca Vivian A,Lovre Dragana The lancet. Diabetes & endocrinology 10.1016/S2213-8587(17)30320-0
    Oral Hypoglycemic Agents Added to Insulin Monotherapy for Type 2 Diabetes. Vos Rimke C,Rutten Guy E H M JAMA CLINICAL QUESTION:Among patients with type 2 diabetes mellitus who do not achieve optimal glycemic control with insulin monotherapy, is the addition of oral hypoglycemic agents associated with benefits (measured by lowering of hemoglobin A1c) or adverse effects? BOTTOM LINE:Adding a sulfonylurea to insulin was associated with more hypoglycemic events compared with insulin alone, but this association was not observed for metformin. Adding a sulfonylurea or metformin to insulin was associated with a decrease in hemoglobin A1c of approximately 1.0%. 10.1001/jama.2017.13463
    Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. Douros Antonios,Dell'Aniello Sophie,Yu Oriana Hoi Yun,Filion Kristian B,Azoulay Laurent,Suissa Samy BMJ (Clinical research ed.) OBJECTIVE:To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes. DESIGN:Population based cohort study. SETTING:General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS:Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. MAIN OUTCOME MEASURES:Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes. RESULTS:Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia. CONCLUSIONS:Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching. 10.1136/bmj.k2693
    Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. Rosenstock Julio,Allison Dale,Birkenfeld Andreas L,Blicher Thalia Marie,Deenadayalan Srikanth,Jacobsen Jacob Bonde,Serusclat Pierre,Violante Rafael,Watada Hirotaka,Davies Melanie, JAMA Importance:Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective:To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants:Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions:Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures:The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results:Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance:Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration:ClinicalTrials.gov Identifier: NCT02607865. 10.1001/jama.2019.2942
    Dapagliflozin Plus Saxagliptin Add-on Therapy Compared With Insulin in Patients With Type 2 Diabetes Poorly Controlled by Metformin With or Without Sulfonylurea Therapy: A Randomized Clinical Trial. Vilsbøll Tina,Ekholm Ella,Johnsson Eva,Dronamraju Nalina,Jabbour Serge,Lind Marcus Diabetes care OBJECTIVE:This study evaluated whether an oral combination of a sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase 4 inhibitor achieved glycemic control similar to basal insulin in patients with type 2 diabetes, poorly controlled with metformin, without increasing hypoglycemia or body weight. RESEARCH DESIGN AND METHODS:In a multinational, open-label, randomized, phase 3 trial (ClinicalTrials.gov reg. no. NCT02551874), adults with type 2 diabetes inadequately controlled on metformin, with or without sulfonylurea, were randomized (1:1) to receive dapagliflozin (DAPA) plus saxagliptin (SAXA) or titrated insulin glargine (INS). The primary end point was change in glycated hemoglobin A (HbA) from baseline to week 24. DAPA + SAXA treatment was tested for noninferiority versus INS. RESULTS:The efficacy data set included 643 patients (mean ± SD HbA, 9.1 ± 1.0% [75 ± 11 mmol/mol]). At week 24, DAPA + SAXA treatment versus INS resulted in noninferior reductions in HbA (adjusted mean ± SE change, -1.7 ± 0.1% vs. -1.5 ± 0.1% [18.3 ± 0.7 mmol/mol vs. 16.8 ± 0.7 mmol/mol]; = 0.118), significantly different body weight change (between-group difference, -3.64 kg [95% CI -4.20 to -3.09]; < 0.001), fewer patients with confirmed hypoglycemia (21.3% vs. 38.4%, < 0.001), more patients achieving HbA <7.0% (53 mmol/mol) without hypoglycemia (20.9% vs. 13.1%, = 0.008), and a similar proportion of patients achieving HbA <7.0% (33.2% vs. 33.5%, = 0.924). Mean reductions in 24-h glucose measurements from baseline to week 2 were greater with DAPA + SAXA than with INS ( < 0.0001). No patients in the DAPA + SAXA group and three patients (0.9%) in the INS group experienced severe hypoglycemia. CONCLUSIONS:Adding DAPA + SAXA to insulin-naive patients with poorly controlled type 2 diabetes achieved similar glycemic control, a lower risk of hypoglycemia, and a clinically relevant body weight difference compared with basal INS. 10.2337/dc18-1988
    β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion. Barella Luiz F,Rossi Mario,Zhu Lu,Cui Yinghong,Mei Fang C,Cheng Xiaodong,Chen Wei,Gurevich Vsevolod V,Wess Jürgen The Journal of clinical investigation Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs. 10.1172/JCI126309