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Aim: To synthesize the evidence on the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adolescents with overweight or obesity., Materials and Methods: For this systematic review and network meta-analysis, we searched five databases and registries until 2 March 2024 for eligible randomized controlled trials (RCTs). The primary outcome was weight change. We did a pairwise meta-analysis to compare GLP-1RAs and placebo, followed by a drug-wise network meta-analysis (NMA) to compare GLP-1RAs against each other., Results: We screened 770 records to include 12 RCTs with 883 participants. The evidence suggests that GLP-1RAs reduced weight (mean difference -4.21 kg, 95% confidence interval [CI] -7.08 to -1.35) and body mass index (BMI; mean difference -2.11 kg/m 2 , 95% CI -3.60 to -0.62). The evidence on waist circumference, body fat percentage and adverse events (AEs) was very uncertain. The results remained consistent with subgroup analyses for coexisting type 2 diabetes. Longer therapy duration led to a greater reduction in weight and BMI. In the NMA, semaglutide led to the greatest weight reduction, followed by exenatide, liraglutide and lixisenatide., Conclusions: The evidence suggests that GLP-1RAs reduce most weight-related outcomes in adolescents, with semaglutide being the most efficacious. There is uncertain evidence on body fat and serious AEs, probably due to fewer studies and low incidence, respectively. Larger RCTs with head-to-head comparisons, pragmatic design, adiposity-related outcomes, and economic evaluation can further guide the use and choice of GLP-1RAs., (© 2024 John Wiley & Sons Ltd.)

Aim: To assess the differential association of risk factors with severe and non-severe hypoglycaemia., Materials and Methods: The Hypoglycaemia Assessment Tool study evaluated the risk of hypoglycaemia over a 4-week period in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) on insulin in 24 countries. Negative binomial regressions were applied to examine the associations of several risk factors with severe and non-severe hypoglycaemia., Results: The median age was 41 years in 5949 patients with T1D and 62 years in 12 914 patients with T2D. The 4-week rates of non-severe hypoglycaemic were 5.57 and 1.40 episodes per person in T1D and T2D, respectively; the corresponding rates for severe hypoglycaemia were 0.94 and 0.30. The excess risk was 42% higher for severe than non-severe hypoglycaemia in females versus males with T2D; 27% higher in patients with T2D with versus without a continuous glucose monitoring (CGM); and 47% lower in patients with T1D with versus without an insulin pump. The excess risk also differed across geographical areas and was marginally lower for severe than non-severe hypoglycaemia for higher values of HbA1c in patients with T2D. Associations with severity of hypoglycaemia were not different for age, diabetes and insulin therapy duration, previous hypoglycaemic episodes and insulin regimen., Conclusions: The risk of severe versus non-severe hypoglycaemia differs in patients with T1D and T2D; sex, the use of a CGM and insulin pump, and geographical areas were differently associated with one type of hypoglycaemia than the other., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: We aimed to determine the macrovascular and microvascular outcomes of intensive versus standard glucose-lowering strategies in type 2 diabetes (T2D) and investigate the relationships between these outcomes and trial arm glycated haemoglobin (HbA1c) reduction., Materials and Methods: In this systematic review and meta-analysis, we identified relevant trials from MEDLINE, Embase, the Cochrane Library, and bibliographies up to August 2023. Macrovascular and microvascular outcomes, along with safety outcomes, were evaluated. Pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and meta-regression was employed to analyse the relationships between outcomes and HbA1c reduction., Results: We included 11 unique RCTs involving 51 469 patients with T2D (intensive therapy, N = 26 691; standard therapy, N = 24 778). Intensive versus standard therapy reduced the risk of non-fatal myocardial infarction (MI) (HR 0.84; 95% CI 0.75-0.94) with no difference in the risk of major adverse cardiovascular events (HR 0.97; 95% CI 0.92-1.03) and other adverse cardiovascular outcomes. Intensive versus standard therapy reduced the risk of retinopathy (HR 0.85; 0.78-0.93), nephropathy (HR 0.71; 0.58-0.87) and composite microvascular outcomes (HR 0.88; 0.77-1.00). Meta-regression analyses showed modest evidence of inverse linear relationships between HbA1c reduction and the outcomes of major adverse cardiovascular events, non-fatal MI, stroke and retinopathy, but these were not statistically significant., Conclusions: In people with T2D, intensive glucose control was associated with a reduced risk of non-fatal MI and several microvascular outcomes, particularly retinopathy and nephropathy. The lack of an effect of intensive glucose-lowering on most macrovascular outcomes calls for a more comprehensive approach to managing cardiovascular risk factors alongside glycaemic control., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice., Design: Cohort study emulating a comparative effectiveness trial (target trial)., Setting: Linked primary care, hospital, and death data in England, 2015-21., Participants: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin., Main Outcome Measures: Primary outcome was absolute change in glycated haemoglobin A 1c (HbA 1c ) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA 1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures., Results: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA 1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA 1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43)., Conclusions: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA 1c , BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure ( v DPP-4 inhibitors) and kidney disease progression ( v sulfonylureas), with no evidence of differences in other clinical endpoints., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institute for Health and Care Research (NIHR). AIA receives salary from the NIHR Biomedical Research Centre via the Oxford Centre for Diabetes, Endocrinology and Metabolism. AB is an economic advisor on the DiRECT trial, with ongoing responsibility for economic analysis during the long term follow-up phase. He serves as a consultant to Salutis Consulting on projects not related to diabetes. JWB has acted as a consultant to AstraZeneca, Bayer, Novartis, and Roche. DN is the UK Kidney Association Director of Informatics Research; she previously was involved in two GSK funded studies in sub-Saharan Africa unrelated to this work. PC sat on an NIHR Health Technology Assessment commissioning committee until September 2021. AHB has acted as consultant to several pharmaceutical companies within the past three years: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Idorsia, Novo Nordisk, Rhythm, Roche, and Sanofi. IJD has unrestricted research grants from and shares in GSK and a research grant from AstraZeneca. KK has acted as a consultant and speaker or received grants for investigator initiated studies for AstraZeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp and Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche, and Applied Therapeutics., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies., Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014-2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined., Findings: Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions., Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors., Competing Interests: Declaration of Competing Interest Avraham Karasik has received research grants and consulting fees from Boehringer Ingelheim; research grants from Astra Zeneca; research grants, consulting fees, and speaker fees from Novo Nordisk. Daisuke Yabe has received consulting/lecture fees from Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Company Limited, and grants from Arkray Inc., Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd., Taisho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, and Terumo Corporation. Dae Jung Kim has received grants support from Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis Korea, Jeil Pharmaceutical, and Chong Kun Dang, speaker fees from Boehringer-Ingelheim, Novo Nordisk, Boryung, Hanmi, Novartis, Donga ST, Celltrion, AstraZeneca, and Dong Wha Pharmaceuticals. Wayne HH Sheu has been an advisor and/or speaker for AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda Pharmaceutical Company. Kamlesh Khunti has acted as a consultant, speaker or received consultation/lecture grants for investigator-initiated studies for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, and Merck Sharp & Dohme, Boehringer Ingelheim, Bayer. Francesco Zaccardi has received speaker fees from Boehringer Ingelheim and Napp Pharmaceuticals. Thomas Nyström has received unrestricted grants from AstraZeneca and NovoNordisk and has been a national advisor of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. Leo Niskanen has received speaker and consulting fees from Boehringer Ingelheim, MSD, AstraZeneca, and Sanofi, research grant to the institution, consulting fees, and speaker fees from Novo Nordisk. Majken Linnemann Jensen, Fabian Hoti, Riho Klement are employees of IQVIA and contracted by Boehringer Ingelheim to conduct the analyses. Soulmaz Fazeli Farsani, Anouk Déruaz-Luyet are employees of Boehringer Ingelheim International GmbH. Moe H Kyaw was employee of Boehringer Ingelheim. Lisette Koeneman is employee of Eli Lilly & Company and owns stock of Eli Lilly & Company. Dorte Vistisen has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S, and Boehringer Ingelheim. She holds shares in Novo Nordisk A/S. Sigrun Halvorsen has received speaker fees from Sanofi, Novartis, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb. Gisle Langslet has received consulting/lecture fees from Amgen, Sanofi, and Boehringer Ingelheim. Elisabetta Patorno has received a research grant from Boehringer Ingelheim. Julio Núñez reports personal fees from AstraZeneca, Novartis, Boehringer-Ingelheim, Eli Lilly, Rovi, Novo Nordisk, and Vifor Pharma (outside the submitted work). Stefanie Lanzinger, Reinhard W Holl, Elise Chia-Hui Tan, Cheli Melzer-Cohen, Kyong Hwa, Bendix Carstensen: None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce body weight and improve cardiometabolic health, but their effect on physical activity is unknown., Research Design and Methods: We pooled data (n = 148) from three randomized trials to investigate the effect of empagliflozin (SGLT2i) and liraglutide (GLP-1RA), in comparison with sitagliptin (dipeptidyl peptidase 4 inhibitor) and dietary therapies, on accelerometer-assessed physical activity., Results: Liraglutide (mean -1,144 steps/day; 95% CI -2,069 to -220), empagliflozin (-1,132 steps/day; -1,739, -524), and sitagliptin (-852 steps/day; -1,625, -78) resulted in reduced total daily physical activity after 6 months (P < 0.01 vs. control). Moderate- to vigorous-intensity physical activity was also reduced. Dietary interventions led to no change or an increase in physical activity., Conclusions: The initiation of all glucose-lowering therapies was associated with reduced physical activity, warranting further investigation., (© 2022 by the American Diabetes Association.)

Aim: To evaluate the efficacy and safety of the initial combination therapy versus a stepwise approach in newly diagnosed type 2 diabetes (T2D) by conducting a systematic review and meta-analysis of observational cohort studies and randomized controlled trials (RCTs)., Methods: Studies were identified from MEDLINE, Embase, the Cochrane Library, and through search of bibliographies to January 2022. Study-specific risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system., Results: Eight articles including four unique RCTs (n = 5527 participants) and one observational cohort study (n = 200) that compared initial combination therapy versus stepwise therapy were included. The RR for myocardial infarction comparing initial combination therapy versus stepwise therapy was 1.21 (95% CI 0.74-2.00). Initial combination therapy reduced levels of fasting plasma glucose and glycated haemoglobin: mean differences -0.97 mmol/L (95% CI -1.41, -0.53) and -24.92 mmol/mol (95% CI -25.67, -24.27), respectively. Initial combination therapy versus stepwise therapy reduced lipid levels, blood pressure and intima media thickness, with no differences in body composition variables, neuropathy, retinopathy or adverse events. Single-study results showed that initial combination therapy reduced creatinine levels and urine albumin excretion rate. The quality of the evidence ranged from moderate to very low., Conclusions: Except for improving cardiometabolic and glycaemic variables, a limited number of studies characterized by small sample sizes show that initial combination therapy for newly diagnosed T2D may be similar in efficacy and safety to stepwise therapy with respect to cardio-renal outcomes. There is a lack of sufficient evidence to recommend initial combination therapy with glucose-lowering agents in newly diagnosed T2D with the aim of preventing cardio-renal outcomes. Definitive RCTs are warranted., (© 2022 John Wiley & Sons Ltd.)

Aims: To compare the cardiovascular, renal and safety outcomes of second-line glucose-lowering agents used in the management of people with type 2 diabetes., Methods: MEDLINE, EMBASE and CENTRAL were searched from inception to 13 July 2021 for randomised controlled trials comparing second-line glucose lowering therapies with placebo, standard care or one another. Primary outcomes included cardiovascular and renal outcomes. Secondary outcomes were non-cardiovascular adverse events. Risk ratios (RRs) and corresponding confidence intervals (CI) or credible intervals (CrI) were reported within pairwise and network meta-analysis. The quality of evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria. Number needed to treat (NNT) and number needed (NNH) to harm were calculated at 5 years using incidence rates and RRs. PROSPERO (CRD42020168322)., Results: We included 38 trials from seven classes of glucose-lowering therapies. Both sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) showed moderate to high certainty in reducing risk of 3-point major adverse cardiovascular events, 3P-MACE (network estimates: SGLT2i [RR 0.90; 95% CrI 0.84-0.96; NNT, 59], GLP1RA [RR 0.88; 95% CrI 0.83-0.93; NNT, 50]), cardiovascular death, all-cause mortality, renal composite outcome and macroalbuminuria. SGLT2i also showed high certainty in reducing risk of hospitalization for heart failure (hHF), ESRD, acute kidney injury, doubling in serum creatinine and decline in eGFR. GLP1RA were associated with lower risk of stroke (high certainty) while glitazone use was associated with an increased risk of hHF (very low certainty). The risk of developing ESRD was lower with the use of sulphonylureas (low certainty). For adverse events, sulphonylureas and insulin were associated with increased hypoglycaemic events (very low to low certainty), while GLP1RA increased the risk of gastrointestinal side effects leading to treatment discontinuation (low certainty). DPP-4i increased risk of acute pancreatitis (low certainty). SGLT2i were associated with increased risk of genital infection, volume depletion (high certainty), amputation and ketoacidosis (moderate certainty). Risk of fracture was increased with the use of glitazones (moderate certainty)., Conclusions: SGLT2i and GLP1RA were associated with lower risk for different cardiorenal end points, when used as an adjunct to metformin in people with type 2 diabetes. Additionally, SGLT2i demonstrated benefits in reducing risk for surrogate end points in kidney disease progression. Safety outcomes differ among the available pharmacotherapies., (© 2021 Diabetes UK.)

Aims: To review and synthesise the contemporary qualitative evidence, relating to the individual, healthcare professional and system-level barriers and facilitators to injectable therapies in people with type 2 diabetes, and evaluate (using an intersectional approach to explore the diverse perspectives of different identities) whether views have changed with treatment and guideline advancements., Methods: A meta-ethnography approach used. Eight databases searched from the years 2006 (GLP-1 analogues introduced) to February 2021. Study selection (using a pre-defined inclusion criteria), quality appraisal and data extraction, conducted independently by two reviewers., Results: Screened 7143 abstracts, assessed 93 full-text papers for eligibility and included 42 studies-using data from 818 individuals with type 2 diabetes and 160 healthcare professionals. Studies covered a diverse range of views from healthcare professionals and individuals, including those relating to older adults and people from ethnic migrant backgrounds, and 10 studies rated moderate to strong research value. Key themes abstracted: barriers (physical/psychological/social) and facilitators (motivation/capability/opportunity)., Conclusions: The first synthesis of contemporary qualitative data to adopt an intersectionality approach and explore diverse views relating to barriers and facilitators that influence engagement with injectable treatments for type 2 diabetes. A model is presented to help patients, health practitioners and policy makers identify barriers and facilitators and understand the complex interplay of physical, psychological and social factors involved when prescribing injectable therapies. Despite advances in injectable treatments and guidelines, findings highlight the many barriers that still exist and show how strongly held culturally-specific health beliefs of people from diverse socio-economic and ethnic backgrounds can become substantial obstacles to treatment., (© 2021 Diabetes UK.)

The aims of our study was compare adherence measured by the medical possession ratio (MPR), time until discontinuation and describe adverse events after adding a DPP-4i, SGLT-2i, or sulfonylureas (SU) to metformin in a primary care population with insufficient glycemic control. We used routinely-collected health data from the SIDIAP database. The included subjects were matched by propensity score. The follow-up period was up to 24 months or premature discontinuation. The primary outcomes were the percentage of subjects with good adherence, treatment discontinuation and adverse events among treatment groups. The proportion of patients with good adherence (MPR> 0.8) after the addition of DPP-4i, SGLT-2i or SU was 53.6%, 68.7%, and 43.0%, respectively. SGLT-2i users were 1.7 times more likely to achieve good adherence compared with DPP-4i users (odds ratio [OR]:1.72, 98% confidence interval [CI]:1.51, 1.96), and 2.8 times more likely compared with SU users (OR: 0.35, 98% CI: 0.07, 0.29). The discontinuation hazard ratios were 1.43 (98%CI: 1.26; 1.62) and 1.60 (98%CI: 1.42; 1.81) times higher among SGLT-2i and SU users than DPP-4i users during the follow-up period. No differences were observed for adverse events among the treatment groups. In conclusion, in our real-world setting, the combination of SGLT-2i with metformin was associated with better adherence. The mean time until discontinuation was longer in the SGLT-2i group in comparison with the DPP-4i or SU groups., Competing Interests: MM-C has received an advisory and or speaking fees from Astra-Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi. JF-N has received advisory and or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, and Boehringer. DM has received advisory and/or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, and Boehringer. KK has acted as a consultant, speaker or received grants for investigator-initiated studies for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Berlin-Chemie AG/Menarini Group, Janssen, and Napp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vlacho, Mata-Cases, Mundet-Tudurí, Vallès-Callol, Real, Farre, Cos, Khunti, Mauricio and Franch-Nadal.)

Background: In patients with type 2 diabetes, hyperglycaemia is an independent risk factor for COVID-19-related mortality. Associations between pre-infection prescription for glucose-lowering drugs and COVID-19-related mortality in people with type 2 diabetes have been postulated but only investigated in small studies and limited to a few agents. We investigated whether there are associations between prescription of different classes of glucose-lowering drugs and risk of COVID-19-related mortality in people with type 2 diabetes., Methods: This was a nationwide observational cohort study done with data from the National Diabetes Audit for people with type 2 diabetes and registered with a general practice in England since 2003. Cox regression was used to estimate the hazard ratio (HR) of COVID-19-related mortality in people prescribed each class of glucose-lowering drug, with covariate adjustment with a propensity score to address confounding by demographic, socioeconomic, and clinical factors., Findings: Among the 2 851 465 people with type 2 diabetes included in our analyses, 13 479 (0·5%) COVID-19-related deaths occurred during the study period (Feb 16 to Aug 31, 2020), corresponding to a rate of 8·9 per 1000 person-years (95% CI 8·7-9·0). The adjusted HR associated with recorded versus no recorded prescription was 0·77 (95% CI 0·73-0·81) for metformin and 1·42 (1·35-1·49) for insulin. Adjusted HRs for prescription of other individual classes of glucose-lowering treatment were as follows: 0·75 (0·48-1·17) for meglitinides, 0·82 (0·74-0·91) for SGLT2 inhibitors, 0·94 (0·82-1·07) for thiazolidinediones, 0·94 (0·89-0·99) for sulfonylureas, 0·94 (0·83-1·07) for GLP-1 receptor agonists, 1·07 (1·01-1·13) for DPP-4 inhibitors, and 1·26 (0·76-2·09) for α-glucosidase inhibitors., Interpretation: Our results provide evidence of associations between prescription of some glucose-lowering drugs and COVID-19-related mortality, although the differences in risk are small and these findings are likely to be due to confounding by indication, in view of the use of different drug classes at different stages of type 2 diabetes disease progression. In the context of the COVID-19 pandemic, there is no clear indication to change prescribing of glucose-lowering drugs in people with type 2 diabetes., Funding: None., Competing Interests: Declaration of interests KK, NH, PKn, PKa, NS, BY, and JV are members of the NDA research committee. KK has been a consultant and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, and Merck Sharp & Dohme (MSD); has received grants in support of investigator-initiated studies from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, MSD, Pfizer, and Boehringer Ingelheim; and has served on advisory boards for Novo Nordisk, Sanofi-Aventis, Lilly, and MSD. FZ has been a speaker for Napp Pharmaceuticals and Boehringer Ingelheim. CB is an adviser to the NHS England and NHS Improvement Diabetes Prevention Programme. NH is funded by Diabetes UK and NHS England and NHS Improvement. PKa is national specialty adviser for diabetes and obesity at NHS England and NHS Improvement. NS has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi; and has received grant support from Boehringer Ingelheim. BY is clinical lead for the NDA and a trustee of Diabetes UK. JV is the national clinical director for diabetes and obesity at NHS England and NHS Improvement. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Diabetes has emerged as an important risk factor for mortality from COVID-19. Metformin, the most commonly prescribed glucose-lowering agent, has been proposed to influence susceptibility to and outcomes of COVID-19 via multiple mechanisms. We investigated whether, in patients with diabetes, metformin is associated with susceptibility to COVID-19 and its outcomes., Research Design and Methods: We performed a propensity score-matched cohort study with active comparators using a large UK primary care dataset. Adults with type 2 diabetes patients and a current prescription for metformin and other glucose-lowering agents (MF+) were compared to those with a current prescription for glucose-lowering agents that did not include metformin (MF-). Outcomes were confirmed COVID-19, suspected/confirmed COVID-19, and associated mortality. A negative control outcome analysis (back pain) was also performed., Results: There were 29 558 and 10 271 patients in the MF+ and MF- groups, respectively, who met the inclusion criteria. In the propensity score-matched analysis, the adjusted hazard ratios for suspected/confirmed COVID-19, confirmed COVID-19, and COVID-19-related mortality were 0.85 (95% CI 0.67, 1.08), 0.80 (95% CI 0.49, 1.30), and 0.87 (95% CI 0.34, 2.20) respectively. The negative outcome control analysis did not suggest unobserved confounding., Conclusion: Current prescription of metformin was not associated with the risk of COVID-19 or COVID-19-related mortality. It is safe to continue prescribing metformin to improve glycemic control in patients with., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To present the longer-term impact of multifactorial treatment of type 2 diabetes on self-reported health status, diabetes-specific quality of life, and diabetes treatment satisfaction at 10-year follow up of the ADDITION-Europe trial., Methods: The ADDITION-Europe trial enrolled 3057 individuals with screen-detected type 2 diabetes from four centres [Denmark, the UK (Cambridge and Leicester) and the Netherlands], between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10-year follow-up was performed at the end of 2014. We measured self-reported health status (36-item Short-Form Health Survey and EQ-5D), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed-effects model was applied to estimate the effect of intensive treatment (intention-to-treat analyses) on patient-reported outcome measures for each centre. Centre-specific estimates were pooled using a fixed effects meta-analysis., Results: There was no difference in patient-reported outcome measures between the routine care and intensive treatment arms in this 10-year follow-up study [EQ-5D: -0.01 (95% CI -0.03, 0.01); Physical Composite Score (36-item Short-Form Health Survey): -0.27 (95% CI -1.11, 0.57), Audit of Diabetes-Dependent Quality of Life questionnaire: -0.01 (95% CI -0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: -0.20 (95% CI -0.70, 0.29)]., Conclusions: Intensive, multifactorial treatment of individuals with screen-detected type 2 diabetes did not affect self-reported health status, diabetes-specific quality of life, or diabetes treatment satisfaction at 10-year follow-up compared to routine care., (© 2020 Diabetes UK.)

Objectives: To evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme., Design: DISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019., Setting: Primary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations., Participants: A total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy., Primary and Secondary Outcome Measures: The proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change., Results: Of the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe., Conclusions: A substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes., Trial Registration Numbers: NCT02322762 and NCT02226822., Competing Interests: Competing interests: KK, MBG, MK, AN, SP, WR, MVS, IS, HW and LJ are members of the DISCOVER Scientific Committee and received financial support from AstraZeneca to attend DISCOVER planning and update meetings. HC and PF are employees of AstraZeneca. NH is a former employee of AstraZeneca. JC-R is an employee of Evidera. In addition, KK has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda, Servier and Pfizer, and research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Pfizer, and also acknowledges support from the National Institute for Health Research Collaboration for Applied Research Collaboration—East Midlands (NIHR ARC—EM) and the National Institute of Health Research (NIHR) Leicester Biomedical Research Centre. MBG has received honoraria from Merck Serono. MK has received honoraria from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec Systems, Intarcia, Janssen, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi and Vifor, and research support from AstraZeneca and Boehringer Ingelheim. AN has received honoraria from AstraZeneca, Eli Lilly, Medtronic and Novo Nordisk, and research support from Artsana, Dexcom, Novo Nordisk and Sanofi. WR has received research support from Novo Nordisk. MVS has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, Novo Nordisk, Sanofi and Servier, and research support from Novo Nordisk and Sanofi. IS has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho and Takeda Pharmaceutical, and research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Japan Foundation for Applied Enzymology, Japan Science and Technology Agency, Kowa, Kyowa Hakko Kirin, Midori Health Management Center, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Suzuken Memorial Foundation and Takeda Pharmaceutical. HW has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Novo Nordisk, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho and Takeda, and research support from Abbott, Astellas Pharma, AstraZeneca, Bayer, Benefit One Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Johnson & Johnson, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nitto Boseki, Novartis, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, Takeda and Terumo Corp. FT is an employee of the Mid America Heart Institute and has received research support from AstraZeneca. LJ has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda, Sanofi and Roche, and research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche and Sanofi., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: Early-onset adult type 2 diabetes (diagnosed between ages 18 and 39 years) is increasingly prevalent and associated with poor long-term outcomes. We hypothesised that individuals with early-onset adult type 2 diabetes were underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines., Methods: We reviewed the mean age of the study populations recruited to 90 prominent trials in type 2 diabetes, including 37 cardio-renal outcomes trials across a range of pharmacological, non-pharmacological and multifactorial interventions, 28 trials from the phase III programmes of three representative glucose-lowering therapies used routinely in clinical practice (empagliflozin, liraglutide and sitagliptin) and 25 prominent trials of diabetes self-management education and support or intensive lifestyle interventions (diet or supervised exercise training). We then estimated the number of individuals within these trials who were aged between 18 and 39 years., Results: Across all 90 trials, the mean age of 268,978 participants was 63 years (range 51-69 years in individual trials). In 73 trials (81%), <5% of participants were estimated to be aged 18-39 years, despite this age group representing ~15-20% of the adult type 2 diabetes population. Twenty-nine of these trials (32%; total 164,953 participants) excluded individuals below 40 years of age altogether., Conclusions/interpretation: Guidelines for early-onset adult type 2 diabetes are extrapolated predominantly from evidence in older individuals. Strategies to support the participation of individuals with early-onset adult type 2 diabetes in future research are imperative to ensure guidelines for these high-risk individuals are evidence-based.

Aims: Using data from DISCOVER (NCT02322762; NCT02226822), a 3-year, global, observational study programme of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we assessed socioeconomic factors associated with hypoglycaemic events and fear of hypoglycaemia., Methods: Data were collected at baseline (second-line therapy initiation) and 6, 12 and 24 months. Factors associated with experiencing a hypoglycaemic event at baseline or during follow-up were determined using a hierarchical logistic regression model and an interval-censored survival analysis, respectively. Fear of hypoglycaemia was assessed using the hypoglycaemia fear survey-II (HFS-II)., Results: The overall proportion of patients reporting hypoglycaemic events during follow-up was 7.3%; this was higher in middle-income countries than in high-income countries (8.4% vs 5.8%, p < 0.001). Factors associated with an increased risk of hypoglycaemia during follow-up included living in a country with a low gross national income, use of glucose-monitoring equipment and second-line treatment with insulin, meglitinides or sulphonylureas (versus metformin). Experiencing hypoglycaemia was associated with increased HFS-II worry and overall scores., Conclusions: Our results highlight the global inequity in the treatment of type 2 diabetes. Increased risk of hypoglycaemia in middle-income countries may be explained by limited treatment options and may be underestimated because of limited access to glucose-monitoring equipment., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WR, BC, MBG, KK, MK, MVS, HW, IS and LJ are members of the DISCOVER Scientific Committee and received financial support from AstraZeneca to attend DISCOVER planning and update meetings. HC, PF and FS are employees of AstraZeneca. NH is a former employee of AstraZeneca. JC-R is an employee of Evidera. In addition, WR has received research support from Novo Nordisk; BC has received payment from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Takeda; MBG has received honoraria from Merck-Serono; KK has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda, Servier and Pfizer, research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Pfizer, and also acknowledges support from the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC-EM) and the NIHR Leicester Biomedical Research Centre; MK has received honoraria from Applied Therapeutics, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec Systems, Intarcia, Janssen, Novartis, Novo Nordisk, Merck (Diabetes) and Sanofi, and research support from AstraZeneca and Boehringer Ingelheim; MVS has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, Novo Nordisk, Sanofi and Servier, and research support from Novo Nordisk and Sanofi; HW has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Novartis, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho and Takeda, and research support from Abbott, Astellas Pharma, AstraZeneca, Bayer, Benefit One Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Johnson & Johnson, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nitto Boseki, Novartis, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, Takeda and Terumo Corp; IS has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho and Takeda Pharmaceutical, and research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Japan Foundation for Applied Enzymology, Japan Science and Technology Agency, Kowa, Kyowa Hakko Kirin, Midori Health Management Center, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Suzuken Memorial Foundation, and Takeda Pharmaceutical; FT is an employee of the Mid America Heart Institute and has received research support from AstraZeneca; and LJ has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda, Sanofi and Roche, and research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche and Sanofi. OK has no disclosures to declare., (Copyright © 2020. Published by Elsevier B.V.)

Aims: Rising prevalence of non-communicable diseases world-wide has made diabetes an important comorbidity in patients with coronavirus disease-19 (COVID-19). We sought to review the risk, severity and mortality in COVID-19 and its relation to the glycemic control, and role of anti-diabetic agents in patients with diabetes., Methods: A Boolean search was made in PubMed, MedRxiv and Google Scholar database until May 10, 2020 and full articles with supplementary appendix were retrieved using the specific key words related to the topic., Results: There is a high prevalence of diabetes in patients with COVID-19. Patients with diabetes had a significantly more severe variety of COVID-19 and increased mortality, compared to the groups without diabetes. Moreover, poor glycemic control is associated with a significantly higher severe COVID-19 and increased mortality, compared to the well-controlled glycemic groups. No data currently available for or against any anti-diabetic agents in COVID-19., Conclusions: Diabetes, in particular poorly-controlled group is associated with a significantly higher risk of severe COVID-19 and mortality. This calls for an optimal glycemic control and an increased emphasis on future preventative therapies including the vaccination programs for these groups in addition to the traditional risk prevention such as social distancing and self-isolation., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Early initiated and long-term sustained intensive glucose control is associated with a significantly decreased risk of cardiovascular events and all-cause mortality, over and above the well-established decline in the risk of microvascular disease. Based on the recent cardiovascular outcome trial (CVOT) data, this review focuses on the various benefits of the newer medications with their positioning in the treatment algorithm and explores the place of the older medications in the management of type 2 diabetes mellitus (T2DM)., Areas Covered: We searched the literature for glucose-lowering therapies for patients with T2DM. We included CVOTs conducted for newer sulphonylureas, thiazolidinediones, insulin degludec, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists., Expert Opinion: Selection of glucose-lowering therapy in the management of T2DM should be individualized and based on patient characteristics, associated comorbidities, patient preference, affordability and adherence to treatment. In view of the benefits seen in the CVOTs with SGLT2 inhibitors and GLP-1 receptor agonists, these newer classes should be the preferred choice in patients with/without established atherosclerotic cardiovascular disease and chronic kidney disease.

The restricted mean survival time (RMST) has been advocated as an alternative or a supplement to the hazard ratio for reporting the effect of an intervention in a randomized clinical trial. The RMST difference allows quantification of the postponement of an outcome during a specified (restricted) interval and corresponds to the difference between the areas under the 2 survival curves for the intervention and control groups. This article presents examples of the use of the RMST in a research and a clinical context. First, the authors demonstrate how the RMST difference can answer research questions about the efficacy of different treatments. Estimates are presented for the effects of pharmacologic or strategy-driven glucose-lowering interventions for adults with type 2 diabetes from 36 trials and 9 follow-up studies reporting cardiovascular outcomes and mortality. The authors show how these measures may be used to mitigate uncertainty about the efficacy of intensive glucose control. Second, the authors demonstrate how the RMST difference may be used in the setting of a clinical consultation to guide the decision to start or discontinue a treatment. They then discuss the advantages of the RMST over the absolute risk difference, the number needed to treat, and the median survival time difference. They argue that the RMST difference is both easy to interpret and flexible in its application to different settings. Finally, they highlight the major limitations of the RMST, including difficulties in comparing studies of heterogeneous designs and in inferring the long-term effects of treatments using trials of short duration, and summarize the available statistical software for calculating the RMST.

The place of Sulphonylurea based insulin secretagogues in the management of Type 2 diabetes appears as controversial today as it was fifty years ago. Newer therapies are associated with less hypoglycaemia and weight gain than Sulphonylureas but currently cost more and lack assurances which come with long-term exposure. Emergence of recent CVOT data for SGLT-2 inhibitors and GLP-1 receptor agonists is likely to influence therapeutic choices and guidance is now supportive of their earlier use in cases at high risk of cardiovascular disease. Meta-analyses of Sulphonylurea trials have failed to indicate a consistent effect (positive or negative) on cardiovascular disease or mortality, although are limited by the relative scarcity of studies directly reporting these outcomes. The CAROLINA trial is reassuring in demonstrating cardiovascular safety for the Sulphonylurea Glimepiride when compared directly with the DPP-4 inhibitor Linagliptin, suggesting either of these agents would be relatively safe second line options after Metformin in the majority of patients. This review provides a balanced assessment of available Sulphonylurea treatments in the context of current cardiovascular outcome trial data (CVOT) data and hopefully assists informed decision making about the place of these drugs in contemporary glucose lowering practice., (Copyright © 2019. Published by Elsevier B.V.)

Aim: To evaluate treatment data from DISCOVER (NCT02322762 and NCT02226822), a global, prospective, observational study programme of patients with type 2 diabetes initiating a second-line glucose-lowering therapy., Materials and Methods: Data were collected using a standardized case report form. First- and second-line treatments were assessed in 14 668 patients from 37 countries across six regions. Among patients prescribed first-line metformin monotherapy, Firth logistic regression models were used to assess factors associated with second-line treatment choices., Results: The most common first-line therapies were metformin monotherapy (57.9%) and combinations of metformin with a sulphonylurea (14.6%). The most common second-line therapies were combinations of metformin with other agents (72.2%), including dipeptidyl peptidase-4 (DPP-4) inhibitors (25.1%) or sulphonylureas (21.3%). Among patients prescribed first-line metformin monotherapy, the most common second-line therapies were combinations of metformin with a DPP-4 inhibitor [32.8%; across-region range (ARR): 2.4%-51.3%] or a sulphonylurea (30.0%; ARR: 18.3%-63.6%); only a few patients received combinations of metformin with sodium-glucose co-transporter-2 inhibitors (6.7%; ARR: 0.0%-10.8%) or glucagon-like peptide-1 receptor agonists (1.9%; ARR: 0.1%-4.5%). Both clinical and non-medical factors were associated with choice of second-line therapy after metformin monotherapy., Conclusions: Fewer patients than expected received metformin monotherapy at first line, and the use of newer therapies at second line was uncommon in some regions of the world. Patients' socioeconomic status was associated with treatment patterns, suggesting that therapy choices are influenced by cost and access., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: To determine at what glycated haemoglobin (HbA1c) level physicians from eight European countries would initiate insulin in type 2 diabetes, which physician or practice related factors influenced this level and whether physicians would differentiate between a younger uncomplicated patient and an older patient with comorbidities., Design: Cross-sectional study with data from the Guideline Adherence to Enhance Care study., Setting and Participants: 410 physicians from both primary and secondary care from Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands and the UK., Outcome Measures: Physicians were asked at which HbA1c level they would initiate insulin for a young, uncomplicated patient (vignette 1) and for an older, complicated patient (vignette 2). We evaluated differences in HbA1c levels between physicians from different countries using analysis of variance. To identify physician and practice related factors associated with HbA1c level at initiation of insulin, we performed multivariable linear regression. Multiple imputation was used to deal with missing data., Results: In Germany, Ireland, Sweden, the Netherlands and the UK, the HbA1c levels for initiating insulin in vignette 2 (range: 60.0 to 66.0 mmol/mol; 7.6% to 8.2%) were higher than for vignette 1 (range: 57.2 to 64.2 mmol/mol; 7.4% to 8.0%). In multivariable analysis, the HbA1c level at which insulin was initiated only differed between countries (vignette 1): Dutch physicians initiated insulin at a lower HbA1c level compared with Belgium, France and the UK. No physician or practice factors were independently associated with HbA1c level at insulin initiation., Conclusions: When deciding on individualised HbA1c targets for insulin initiation, physicians from five countries took patient's age and comorbidity into account. The HbA1c level at which physicians would initiate insulin therapy differed between countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diabetes in later life is associated with a range of factors increasing the complexity of glycaemic management. This position statement, developed from an extensive literature review of the subject area, represents a consensus opinion of primary care clinicians and diabetes specialists. It highlights many challenges facing older people living with type 2 diabetes and aims to support primary care clinicians in advocating a comprehensive, holistic approach. It emphasises the importance of the wishes of the individual and their carers when determining glycaemic goals, as well as the need to balance intended benefits of treatment against the risk of adverse treatment effects. Its ultimate aim is to promote consistent high-quality care for older people with diabetes., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: To describe the clinical histories and management of adults with type 2 diabetes who were not reaching their target glycated hemoglobin (A1C) levels and to identify barriers to achieving therapeutic goals., Methods: Practice assessment surveys and practice audits were completed by 88 primary care physicians (PCPs) in the Diabetes Mellitus Assessment of Clinical managemenT In ONtario (DM-ACTION) program and by 56 diabetes specialists in the Diabetes Mellitus IMproving PAtient Care in our communiTies (DM-IMPACT) program. The DM-ACTION audit analyzed data from 1,173 adults with A1C levels ≥7.3% who were not prescribed insulin; the DM-IMPACT audit included 135 individuals with similar characteristics., Results: Most PCPs (92%) and specialists (88%) stated that they typically recommend A1C levels of ≤7.0%; more than 90% indicated that they adjusted antihyperglycemic therapy within 3 months if suboptimal A1C targets endured. Among the DM-ACTION patients, the median A1C level was 7.8%; the median time between the last 2 A1C tests was 5 months; 58% were taking ≤2 noninsulin antihyperglycemic agents; and adjustment of glucose-lowering therapy was noted for only 56%. The corresponding values for the DM-IMPACT patients were 8.0%, 4 months, 43% and 68%, respectively. PCPs and specialists attributed patients' factors and patients' adherence as primary causes of poor achievement of guideline-recommended targets. PCPs perceived patients' factors as the predominant barrier to optimizing care, but the specialists believed that therapeutic inertia stems from a wide range and a varied combination of patient-centric factors., Conclusions: Type 2 diabetes remains a health-care challenge in Canada and globally. Primary care physicians and specialists attributed patients' factors as principal obstacles to optimal diabetes management. However, physician-associated therapeutic inertia may also be an important barrier to unmet therapeutic goals., (Copyright © 2018 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Aims: To determine the incidence and severity of self-reported hypoglycaemia in a primary care population with type 2 diabetes. The study also aimed to compare incidence by treatment regimen., Materials and Methods: A prospective observational study in 17 centres throughout the UK was conducted. Recruitment was based on treatment regimen (metformin alone, sulphonylurea-, insulin- or incretin-based therapy). Participants were asked to keep a blood glucose diary and self-report hypoglycaemia episodes [non-severe (self-treated) and severe (requiring external help)] over a 12-month period., Results: Three hundred and twenty-five participants were enrolled, of whom 274 (84%) returned ≥1 monthly diaries. Overall, 39% reported experiencing hypoglycaemia; 32% recorded ≥1 symptomatic, 36% ≥1 non-severe, and 7% ≥1 severe episodes. By treatment, incidence (events per person/year) for any hypoglycaemia type was 4.39 for insulin, 2.34 for sulphonylurea, 0.76 for metformin, and 0.56 for incretin-based therapy. Compared with metformin, risk of non-severe hypoglycaemia was ~3 times higher for participants on sulphonylureas and > 5 times higher for those on insulin [incidence rate ratio (IRR) 3.02 (1.76-5.18), P < 0.001, and IRR 5.96 (3.48-10.2), P < 0.001, respectively]. For severe episodes, the incidence for sulphonylurea (0.09) was similar to metformin (0.07) and incretin-based therapy (0.07); for insulin the risk remained almost 5 times higher than metformin [incidence 0.32; IRR 4.55 (1.28-16.20), P = 0.019]., Conclusions: Hypoglycaemia represents a substantial burden for people with type 2 diabetes. Sulphonylureas and insulin are both associated with a risk of reported non-severe hypoglycaemia, but only insulin with severe episodes. This suggests the importance of the continued use of sulphonylureas in appropriate patients with type 2 diabetes., (© 2019 John Wiley & Sons Ltd.)

Objective: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a new method to objectively and robustly detect nonadherence. We applied this technique to study nonadherence to cardiovascular medications in people with type 2 diabetes (T2DM)., Research Design and Methods: Routine urine samples, received at the time of the annual diabetes review from 228 people with T2DM in primary care, were assessed for adherence by LC-MS/MS., Results: A total of 28.1% patients ( N = 64) were nonadherent to antidiabetic, antihypertensive, and/or lipid-lowering medications. Nonadherence to statins was the highest at 23.7%, and nonadherence to oral hypoglycemic agents was 9.3%. HbA 1c , albumin-to-creatinine ratio, and lipid profiles were significantly higher in the patients who were nonadherent compared with those who were adherent to treatment., Conclusions: This unique study shows that routine urine samples can be used for adherence testing screening by LC-MS/MS and has demonstrated high nonadherence rates especially to statins in people with T2DM. Future intervention studies using LC-MS/MS as a diagnostic/therapeutic tool may help to improve clinical outcomes., (© 2019 by the American Diabetes Association.)

Aims: To describe in a real-world setting the achievement of physician-selected individualized HbA1c targets in individuals with type 2 diabetes, newly or recently initiated with basal insulin, and the association of hypoglycaemia with target achievement., Materials and Methods: A 12-week, prospective, single-arm, observational study of adults with type 2 diabetes, either newly initiated with any basal insulin or start on basal insulin within the preceding 12 months. At enrollment, eligible participants from 28 countries were treated with or without oral antihyperglycaemic drugs and/or GLP-1 receptor agonists., Results: Individualized targets for almost all of the 3139 evaluable participants (99.7%) had been set by their physicians, with 57% of participants having HbA1c targets between 7.0% and <7.5% (53 and <58 mmol/mol). By week 12, 28% and 27% of newly and previously initiated participants, respectively, achieved individualized HbA1c targets with modest average increases in daily insulin dose of 9 and 5 U (0.10 and 0.06 U/kg), respectively, from baseline (14 and 23 U [0.17 and 0.29 U/kg], respectively). Overall, 16% of participants experienced at least one episode of hypoglycaemia. Both the incidence and frequency of hypoglycaemia, but not the severity, were positively associated with a higher likelihood of achieving individualized HbA1c targets (P < 0.05)., Conclusions: In this prospective real-world study, most participants using basal insulin did not achieve the individualized HbA1c targets set by their physicians. Participants who experienced symptomatic hypoglycaemia were more likely to achieve HbA1c targets than those who did not., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To assess glycaemic control after treatment intensification in patients with type 2 diabetes uncontrolled on ≥2 non-insulin antidiabetic drugs (NIADS)., Methods: A retrospective cohort study, using electronic health records from the SIDIAP database (2010-2014), was conducted. Intensification was defined as the prescription of any new antidiabetic drug in patients treated with ≥2 NIADS and HbA1c >7%. The primary outcome was the absolute change in HbA1c 6-12 months after any intensification. Secondary analyses included the percentage of patients reaching HbA1c <7%, HbA1c <8%, and a reduction of HbA1c >1% after the first intensification., Results: There were 21 241 intensifications in 15 205 patients with a mean (SD) HbA1c of 9.02% (±1.35). Insulin and dipeptidyl peptidase-4 inhibitors (DPP4i) were the most frequently added therapies. The mean baseline-adjusted HbA1c reduction was 0.78% (95% CI, -0.80 to -0.76), varying from -0.69% with DPP4i to -0.85% with glucagon-like peptide-1 receptor agonists while the addition of insulin was associated with a reduction >1%. After the first intensification, 48.9% of patients achieved HbA1c <8%, 16.2% HbA1c <7%, and 43.1% a reduction >1%. High previous HbA1c was positively associated with the reduction of HbA1c >1% [odds ratio (OR) 2.13 (95% CI: 2.05-2.21)], but inversely associated with the attainment of HbA1c <7% [OR 0.64 (0.61-0.67)] or < 8% [OR 0.63 (0.60-0.65)]. Older age, male gender, higher Charlson index, and short diabetes duration were associated with achievement of HbA1c <7%., Conclusions: Despite intensification, most patients failed the glycaemic goal of HbA1c <7%. The reduction depended mainly on preintensification HbA1c values, with small differences between drugs., (© 2019 John Wiley & Sons Ltd.)

Background and Aims: The association of beta-blockers and their selectivity with mortality and cardiovascular events in patients with and without hypoglycaemia is unknown., Methods and Results: Insulin-treated patients with diabetes were identified within the UK CPRD database. All-cause deaths, cardiovascular events, and hypoglycaemic episodes were captured to assess the interaction between beta-blocker therapy and selectivity with hypoglycaemia. 13,682 patients, of which 2036 (14.9%) with at least one hypoglycaemic episode, were included; 3148 deaths and 1235 cardiovascular events were recorded during a median of 2.3 and 4.7 years in patients with and without incident hypoglycaemia, respectively. Treatment with any beta-blocker was not associated with risk of death in both patients with and without hypoglycaemia, without significant interaction. Compared to no therapy, non-selective beta-blockers were associated with higher risk of death in patients without hypoglycaemia (hazard ratio (HR) 2.93 [1.26-6.83] in the fully adjusted model) but not in those with hypoglycaemia; interactions was not significant. For beta1-selective beta-blockers, there was no association with mortality in both patients with and without hypoglycaemia, without significant interaction. After missing data imputation, results were consistent for non-selective beta-blockers (HR in patients without hypoglycaemia 1.59 [1.22-2.08]) while indicated a reduced risk of death for beta1-selective beta-blockers in patients with hypoglycaemia (HR 0.76 [0.61-0.94]). Due to few cardiovascular events, complete-case analysis compared only any vs no beta-blocker therapy and indicated no associations with therapy or interaction by hypoglycaemia., Conclusion: In patients with hypoglycaemic episodes, treatment with beta1-selective beta-blockers may potentially reduce the risk of death. These explorative findings and the potential role of confounding by indication need to be evaluated in other studies., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Optimal diabetes care requires clear understanding of the incidence of hypoglycaemia in real-world clinical practice. Current data on hypoglycaemia are generally limited to those reported from randomised controlled clinical trials. The Hypoglycaemia Assessment Tool (HAT) study, a non-interventional real-world study of hypoglycaemia, assessed hypoglycaemia in 27 585 individuals across 24 countries. The present study compared the incidence of hypoglycaemia from the HAT study with other similarly designed, large, real-world studies., Materials and Methods: A literature search of PubMed (1995-2017) for population-based studies of insulin-treated patients with type 1 or type 2 diabetes (T1D, T2D), excluding clinical trials and reviews, identified comparable population-based studies reporting the incidence of hypoglycaemia., Results: The 24 comparative studies, including more than 24 000 participants with T1D and more than 160 000 participants with T2D, varied in design, size, inclusion criteria, definitions of hypoglycaemia and method of recording hypoglycaemia. Reported rates (events per patient-year [PPY]) of hypoglycaemia were higher in patients with T1D than in those with T2D (overall T1D, 21.8-73.3 and T2D, 1.3-37.7; mild/non-severe T1D, 29.0-126.7 and T2D, 1.3-41.5; severe T1D, 0.7-5.8 and T2D, 0.0-2.5; nocturnal T1D, 2.6-11.3 and T2D, 0.38-9.7) and were similar to the ranges found in the HAT study., Conclusions: The HAT data on hypoglycaemia incidence were comparable with those from other real-world studies and indicate a high incidence of hypoglycaemia among insulin-treated patients. Differences in rates among studies are mostly explained by differences in patient populations and study methodology. The goal of reducing hypoglycaemia should be a target for continued educational and evidence-based pharmacological interventions., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To compare the cardiovascular efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with Type 2 diabetes., Methods: Electronic databases were searched from inception to 22 October 2018 for randomized controlled trials designed to assess the cardiovascular efficacy of SGLT2 inhibitors or GLP-1RAs with regard to a three-point composite measure of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular mortality). Cardiovascular and safety data were synthesized using Bayesian network meta-analyses., Results: Eight trials, including 60 082 participants, were deemed eligible for the network meta-analysis. Both SGLT2 inhibitors [hazard ratio 0.86 (95% credible interval 0.74, 1.01]) and GLP-1RAs [hazard ratio 0.88 (95% credible interval 0.78, 0.98)] reduced the three-point composite measure compared to placebo, with no evidence of differences between them [GLP-1RAs vs SGLT2 inhibitors: hazard ratio 1.02 (95% credible interval 0.83, 1.23)]. SGLT2 inhibitors reduced risk of hospital admission for heart failure compared to placebo [hazard ratio 0.67 (95% credible interval 0.53, 0.85)] and GLP-1RAs [hazard ratio 0.71 (95% credible interval 0.53, 0.93)]. No differences were found between the two drug classes in non-fatal stroke, non-fatal myocardial infarction, cardiovascular mortality, all-cause mortality or safety outcomes., Conclusions: SGLT2 inhibitors and GLP-1RAs reduced the three-point major adverse cardiovascular event risk compared to placebo, with no differences between them. Compared with GLP-1RAs and placebo, SGLT2 inhibitors led to a larger reduction in hospital admission for heart failure risk., (© 2019 Diabetes UK.)

The recent introduction of the second-generation long-acting analogue insulins degludec and insulin glargine U300 have increased the choice of basal insulin therapy for patients with type 2 diabetes. The pharmacokinetic and pharmacodynamic properties of these insulins result in a flatter profile that lasts over 24 h and provides an increased window of administration of 6 h once daily. Large-scale multicentre randomised clinical trial programmes (BEGIN for degludec U100 and U200 and EDITION for glargine U300) evaluating these insulin therapies against glargine U100 have demonstrated that they are either non-inferior or superior for glycaemic efficacy and safety, but less likely to result in severe or nocturnal hypoglycaemia than glargine U100. The disposable pen devices for these insulins have been designed with patient satisfaction and convenience in mind. No concerns have arisen with adverse events with insulin analogues or cardiovascular safety from the ORIGIN and DEVOTE trials. As they demonstrate equivalent glycaemic efficacy to other basal insulins, they should be considered more in selected patient groups including those with recurrent or increased risk of hypoglycaemia, especially severe or nocturnal episodes, in the elderly or those living alone, and in patients with multiple co-morbidities such as cardiovascular or renal disease.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are two classes of glucose-lowering drugs gaining popularity in the treatment of type 2 diabetes mellitus (T2DM). Current guidelines suggest patient-centred approaches when deciding between available hyperglycaemia drugs with no indication to which specific drug should be administered. Despite systematic reviews and meta-analyses being conducted within SGLT-2is and GLP-1RAs, differences across these classes of drugs have not been investigated. Therefore, this systematic review and network meta-analysis (NMA) will aim to compare the efficacy and safety profiles across and within SGLT-2is and GLP-1RAs., Methods: PubMed, the Cochrane Central Register of Controlled Trials and ISI Web of Science will be searched from inception for published randomised controlled trials conducted in patients with T2DM, with at least two arms consisting of SGLT-2is, GLP-1RAs or control/placebo. Title and abstracts will be screened by two independent reviewers with conflicts resolved by a third. Data will be extracted by the primary researcher, a random sample will be checked by an independent reviewer. Risk of bias will be assessed using the Cochrane Risk of Bias Tool and overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.Study characteristics, participants baseline characteristics, mean change in cardiometabolic outcomes and number of adverse events will be extracted for each study. Primary outcome will be the mean change in glycated haemoglobin (HbA 1c ) (%, mmol/mol). Initial random-effects pairwise meta-analysis will be conducted for each unique treatment comparison where heterogeneity will be assessed. A Bayesian NMA approach will be adopted where random-effects generalised linear models will be fitted in WinBUGS. Sensitivity analysis will be conducted to assess choices of prior distributions and length of burn-in and sample., Ethics and Dissemination: Ethics approval is not required for this study. Results from this study will be published in a peer-review journal., Prospero Registration Number: CRD42018091306., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To investigate the risk of hypoglycaemia in people aged ≥65 years with type 2 diabetes mellitus (T2DM) treated with linagliptin, in the largest pooled analysis performed to date., Materials and Methods: One thousand four hundred and eighty-nine patients aged ≥65 years with T2DM were pooled from 11 randomised, double-blind, parallel group, placebo-controlled trials evaluating linagliptin 5 mg alone, or in addition to various background therapies. The primary safety endpoint was the incidence of investigator-defined hypoglycaemia., Results: There was no significant difference in the risk of hypoglycaemia between linagliptin and placebo in the all-patient population at 24 weeks (hazard ratio [HR] 1.07; 95% confidence interval [CI]: 0.84, 1.36; P = 0.5943)-despite significant (P < 0.0001) improvements in glycaemic control-and 1 year (HR 1.02; 95% CI: 0.81, 1.27; P = 0.8803). Similar findings were observed for linagliptin vs placebo in subgroup analyses by background medication (eg, sulphonylureas (SUs) and/or insulin vs no such drugs), age, baseline glycated haemoglobin (HbA1c), ethnicity, and baseline estimated glomerular filtration rate. Patients with a baseline HbA1c ≥7.5% had significantly higher odds of achieving HbA1c <7.5% without hypoglycaemia in the linagliptin group compared with placebo at 24 weeks (34.1% vs 13.7%; 95% CI: 2.04, 4.12; P < 0.0001)., Conclusions: This pooled analysis indicates that linagliptin was effective in treating older people with T2DM towards their HbA1c targets with a favourable safety and tolerability profile and low risk of hypoglycaemia. The safety profile was maintained even on background therapies with known risk of hypoglycaemia, such as insulin and SU., (© 2018 John Wiley & Sons Ltd.)

Objective: The goal of this study was to evaluate the association between the timing of treatment intensification and subsequent glycemic control among patients with type 2 diabetes in whom monotherapy fails., Research Design and Methods: This retrospective analysis of the U.K. Clinical Practice Research Datalink database focused on patients with type 2 diabetes and one or more HbA 1c measurements ≥7% (≥53 mmol/mol) after ≥3 months of metformin or sulfonylurea monotherapy (first measurement meeting these criteria was taken as the study index date). Baseline (6 months before the index date) characteristics were stratified by time from the index date to intensification (early: <12 months; intermediate: 12 to <24 months; late: 24 to <36 months). Intensification was defined as initiating after the index date one or more noninsulin antidiabetes medication in addition to metformin or a sulfonylurea. Association between time to intensification and subsequent glycemic control (first HbA 1c <7% [<53 mmol/mol] after intensification) was evaluated using Kaplan-Meier analyses and Cox proportional hazard models that accounted for baseline differences., Results: Of the 93,515 patients who met the study criteria (mean age 60 years; ∼59% male; 80% taking metformin), 23,761 (25%) intensified <12 months after the index date; 11,908 (13%) intensified after 12 to <24 months; and 7,146 (8%) intensified after 24 to <36 months. Patients who intensified treatment ≥36 months after the index date ( n = 9,638 [10%]) and those with no evidence of treatment intensification during the observable follow-up period ( n = 41,062 [44%]) were not included in further analyses. The median times from intensification to control were 20.0, 24.1, and 25.7 months, respectively, for the early, intermediate, and late intensification cohorts. After adjustment for baseline differences, the likelihood of attaining glycemic control was 22% and 28% lower for patients in the intermediate and late intensification groups, respectively, compared with those intensifying early ( P < 0.0001)., Conclusions: Earlier treatment intensification is associated with shorter time to subsequent glycemic control, independent of whether patients initiate first-line treatment with metformin or a sulfonylurea., (© 2018 by the American Diabetes Association.)

Sulphonylureas have been commercially available since the 1950s, but their use continues to be associated with controversy. Although adverse cardiovascular outcomes in some observational studies have raised concerns about sulphonylureas, findings from relatively recent, robust, and high-quality systematic reviews have indicated no increased risk of all-cause mortality associated with sulphonylureas compared with other active treatments. Results from large, multicentre, randomised controlled trials such as the UK Prospective Diabetes Study and ADVANCE have confirmed the microvascular benefits of sulphonylureas, a reduction in the incidence or worsening of nephropathy and retinopathy, and no increase in all-cause mortality, although whether these benefits were due to sulphonylurea therapy and not an overall glucose-lowering effect could not be confirmed. A comparison of sulphonylureas and pioglitazone in the TOSCA.IT trial also confirmed the efficacy and cardiovascular safety of sulphonylureas. Investigators of randomised controlled trials have reported an increased risk of hypoglycaemia and weight gain with sulphonylureas, but data from observational studies suggest that the incidence of severe hypoglycaemia is lower in people taking sulphonylurea than in people taking insulin, and weight gain with sulphonylureas has been relatively modest in large cohort studies. 80% of people with diabetes live in low-to-middle income countries, so the effectiveness, affordability, and safety of sulphonylureas are particularly important considerations when prescribing glucose-lowering therapy. Results of ongoing head-to-head studies with new drugs, such as the comparison of glimepiride with linagliptin in the CAROLINA study and the comparison of various therapies (including sulphonylureas) for glycaemic control in the GRADE study, will determine the place of sulphonylureas in glucose-lowering therapy algorithms for patients with type 2 diabetes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Intensification of metformin monotherapy with additional glucose-lowering drugs is often required in patients with type 2 diabetes (T2D). This study evaluated changes in HbA1c and weight, as well as treatment persistence, associated with different second-line therapies used in UK clinical practice., Methods: The UK Clinical Practice Research Datalink was used to identify patients with T2D who initiated second-line therapy after metformin monotherapy between 1 August 2013 and 14 June 2016. Treatment persistence and changes in HbA1c and weight were assessed at 6-month intervals up to 18 months., Results: In total, 9097 patients (mean age 61.2 years, 57.2% men, mean [standard deviation] HbA1c 9.0% [1.8]/ 75 mmol/mol [19.7]) were included in the analysis, with a median 2.3 years between initiating metformin monotherapy and initiating second-line therapy. Patients were stratified according to second-line therapy: metformin in combination with sulfonylurea (SU; n = 4655 [51.2%]), a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor; n = 2899 [31.9%]), or a sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor; n = 441 [4.9%]) or other therapies (all other second-line treatments; n = 1102 [12.1%]). At 18 months, the cumulative proportion of patients changing treatment was lowest for those who received metformin plus an SGLT-2 inhibitor (42.3%), followed by patients on metformin plus SU or metformin plus a DPP-4 inhibitor (46.8%). HbA1c reductions were seen with all second-line therapies, with an overall mean (standard error) reduction of -1.23% (0.05)/-13.4 mmol/mol (0.5). Changes were directly, but not linearly, related to baseline HbA1c and were greater in those with higher HbA1c at baseline. Weight loss from baseline was greatest in patients treated with metformin plus either an SGLT-2 inhibitor (-4.2 kg) or a DPP-4 inhibitor (-1.5 kg). The highest proportion of patients who achieved the composite outcome of HbA1c reduction ≥ 0.5%, body weight loss ≥ 2.0 kg and treatment persistence for 18 months was observed in those receiving metformin plus an SGLT-2 inhibitor (36.5%)., Conclusions: In this population-based cohort, all second-line therapies added to metformin monotherapy improved glycaemic control, but the lowest treatment change/discontinuation rate and most sustained weight loss was seen with patients receiving metformin plus an SGLT-2 inhibitor.

Background: We evaluated the antihyperglycemic efficacy and safety of adding the dipeptidyl dipeptidase-4 inhibitor alogliptin to metformin and sulphonylurea in the treatment of type 2 diabetes in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care Trial., Methods: Patients with type 2 diabetes and recent acute coronary syndrome were randomized to alogliptin or placebo and standard of care. Participants were followed for up to 40 (median 18) months. In a subgroup taking metformin and sulphonylurea at baseline, we evaluated change from baseline in glycated hemoglobin (HbA1c), adverse events, cardiovascular outcomes, laboratory data, and other safety parameters., Results: There were 1398 patients receiving baseline dual therapy (metformin and sulphonylurea only) randomized to alogliptin (N = 693) or placebo (N = 705); 550 patients receiving alogliptin and 505 patients receiving placebo completed the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care without addition of other antihyperglycemic therapies (P = .008). Changes from baseline to last visit in HbA1c were -0.4% on alogliptin and +0.1% on placebo (P < .001) in all those with baseline dual therapy and -0.4% for alogliptin and +0.2% for placebo (P < .001) in those without additional therapies. Reported rates of hypoglycemia were 8.8% for alogliptin and 6.7% for placebo (P = .16). Cardiovascular death and all-cause mortality rates were lower in those receiving alogliptin compared with those receiving placebo (hazard ratio, 0.49; 95% confidence interval, 0.28-0.84 and hazard ratio, 0.61; 95% confidence interval, 0.38-0.96, respectively)., Conclusions: Addition of the dipeptidyl peptidase-4 inhibitor alogliptin to dual therapy with metformin plus sulfonylurea significantly reduced HbA1c and was well tolerated. Lower mortality rates were seen in patients treated with alogliptin in this subgroup., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims/hypothesis: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality., Methods: We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time., Results: Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000-2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000-2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA., Conclusions/interpretation: Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia., Data Availability: Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1.

Background: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]., Objective: To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data., Design: A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site., Setting: General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire., Participants: Males and females aged ≥ 40 years with NDH who had a high risk of CVD., Interventions: Prolonged-release metformin (500 mg) (Glucophage ® SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post., Main Outcome Measures: Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life., Results: We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m 2 (SD 4.5 kg/m 2 )] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [-0.82 mmol/mol, 95% confidence interval (CI) -1.39 to -0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m 2 , 95% CI -0.2 to 4.81 ml/minute/1.73 m 2 ) and mean low-density lipoprotein cholesterol level (-0.11 mmol/l, 95% CI -0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B 12 level (-16.4 ng/l, 95% CI -32.9 to -0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related., Limitations: Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts., Conclusions: A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence., Trial Registration: Current Controlled Trials ISRCTN34875079., Funding: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo., Competing Interests: Kamlesh Khunti received honoraria and research grants from AstraZeneca plc, Novartis Pharmaceuticals UK Ltd, Novo Nordisk Ltd, Sanofi S.A., Eli Lilly and Company, Merck Sharp & Dohme Corp., Janssen Research and Development, Boehringer Ingelheim Ltd and Roche Diagnostics Ltd. He has acted as an advisor to the NHS Health Check programme, National Institute for Health and Care Excellence (NICE) Guidance and the Diabetes Prevention Programme External Reference Group. M Angelyn Bethel reports non-financial support from Merck Serono during the conduct of the study. Outside the submitted work, she received grants from Merck Sharp & Dohme Corp. and AstraZeneca, acted as an advisory board member for AstraZeneca, Boehringer Ingelheim and Novo Nordisk, as a speaker for Sanofi and received non-financial support from Bayer plc. Rury R Holman reports ACE (Acarbose Cardiovascular Evaluation) trial funding and lecture fees from Bayer, trial funding from AstraZeneca and Merck Sharp & Dohme Corp. and lecture fees from Boehringer Ingelheim, outside the submitted work. He acted as an advisory board member for Merck, Sharp & Dohme, Elcelyx Therapeutics, Inc., Novartis Pharmaceuticals UK, Novo Nordisk and Servier Laboratories Ltd. Melanie Davies has acted as a consultant, advisory board member and speaker for Novo Nordisk, Sanofi, Eli Lilly and Company, Merck Sharp & Dohme Corp., Boehringer Ingelheim, AstraZeneca and Janssen Research and Development, as an advisory board member for Servier Laboratories and as a speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International, Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim and Janssen Research and Development. She has acted as an advisor to the NHS Health Check programme and the NICE Guidance and is Director of a National Institute for Health Research Biomedical Centre and a Clinical Trials Unit. John R Petrie reports personal fees from Novo Nordisk, Eli Lilly and Company, Janssen Research and Development and Boehringer Ingelheim, grants, personal fees and non-financial support from Sanofi, non-financial support from Merck KGaA and Itamar Medical Ltd, grants from the Juvenile Diabetes Research Foundation Ltd and grants and personal fees from Quintiles (now IQVIA), outside the submitted work. Martin Rutter reports grants from Novo Nordisk, outside the submitted work. He owns stocks and shares in GlaxoSmithKline plc and acted as an advisory board member for Roche Diagnostics Ltd. Naveed Sattar reports personal fees from Boehringer Ingelheim, Janssen Research and Development, Novo Nordisk and Eli Lilly and Company and grants and personal fees from AstraZeneca, outside the submitted work. Simon J Griffin reports receiving an honorarium and reimbursement of travel expenses from Eli Lilly and Company, associated with membership of an Independent Data Monitoring Committee for a randomised trial of a medication to lower glucose levels, and an honorarium from Janssen Research and Development for speaking at an educational meeting in 2015.

Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients' long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: As the therapeutic options in the management of type 2 diabetes increase, there is an increase confusion among health care professionals, thus leading to the phenomenon of therapeutic inertia. This is the failure to escalate or de-escalate treatment when the clinical need for this is required. It has been studied extensively in various settings, however, it has never been reported in any studies focusing solely on primary care physicians with an interest in diabetes. This group is increasingly becoming the focus of managing complex diabetes care in the community, albeit with the support from specialists., Methods: In this retrospective audit, we assessed the prevalence of the phenomenon of therapeutic inertia amongst primary care physicians with an interest in diabetes in UK. We also assessed the predictive abilities of various patient level characteristics on therapeutic inertia amongst this group of clinicians., Results: Out of the 240 patients reported on, therapeutic inertia was judged to have occurred in 53 (22.1%) of patients. The full model containing all the selected variables was not statistically significant, p=0.59. So the model was not able to distinguish between situations in which therapeutic inertia occurred and when it did not occur. None of the patient level characteristics on its own was predictive of therapeutic inertia., Conclusion: Therapeutic inertia was present only in about a fifth of patient patients with diabetes being managed by primary care physicians with an interest in diabetes., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

With the rising incidence and prevalence rates of type 2 diabetes globally, it is imperative that diabetes prevention strategies are implemented to stem the flow of new cases. Successful interventions include both lifestyle modification and pharmaceutical agents, and large, multicentre, randomised, controlled studies in different populations have identified the benefits of both. However, translating positive trial outcomes to the real world is particularly challenging, as lifestyle interventions require regular reinforcement from healthcare professionals to be maintained. Pharmaceutical therapies may therefore play an adjunctive role in combination with lifestyle to prevent diabetes. Population-based strategies are also necessary to reduce sedentary behaviour and obesity. Well-established glucose-lowering therapies such as metformin, sulphonylureas, thiazolidinediones and insulin and newer agents such as incretin therapies and sodium glucose co-transporter 2 inhibitors have all been investigated in randomised controlled trials for diabetes prevention with varying success. Non-glucose-lowering therapies such as orlistat and renin angiotensin system blockers can prevent diabetes, whereas statins are associated with slightly increased risk. Diabetes prevention strategies should carefully consider the use of these agents according to individual patient circumstances and phenotypic profile.

The incretin therapies glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-IV (DPP-IV) inhibitors are now well-established as second and third-line therapies and in combination with insulin for the treatment of type 2 diabetes. Over the last decade, there is accumulating evidence of their efficacy and safety from both large multicentre randomized clinical trials (RCT) and observational studies. Cardiovascular outcome trials have confirmed that several of these agents are also non-inferior to placebo with the GLP-1 RA liraglutide and semaglutide recently found to be superior in terms of major adverse cardiovascular events. Observational studies and post-marketing surveillance provide real world evidence of safety and effectiveness of these agents and have provided reassurance that signals for pancreatitis and pancreatic cancer seen in clinical trials are not of major concern in large patient populations. Well-designed real world studies complement RCTs and systematic reviews but appropriate data and methodologies, which are constantly improving, are necessary to answer appropriate clinical questions relating to the use of incretin therapies., (© 2018 John Wiley & Sons Ltd.)

Aim: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies., Materials and Methods: This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance., Results: Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was -1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, -0.45% per unit increase in HbA1c; HbA1c ≥9%, -0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92-1.09%; P < .001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001])., Conclusions: Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade., Materials and Methods: Systematic searches for articles published from January 1, 2004 to August 1, 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form., Results: The final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low- to middle-income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta-analysis., Conclusions: Therapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)