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To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy.This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values.A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter.Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

OBJECTIVE To explore risks and associated mediation effects of developing chronic kidney disease (CKD) and heart failure (HF) in young- and usual-onset type 2 diabetes (T2D) between White Americans (WAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS From U.S. medical records, 1,491,672 WAs and 31,133 AAs were identified and stratified by T2D age of onset (18–39, 40–49, 50–59, 60–70 years). Risks, mediation effects, and time to CKD and HF were evaluated, adjusting for time-varying confounders. RESULTS In the 18–39, 40–49, 50–59, 60–70 age-groups, the hazard ratios (of developing CKD and HF in AAs versus WAs were 1.21 (95% CI 1.17–1.26) and 2.21 (1.98–2.45), 1.25 (1.22–1.28) and 1.86 (1.75–1.97), 1.21 (1.19–1.24) and 1.54 (1.48–1.60), and 1.10 (1.08–1.12) and 1.11 (1.07–1.15), respectively. In AAs and WAs aged 18–39 years, time in years to CKD (8.7 [95% CI 8.2–9.1] and 9.7 [9.2–10.2]) and HF (10.3 [9.3–11.2] and 12.1 [10.6–13.5]) were, on average, 3.6 and 4.0 and 3.1 and 4.1 years longer compared with those diagnosed at age 60–70 years. Compared with females, AA males aged CONCLUSIONS Developing cardiorenal complications within an average of 10 years of young-onset T2DM and high mediation effects of CKD on HF call for revisiting guidelines on early diagnosis and proactive treatment strategies for effective management of cardiometabolic risk.

International audience; Aim: To identify distinct HbA1c trajectories in people with type 2 diabetes (T2D) starting second-line glucose-lowering therapy.Materials and Methods: DISCOVER was a 3-year observational study of individuals with T2D beginning second-line glucose-lowering therapy. Data were collected at initiation of second-line treatment (baseline) and at 6, 12, 24 and 36 months. Latent class growth modelling was used to identify groups with distinct HbA1c trajectories.Results: After exclusions, 9295 participants were assessed. Four distinct HbA1c trajectories were identified. Mean HbA1c levels decreased between baseline and 6 months in all groups; 72.4% of participants showed stable good levels of glycaemic control over the remainder of follow-up, 18.0% showed stable moderate levels of glycaemic control and 2.9% showed stable poor levels of glycaemic control. Only 6.7% of participants showed highly improved glycaemic control at month 6 and stable control over the rest of follow-up. For all groups, dual oral therapy use decreased over time, compensated for by the increasing use of other treatment regimens. Use of injectable agents increased over time in groups with moderate and poor glycaemic control. Logistic regression models suggested that participants from high-income countries were more probable to be in the stable good trajectory group.Conclusions: Most people receiving second-line glucose-lowering treatment in this global cohort achieved stable good or highly improved long-term glycaemic control. One-fifth of participants showed moderate or poor glycaemic control during follow-up. Further large-scale studies are required to characterize possible factors associated with patterns of glycaemic control to inform personalized diabetes treatment.

We report the prevalence and change in severity of chronic kidney disease (CKD) in DISCOVER, a global, 3-year, prospective, observational study of patients with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy. CKD stages were defined according to estimated glomerular filtration rate (eGFR). Overall, 7843 patients from 35 countries had a baseline serum creatinine measurement. Of these (56.7% male; mean age: 58.1 years; mean eGFR: 87.5 mL/min/1.73m2 ), baseline prevalence estimates for stage 0-1, 2, 3, and 4-5 CKD were 51.4%, 37.7%, 9.4%, and 1.4%, respectively. A total of 5819 patients (74.2%) also had at least one follow-up serum creatinine measurement (median time between measurements: 2.9 years, interquartile range: 1.9-3.0 years). Mean eGFR decreased slightly to 85.7 mL/min/1.73m2 over follow-up. CKD progression (increase of ≥1 stage) occurred in 15.7% of patients, and regression (decrease of ≥1 stage) in 12.0%. In summary, a substantial proportion of patients with T2D developed CKD or had CKD progression after the initiation of second-line therapy. Renal function should be regularly monitored in these patients, to ensure early CKD diagnosis and treatment. This article is protected by copyright. All rights reserved.

Background Real-world data for patients with chronic kidney disease (CKD), specifically pertaining to clinical management, metabolic control, treatment patterns, quality of life (QoL) and dietary patterns, are limited. Understanding these gaps using real-world, routine care data will improve our understanding of the challenges and consequences faced by patients with CKD, and will facilitate the long-term goal of improving their management and prognosis. Methods DISCOVER CKD follows an enriched hybrid study design, with both retrospective and prospective patient cohorts, integrating primary and secondary data from patients with CKD from China, Italy, Japan, Sweden, the UK and the USA. Data will be prospectively captured over a 3-year period from >1000 patients with CKD who will be followed up for at least 1 year via electronic case report form entry during routine clinical visits and also via a mobile/tablet-based application, enabling the capture of patient-reported outcomes (PROs). In-depth interviews will be conducted in a subset of ∼100 patients. Separately, secondary data will be retrospectively captured from >2 000 000 patients with CKD, extracted from existing datasets and registries. Results The DISCOVER CKD program captures and will report on patient demographics, biomarker and laboratory measurements, medical histories, clinical outcomes, healthcare resource utilization, medications, dietary patterns, physical activity and PROs (including QoL and qualitative interviews). Conclusions The DISCOVER CKD program will provide contemporary real-world insight to inform clinical practice and improve our understanding of the epidemiology and clinical and economic burden of CKD, as well as determinants of clinical outcomes and PROs from a range of geographical regions in a real-world CKD setting.

Several medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another “safer” therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s12012-021-09659-w.

This study of real‐world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium‐glucose cotransporter‐2 (SGLT2) inhibitors versus other glucose‐lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity‐matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (

To understand geographical and temporal patterns in the diabetes gap, the excess mortality risk associated with type 2 diabetes (T2D), in three high-income countries.Using databases from Canada (Ontario), Spain (Catalonia) and the UK (England), we harmonized the study design and the analytical strategy to extract information on subjects aged over 35 years with incident T2D between 1998 and 2018 matched to up to five subjects without diabetes. We used Poisson models to estimate age-specific mortality trends by diabetes status and rate ratios and rate differences associated with T2D.In more than 6 million people, 694 454 deaths occurred during a follow-up of 52 million person-years. Trends in all-cause mortality rates differed between Ontario and England; yet, the diabetes gaps were very similar in recent years: in 2018, we estimated 1.3 (95% confidence interval: 0.8, 1.8) and 0.8 (0.2, 1.5) more deaths per 1000 person-years in 50-year-old men with diabetes in Ontario and England, respectively, and 8.9 (6.1, 11.7) and 12.1 (9.1, 15.1) in 80-year-old men; between-country differences were small also in women. In Catalonia, rate ratios comparing T2D with no diabetes in men in 2018 were 1.53 (1.11, 2.11) at 50 years old, 0.88 (0.72, 1.06) at 60 years old, 0.74 (0.60, 0.90) at 70 years old and 0.81 (0.66, 1.00) at 80 years old, indicating lower mortality rates in men with T2D from the age of 60 years; rates were similar in women with and without diabetes at all ages. The diabetes gaps in cardiorenal mortality mirrored those of all-cause mortality: we observed consistent reductions in the proportions of cardiorenal deaths in subjects aged 80 years but variations in subjects aged ≤70 years, regardless of the presence of diabetes.By reducing the confounding impact of epidemiological and analytical differences, this study showed geographical similarities and differences in the diabetes gap: an excess risk of all-cause and cardiorenal mortality in subjects with T2D is still present in Ontario and England in recent years, particularly in elderly subjects. Conversely, there were very small gaps in young men with T2D or even lower mortality rates in older subjects with T2D in Catalonia.

Objective: To explore risks and associated mediation effects of developing chronic kidney disease (CKD) and heart failure (HF) in young- and usual-onset T2DM among White Caucasian (WC) and African American (AA). Research Design and Methods: From US medical records, 1,491,672 WC and 31,133 AA were identified and stratified by T2DM-onset age (18-39 /40-49 /50-59 /60-70 years). Risks, mediation effects and time to CKD and HF were evaluated adjusting for time-varying confounders. Results: In 18-39, 40-49, 50-59, 60-70 year-groups, HR (95% CI) of developing CKD /HF in AA compared to WC were 1.21 (1.17-1.26) /2.21 (1.98-2.45), 1.25 (1.22-1.28) /1.86 (1.75-1.97), 1.21 (1.19-1.24) /1.54 (1.48-1.60), 1.10 (1.08-1.12) /1.11 (1.07-1.15) respectively. In AA /WC aged 18-39 years, time (CI) in years to CKD [8.7 (8.2-9.1) /9.7 (9.2-10.2)] and HF [10.3 (9.3-11.2) /12.1 (10.6-13.5)] were on average 3.6 /4.0 and 3.1 /4.1 years longer compared to those diagnosed at 60-70 years. Compared to females, AA males aged The mediation effects (%) of CKD on the HF risk difference between ethnicities across age-groups (range: 54-91%) were higher compared to those of HF on CKD risk difference between ethnicities across age-groups (range: 13-39%). Conclusions: Developing cardio-renal complications on average within 10 years of young-onset T2DM, and high mediation effect of CKD on HF call for revisiting guidelines on early diagnosis and pro-active treatment strategies for effective management of cardio-metabolic risk.

Rationale: CRCs are known to be key determinants of patient outcomes in T2D; however, the burden of undiagnosed CRCs in unselected T2D population remains unclear, particularly in low-to-middle income countries (LMICs) . ‘Take CaRe of Me’ (TCOM) programme aims to determine the global burden and treatment patterns of CRCs in people with T2D without prior history of cardiovascular (CV) and renal disease. Methods: TCOM programme records data in a cloud based repository after being reported by primary care physicians on albuminuria, eGFR, CV risk, echocardiography and treatment patterns in adults with T2D and no CRCs at index visit for early identification of CRCs. We present a descriptive analysis (up to Dec 2021) of baseline cardiorenal factors from 6 LMICs. Results: We recruited 11335 adults (mean [±SD] age, 54.8±11.4 yrs; 57.9% women, mean T2D duration, 9.8±8.0 yrs) . Mean HbA1c was 8.3±2.2% (65.8% with HbA1c >7%) . Individuals with moderate-to-high renal risk (per urine albumin-creatinine ratio) ranged from 24.8% (Mexico) to 45.1% (Philippines) and with high/very high CV risk (per ESC 2019) ranged from 31.6% (Philippines) to 45.0% (Egypt) (Table) . Discussion: There is high burden of unrecognized CRCs in T2D in real-world setting, with >35% having moderate-to-high renal and high/very high CV risks. Our results point at the unmet need for early diagnosis, risk factor management and use of cardiorenoprotective glucose lowering drugs. Disclosure K.Khunti: Consultant; Abbott, Amgen Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Napp Pharmaceuticals Limited, Novartis AG, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.I.Silva: Employee; AstraZeneca. F.Surmont: Employee; AstraZeneca. H.Vasnawala: None. E.Vazquez-mendez: None. P.Fenici: Employee; AstraZeneca. S.Goncalves: None. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Joshi: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Dr. Reddy’s Laboratories Ltd., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Consultant; Biocon, Glenmark Pharmaceuticals, Sanofi, USV Private Limited. M.N.Kosiborod: Advisory Panel; Amgen Inc., Applied Therapeutics, Bayer AG, Eli Lilly and Company, ESPERION Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Pharmacosmos A/S, Sanofi, Vifor Pharma Management Ltd., Consultant; Alnylam Pharmaceuticals, Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. C.S.Lam: Other Relationship; Prosciento Inc, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Abbott, Actelion, Amgen, AnaCardio , Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cytokinetics, Darma., EchoNous, Impulse Dynamics, Ionis Pharma, Janssen R&D, Medscape/WebM, Us2.ai. A.Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, PIKDARE S.p.A., Sanofi, Shionogi & Co., Ltd., Swedish Orphan Biovitrum AB, Speaker's Bureau; Eli Lilly and Company. L.Ramirez: Employee; AstraZeneca. Funding TCoM study was funded by AstraZeneca International

Aims The economic burden of diabetes is driven by the management of vascular complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated reductions in cardiovascular and renal complications, including hospitalization for heart failure (HHF) and renal disease progression, in randomized clinical trials. The objective of this study was to evaluate the cost-effectiveness of the SGLT2i class versus standard of care in type 2 diabetes mellitus (T2DM), using evidence from both clinical trial and real-world studies. Methods An established T2DM model was adapted to use contemporary outcomes evidence from real-world studies and randomized controlled trial evaluations of SGLT2i, and extrapolated over a lifetime for HHF, myocardial infarction, stroke, end-stage renal disease and all-cause mortality. The economic analysis considered adults with T2DM, with and without established cardiovascular disease, and was conducted over a lifetime from the perspective of the health care payer in the United Kingdom, United States and China, discounted at country-specific rates. Results SGLT2i were consistently associated with increased treatment costs, reduced complication costs and gains in quality-adjusted life years driven by differences in projected life expectancy, cardiovascular and microvascular morbidity and weight loss. SGLT2i were estimated to be cost-saving or cost-effective at relevant thresholds for the overall population in the United Kingdom, United States and China, with cost-effectiveness being the greatest in higher risk subgroups. Conclusions The findings highlight the need to take into account cost savings from reducing common, morbid and preventable T2DM complications when considering the cost of diabetes medications.

There are limited data on cardiovascular efficacy and safety of type 2 diabetes therapies in Japan, where treatments are characterized by lower metformin use and higher dipeptidyl peptidase‐4 inhibitor (DPP4i) use versus other countries. We investigated the cardiovascular outcomes in Japanese patients with type 2 diabetes initiating sodium–glucose cotransporter 2 inhibitors (SGLT2i) matched 1:1 to patients initiating other glucose‐lowering drugs (33,890 patients/group) or DPP4i (9,876 patients/group). SGLT2i initiation was associated with lower risks (hazard ratio of in‐hospital death [death] 0.56, 95% confidence interval [CI] 0.47–0.67; hospitalization for heart failure 0.75, 95% CI 0.64–0.89; composite of hospitalization for heart failure or death 0.65, 95% CI 0.58–0.74 and stroke 0.66, 95% CI 0.52–0.84 versus other glucose‐lowering drugs and lower risks of death 0.52, 95% CI 0.36–0.73) and composite of hospitalization for heart failure or death (0.65, 95% CI 0.51–0.83) versus DPP4i. In conclusion, SGLT2i initiators had lower risks of cardiovascular events versus other glucose‐lowering drug initiators and, uniquely, versus DPP4i initiators in Japanese real‐world practice., We investigated the cardiovascular outcomes in Japanese patients with type 2 diabetes initiating sodium–glucose cotransporter 2 inhibitors matched 1:1 to patients initiating other glucose‐lowering drugs. Sodium–glucose cotransporter 2 inhibitor initiation was associated with lower risks of in‐hospital death, hospitalization for heart failure and the composite of hospitalization for heart failure or death versus other glucose‐lowering drugs. Similar results were observed in a comparison of SGLT2i versus dipeptidyl peptidase‐4 inhibitors. These results in a Japanese real‐world cohort are consistent with those reported in large, international clinical trials of cardiovascular outcomes with sodium–glucose cotransporter 2 inhibitors.

Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61–0·77; p

DISCOVER is a 3-year observational study program of 15,983 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. We investigated the association between socioeconomic status and both the availability of a baseline glycated hemoglobin (HbA1c) measurement and poor glycemic control (HbA1c level ≥ 9.0%) in participants enrolled in DISCOVER. Factors associated with a lack of baseline HbA1c measurement or an HbA1c level ≥ 9.0% were assessed using three-level hierarchical logistic models. Overall, 19.1% of participants did not have a baseline HbA1c measurement recorded. Lower-middle country income (vs. high) and primary/no formal education (vs. university education) were independently associated with a reduced likelihood of having a baseline HbA1c measurement (odds ratio [95% confidence interval]: 0.11 [0.03–0.49] and 0.81 [0.66–0.98], respectively. Of the participants with an available HbA1c measurement, 26.9% had an HbA1c level ≥ 9.0%; 68.7% of these individuals were from lower- or upper-middle-income countries. Factors associated with an increased likelihood of poor glycemic control included low country income, treatment at a site with public and/or governmental funding (vs. private funding) and having public or no health insurance (vs. private). A substantial proportion of DISCOVER participants did not have an HbA1c measurement; more than one-quarter of these participants had poorly controlled type 2 diabetes. Both individual- and country-level socioeconomic factors are associated with the quality of care regarding glycemic control. Awareness of these factors could help improve the management of patients with type 2 diabetes.

Aim: The DISCOVER Global Registry (DGR) aims to provide insights into patient attributes and treatment patterns in patients with type 2 diabetes mellitus (T2DM) seen in clinical practice and understand the patterns and impact of treatment strategies on cardio-renal-metabolic multimorbidities. It aims to augment the real-world evidence base created by the DISCOVER study.Methods: The ongoing study is a global, prospective, open-source, physician-led registry and involves non interventional data collection through cloud-based electronic case report form platform from participants with T2DM receiving care as part of routine clinical practice. The DGR will collect longitudinal prospective data on the following: (a) patient, healthcare provider, and healthcare system characteristics; (b) treatment patterns and factors influencing therapy changes; (c) disease duration and glycemic control; (d) management of micro and/or macrovascular complications; (e) management of associated risk factors; (f) outcomes (hospitalization/death), (g) quality of care indicators (eye/foot examination); (h) healthcare resource utilization; and (i) patient-reported outcomes.Conclusion: Establishment of this long-term, scalable, and sustainable global registry offers opportunities to enhance understanding of care gaps, establish quality benchmarks, and understand the role of various treatment strategies in addressing the multifactorial pathophysiology of T2DM and associated comorbidities- potentially enabling transformation of clinical data into actionable insights for improving patient outcomes.

To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy.HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories.Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia.Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Summary Background Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. Findings After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34–1·72, p Interpretation In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding AstraZeneca.

Aim To assess glycaemic control and factors associated with poor glycaemic control at initiation of second‐line therapy in the DISCOVER programme. Materials and methods DISCOVER (NCT02322762 and NCT02226822) comprises two similar prospective observational studies of 15 992 people with type 2 diabetes (T2D) initiating second‐line glucose‐lowering therapy in 38 countries across six regions (Africa, Americas, South‐East Asia, Eastern Mediterranean, Europe and Western Pacific). Data were collected using a standardized case report form. Glycated haemoglobin (HbA1c) levels were measured according to standard clinical practice in each country, and factors associated with poor glycaemic control (HbA1c >8.0%) were evaluated using hierarchical regression models. Results HbA1c levels were available for 80.9% of patients (across‐region range [ARR] 57.5%‐97.5%); 92.2% (ARR 59.2%‐99.1%) of patients had either HbA1c or fasting plasma glucose levels available. The mean HbA1c was 8.3% (ARR 7.9%‐8.7%). In total, 26.7% of patients had an HbA1c level ≥9.0%, with the highest proportions in South‐East Asia (35.6%). Factors associated with having HbA1c >8.0% at initiation of second‐line therapy included low education level, low country income, and longer time since T2D diagnosis. Conclusions The poor levels of glycaemic control at initiation of second‐line therapy suggest that intensification of glucose‐lowering treatment is delayed in many patients with T2D. In some countries, HbA1c levels are not routinely measured. These findings highlight an urgent need for interventions to improve monitoring and management of glycaemic control worldwide, particularly in lower‐middle‐ and upper‐middle‐income countries.

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.

IntroductionAlthough individualized target glycated hemoglobin (HbA1c) levels are recommended in older people with type 2 diabetes, studies report high levels of potential overtreatment. We aimed to investigate the proportion of older patients (aged ≥65 years) who potentially received an inappropriately intensive treatment (HbA1c level Research design and methodsDISCOVER is a 3-year observational study program of 15 992 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. Data were collected at baseline (initiation of second-line therapy) and at 6, 12, and 24 months. Factors associated with an inappropriately intensive treatment or using high-risk medications were assessed using a hierarchical regression model.ResultsOf the 3344 older patients with baseline HbA1c data in our analytic cohort, 23.5% received inappropriate treatment intensification. Among those who had follow-up HbA1c data, 55.2%, 54.2%, and 53.5% were inappropriately tightly controlled at 6, 12, and 24 months, respectively, with higher proportions in high-income than in middle-income countries. The proportion of patients receiving high-risk medications was higher in middle-income countries than in high-income countries. Gross national income (per US$5000 increment) was associated with increased odds of inappropriately intensive treatment but with decreased odds of receiving high-risk medications.ConclusionsA large proportion of older DISCOVER patients received an inappropriately intensive glucose-lowering treatment across the 2 years of follow-up, with substantial regional variation. The use of high-risk medications in these patients is particularly concerning.

Aim To investigate factors associated with health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (T2D) at initiation of second-line glucose-lowering therapy. Methods DISCOVER is a 3-year, prospective observational study of patients with T2D initiating second-line glucose-lowering therapy, conducted in 38 countries. HRQoL at baseline was assessed using the physical and mental component summary (PCS; MCS) scores of the 36-Item Short Form Health Survey version 2 (SF-36v2) in 31 countries (n = 8309) and the Hypoglycaemia Fear Survey-II (HFS-II) in 23 countries (n = 6516). Factors associated with differences in HRQoL were assessed using multivariable hierarchical regression models. Results Mean PCS and MCS scores were 48.0 (standard deviation [SD]: 7.8) and 45.5 (SD: 10.4), respectively. Factors associated with significantly lower SF-36v2 scores included being female, having a history of macrovascular complications and first-line treatment with oral combinations (vs metformin monotherapy). Mean HFS-II behaviour and worry scores were 8.2 (SD: 9.9) and 7.3 (SD: 11.8), respectively. Increased fear of hypoglycaemia was significantly associated with lower SF-36v2 scores. Conclusions Several patient-, disease- and treatment-related characteristics correlated with HRQoL, indicating that a multifactorial approach is needed to maintain HRQoL in patients with T2D.

Background Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium–glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain. Methods CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke). Results After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47–0.74; p Conclusions In this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD.

Aims To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort.Materials and Methods Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death.Results There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 +/- 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 +/- 27.4 mL/min/1.73m(2), and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m(2) and those with eGFR = 90 and 60 to 90 mL/min/1.73m(2).Conclusion In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.

Purpose This study aimed to assess awareness of glycated hemoglobin (A1C) testing and targets, perceived level of glycemic control and risk of complications, attitudes toward medications and self-management, and regimen-related distress in an international sample of patients with type 2 diabetes (T2D). Methods The descriptive study used a single time-point survey of adults in online health communities in the USA, Canada, the UK, Germany, Spain, and Mexico, who self-reported T2D diagnosed by a physician. Results In total, 661 patients participated. Awareness of their A1C value at last test varied considerably between countries (42%-89%), as did awareness of having an A1C target (26%- 70%). Self-reported A1C values were similar across US, Canadian, and European respondents (mean, 6.8%-7.3%). Approximately two-thirds of respondents from these countries (66%-71%) reported that their T2D was very or fairly well controlled, and few (5%-15%) expected to experience serious complications within 1 year. However, many respondents expected to experience microvascular (rather than macrovascular) complications in this time frame (eg, nerve pain, 5%-47%). Self-reported adherence to oral medication was generally high, with most respondents (86%-98%) taking their pills or tablets as directed by their healthcare provider, although for insulin injections adherence was lower in the USA (71%) and Mexico (78%) than in the other countries (86%-95%). The majority of respondents across countries (71%-79%) reported that taking injectable medications was not at all or a little burdensome. Respondents across countries appeared to be reasonably confident that they could adequately manage their blood sugar levels; despite this, a sizeable minority (21%-35%) had clinically significant levels of regimen-related distress. Conclusion Limited patient awareness of their A1C value and the potential complications of poorly controlled T2D, particularly regarding cardiovascular complications, may be a widespread problem. Furthermore, greater patient support may be needed to improve self-management of T2D and to reduce regimen-related distress.

OBJECTIVE The sodium–glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole. RESEARCH DESIGN AND METHODS SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. RESULTS In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49–1.28]), as did dapagliflozin users (0.55 [0.26–1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27–0.95]; dapagliflozin: 0.66 [0.25–1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87–2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01–3.54] mL/min/1.73 m2 per year). CONCLUSIONS This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline.

Aim To investigate global patterns of cardiovascular risk factor control in patients with type 2 diabetes mellitus (T2D). Methods DISCOVER is an international, observational cohort study of patients with T2D beginning second‐line glucose‐lowering therapy. Risk factor management was examined among eligible patients (ie, those with the risk factor) at study baseline. Inter‐country variability was estimated using median odds ratios (MORs). Results Among 14 343 patients with T2D from 34 countries, the mean age was 57.4 ± 12.0 years and the median (interquartile range) duration of T2D was 4.2 (2.0–8.0) years; 11.8% had documented atherosclerotic cardiovascular disease (ASCVD). Among eligible patients, blood pressure was controlled in 67.5% (9284/13756), statins were prescribed in 43.7% (5775/13208), angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers were prescribed in 55.6% (5292/9512), aspirin was prescribed in 53.3% of those with established ASCVD (876/1645), and 84.4% (12 102/14343) were non‐smoking. Only 21.5% of patients (3088/14343) had optimal risk factor management (defined as control of all eligible measures), with wide inter‐country variability (10%–44%), even after adjusting for patient and site differences (MOR 1.47, 95% confidence interval 1.24–1.66). Conclusion Globally, comprehensive control of ASCVD risk factors is not being achieved in most patients, with wide variability among countries unaccounted for by patient and site differences. Better country‐specific strategies are needed to implement comprehensive cardiovascular risk factor control consistently in patients with T2D to improve long‐term outcomes.