Considerations when planning and conducting large global observational studies: Experience from the DISCOVER study of patients with type 2 diabetes.

DISCOVER is a global programme of observational research that includes patients with type 2 diabetes initiating second-line glucose-lowering therapy from 38 countries worldwide, including many with little or no previous epidemiological data available. More than 15,000 patients were followed-up for 3 years, and comprehensive data were collected using a standardized electronic case report form at enrolment, and 6, 12, 24 and 36 months. The study has formed the basis for a long-term registry that is intended to expand the geographic and clinical scope of the study and allow data collection beyond 3 years. In this review, critical aspects of study planning and implementation are summarized, along with challenges that were faced, to provide a resource for researchers planning similar studies. In particular, it is essential to set realistic expectations regarding the degree of study representativeness that can be achieved, allow for sufficient time to obtain ethics committee approval, develop tools to help recruit patients effectively, ensure that data collection systems are robust, user-friendly and adaptable, plan adequate remote and on-site monitoring, maximize patient retention through continuous engagement with study sites and ensure that everyone involved in the study forms a friendly and effective team. Observational studies such as DISCOVER are crucial for understanding disease epidemiology and management in real-world settings. They are also increasingly used by governmental, regulatory and payor agencies for post-marketing surveillance and when considering new drug submissions. The development of future studies of similar scope and ambition to DISCOVER is encouraged.

Treatment patterns and glycated haemoglobin levels over 36 months in individuals with type 2 diabetes initiating second-line glucose-lowering therapy: The global DISCOVER study.

AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Socioeconomic Factors Associated With Glycemic Measurement and Poor HbA1c Control in People With Type 2 Diabetes: The Global DISCOVER Study.

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.

Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study.

BACKGROUND: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications. METHODS: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up. RESULTS: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21 -1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84 -4.06). CONCLUSIONS: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.

Design and rationale of DISCOVER global registry in type 2 diabetes: Real-world insights of treatment patterns and its relationship with cardiovascular, renal, and metabolic multimorbidities.

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.

Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data.

BACKGROUND: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics. METHODS: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. RESULTS: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region. CONCLUSIONS: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614.

Early versus late intensification of glucose-lowering therapy in patients with type 2 diabetes: Results from the DISCOVER study.

AIMS: To assess the effects of glycated haemoglobin (HbA1c) levels at time of glucose-lowering treatment intensification in DISCOVER, a global observational study of patients with type 2 diabetes (T2D) initiating second-line therapy. Outcomes of interest were glycaemic control, hypoglycaemia, and need for further intensification during 3 years of follow-up. METHODS: We included patients who intensified treatment (add-on or insulin initiation) upon initiation of second-line therapy (baseline). Outcomes were assessed according to baseline HbA1c: HbA1c ≤ 7·5% (early intensification) or HbA1c > 7·5% (late intensification). Factors associated with early or late intensification were assessed using multivariate logistic regression. RESULTS: Of the 9575 patients included, 3275 (34·2%) intensified treatment early and 6300 (65·8%) intensified treatment late. During follow-up, mean (SD) HbA1c was lower in the early- than in the late-intensification group (6·9% [0·95%] vs 7·5% [1·28%] at 36 months). More patients had HbA1c < 7·0% in the early- than in the late-intensification group (61·8% vs 37·9% at 36 months; p < 0·001). The risk of further intensification was higher in the late-intensification group (hazard ratio 1·88 [95% confidence interval 1·68-2·09]). Occurrence of hypoglycaemia was similar in both groups. CONCLUSIONS: Late intensification of glucose-lowering therapy after first-line treatment failure reduces the likelihood of reaching recommended treatment goals.

Type 2 diabetes and heart failure: insights from the global DISCOVER study.

AIMS: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)]. METHODS AND RESULTS: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter-quartile range 1.0-3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose-lowering medications. Among 9313 patients with follow-up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre-existing or concomitant CAD, and 73% were diagnosed in the outpatient setting. CONCLUSIONS: In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D.

Safety of As-Needed Budesonide-Formoterol in Mild Asthma: Data from the Two Phase III SYGMA Studies.

INTRODUCTION: Budesonide-formoterol taken as needed is an emerging treatment for mild asthma. OBJECTIVE: We used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide. METHODS: SYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 µg, twice-daily budesonide 200 µg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone. RESULTS: The pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%). CONCLUSIONS: Budesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified. CLINICALTRIAL. GOV IDENTIFIERS: NCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).

Global patterns of comprehensive cardiovascular risk factor control in patients with type 2 diabetes mellitus: Insights from the DISCOVER study.

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.

Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors: an analysis from the CVD-REAL 2 multinational cohort study.

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<0·0001), all-cause death (0·59, 0·52-0·67; p<0·0001), and the composite of hospitalisation for heart failure or all-cause death (0·64, 0·57-0·72; p<0·0001). Risks of myocardial infarction (HR 0·88, 0·80-0·98; p=0·020) and stroke (0·85 0·77-0·93; p=0·0004) were significantly but modestly lower with SGLT2 inhibitors versus DPP-4 inhibitors. INTERPRETATION: In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes. FUNDING: AstraZeneca.

Socioeconomic factors associated with hypoglycaemia in patients starting second-line glucose-lowering therapy: The DISCOVER study.

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.

Treatment patterns and associated factors in 14 668 people with type 2 diabetes initiating a second-line therapy: Results from the global DISCOVER study programme.

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.

Type 2 diabetes treatment and outcomes worldwide: A short review of the DISCOVER study programme.

The global burden of type 2 diabetes (T2D) is increasing, indicating an urgent need for improved disease prevention and management strategies. Contemporary, global, real-world data, collected in a consistent way, on the characteristics, treatment and outcomes of people with T2D are lacking, particularly in low- and middle-income countries where disease burden is increasing most rapidly. The DISCOVER study programme (ClinicalTrials.gov identifiers: NCT02322762 and NCT02226822) is a global, prospective, 3-year programme of observational research, which has been designed to fill this knowledge gap. DISCOVER is being conducted in 38 countries across six continents, including several lower-middle- and upper-middle-income countries where patients have rarely or never been studied previously. In total, 15 992 people with T2D who had initiated a second-line glucose-lowering therapy have been recruited. Data being collected include information on demographics, clinical and treatment characteristics, socio-economic status, clinical outcomes and patient-reported outcomes. Findings from DISCOVER will provide unique insights into current patterns of T2D care worldwide, which should contribute to informing clinical guidelines and health policy, and may help to improve patient care.

Eligibility of patients with type 2 diabetes for sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials: a global perspective from the DISCOVER study.

Objective: To assess the eligibility of patients participating in DISCOVER (a 3-year, prospective, observational study program of 15 992 patients with type 2 diabetes [T2D] initiating a second-line glucose-lowering therapy across 38 countries) for four cardiovascular outcomes trials (CVOTs) of sodium-glucose cotransporter 2 inhibitors (CANagliflozin cardioVascular Assessment Study [CANVAS], Dapagliflozin effect on CardiovascuLAR Events trial [DECLARE-TIMI 58], EMPAgliflozin cardiovascular OUTCOME event trial [EMPA-REG OUTCOME], and eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial [VERTIS-CV]). Research design and methods: In this cross-sectional analysis, baseline characteristics of DISCOVER patients were compared with the inclusion and exclusion criteria of the CVOTs to assess patient eligibility, overall and in four regions (Asia-Pacific, Europe, Latin America, and Middle East and Africa). Results: Overall, 11 385 patients (71.2%) had sufficient data for the analysis; 56.1% were men. The mean age and time since T2D diagnosis were 57.4 and 5.6 years, respectively. The mean glycated hemoglobin level was 8.3%. DISCOVER patients were younger, and fewer had a history of cardiovascular disease, than those enrolled in the CVOTs. Eligibility varied across the CVOTs; the proportion of eligible DISCOVER patients was highest for DECLARE-TIMI 58 (40.5%), followed by CANVAS (19.9%), VERTIS-CV (7.2%), and EMPA-REG OUTCOME (7.1%); 54.6% of patients were not eligible for any CVOT. Eligibility for each CVOT varied across regions, which was explained by the differing proportions of patients with established cardiovascular disease. Conclusions: In a large, international population of patients with T2D initiating a second-line glucose-lowering therapy, DECLARE-TIMI 58 was the most inclusive CVOT, suggesting that its study population will be more representative of patients encountered in routine clinical practice than those of CANVAS, EMPA-REG OUTCOME, and VERTIS-CV.

Diabetes management and treatment approaches outside of North America and West Europe in 2006 and 2015.

AIMS: The impact of introducing new classes of glucose-lowering medication (GLM) on diabetes management remains unclear, especially outside North America and Western Europe. Therefore, we aimed to analyse trends in glycaemic control and the usage of new and old GLMs in people with type 2 diabetes from 2006 to 2015. METHODS: Summary data from clinical services from nine countries outside North America and Western Europe were collected and pooled for statistical analysis. Each site summarized individual-level data from out-patient medical records for 2006 and 2015. Data included: demographics; HbA1c and fasting plasma glucose levels; and the proportions of patients taking GLM as monotherapy, combination therapy and/or insulin. RESULTS: Between 2006 and 2015, glycaemic control remained stable, although body mass index and duration of diabetes increased in most sites. The proportion of people on GLM increased, and the therapeutic regimens became more complex. There were increases in the use of insulin and triple therapy in most sites, while monotherapy, particularly in relation to sulphonylureas, decreased. Despite the introduction of new GLMs, such as DPP-4 inhibitors, insulin use increased over time. CONCLUSIONS: There was no clear evidence that the use of new classes of GLMs was associated with improvements in glycaemic control or reduced the reliance on insulin. These findings were consistent across a range of economic and geographic settings.

Treatment of type 2 diabetes mellitus worldwide: Baseline patient characteristics in the global DISCOVER study.

AIMS: To describe the characteristics and treatment of patients with type 2 diabetes mellitus initiating a second-line glucose-lowering therapy in the global DISCOVER study programme. METHODS: DISCOVER comprises two similar 3-year prospective observational studies (NCT02322762 and NCT02226822), involving 15,992 patients initiating a second-line glucose-lowering therapy in 38 countries across six regions (Africa, Americas, South-East Asia, Eastern Mediterranean, Europe and Western Pacific). RESULTS: Overall, 54.2% of patients were male (across region range [ARR]: 37.7-58.6%). At baseline, mean age and time since diagnosis of type 2 diabetes mellitus were 57.2 (ARR: 53.1-61.9)and 5.6 (ARR: 4.6-6.9) years, respectively. Median glycated haemoglobin (HbA1c) was 63.9 mmol/mol (8.0%; ARR: 7.6-8.3%). Microvascular and macrovascular complications were reported in 18.9% (ARR: 14.5-23.5%) and 12.7% (ARR: 5.0-26.6%) of patients, respectively. First-line treatments were mostly metformin monotherapy (55.6%; ARR: 42.5-83.6%) and combinations of metformin with a sulfonylurea (14.4%; ARR: 5.8-31.1%). The most commonly prescribed second-line therapies were combinations of metformin with a dipeptidyl peptidase-4 inhibitor (23.5%; ARR: 2.2-29.6%) or a sulfonylurea (20.9%; ARR: 13.6-57.1%). CONCLUSIONS: DISCOVER demonstrates considerable global variation in the treatment of type 2 diabetes mellitus, and a need for more aggressive risk factor control.

Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program).

BACKGROUND: The global prevalence of type 2 diabetes-related complications is not well described. We assessed prevalence of vascular complications at baseline in DISCOVER (NCT02322762; NCT02226822), a global, prospective, observational study program of 15,992 patients with type 2 diabetes initiating second-line therapy, conducted across 38 countries. METHODS: Patients were recruited from primary and specialist healthcare settings. Data were collected using a standardized case report form. Prevalence estimates of microvascular and macrovascular complications at baseline were assessed overall and by country and region, and were standardized for age and sex. Modified Poisson regression was used to assess factors associated with the prevalence of complications. RESULTS: The median duration of type 2 diabetes was 4.1 years (interquartile range [IQR]: 1.9-7.9 years), and the median glycated hemoglobin (HbA1c) level was 8.0% (IQR: 7.2-9.1%). The crude prevalences of microvascular and macrovascular complications were 18.8% and 12.7%, respectively. Common microvascular complications were peripheral neuropathy (7.7%), chronic kidney disease (5.0%), and albuminuria (4.3%). Common macrovascular complications were coronary artery disease (8.2%), heart failure (3.3%) and stroke (2.2%). The age- and sex-standardized prevalence of microvascular complications was 17.9% (95% confidence interval [CI] 17.3-18.6%), ranging from 14.2% in the Americas to 20.4% in Europe. The age- and sex-standardized prevalence of macrovascular complications was 9.2% (95% CI 8.7-9.7%), ranging from 4.1% in South-East Asia to 18.8% in Europe. Factors positively associated with vascular complications included age (per 10-year increment), male sex, diabetes duration (per 1-year increment), and history of hypoglycemia, with rate ratios (95% CIs) for microvascular complications of 1.14 (1.09-1.19), 1.30 (1.20-1.42), 1.03 (1.02-1.04) and 1.45 (1.25-1.69), respectively, and for macrovascular complications of 1.41 (1.34-1.48), 1.29 (1.16-1.45), 1.02 (1.01-1.02) and 1.24 (1.04-1.48), respectively. HbA1c levels (per 1.0% increment) were positively associated with microvascular (1.05 [1.02-1.08]) but not macrovascular (1.00 [0.97-1.04]) complications. CONCLUSIONS: The global burden of microvascular and macrovascular complications is substantial in these patients with type 2 diabetes who are relatively early in the disease process. These findings highlight an opportunity for aggressive early risk factor modification, particularly in regions with a high prevalence of complications. Trial registration ClinicalTrials.gov; NCT02322762. Registered 23 December 2014. https://clinicaltrials.gov/ct2/show/NCT02322762 . ClinicalTrials.gov; NCT02226822. Registered 27 August 2014. https://clinicaltrials.gov/ct2/show/NCT02226822.

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study.

BACKGROUND: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. OBJECTIVES: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. METHODS: New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis. RESULTS: After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. CONCLUSIONS: In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614).