Evolution of economic burden of heart failure by ejection fraction in newly diagnosed patients in Spain.

OBJECTIVE: To describe healthcare resource utilization (HCRU) and costs, in patients with newly diagnosed heart failure (HF) according to ejection fraction (EF) in Spain. METHODS: Retrospective cohort study that analyzed anonymized, integrated and computerised medical records in Spain. Patients with ≥ 1 new HF diagnosis between January 2013 and September 2019 were included and followed-up during a 4-year period. Rates per 100 person-years of HCRU and costs were estimated. RESULTS: Nineteen thousand nine hundred sixty-one patients were included, of whom 43.5%, 26.3%, 5.1% and 25.1% had HF with reduced, preserved, mildly reduced and unknown EF, respectively. From year 1 to 4, HF rates of outpatient visits decreased from 1149.5 (95% CI 1140.8-1159.3) to 765.5 (95% CI 745.9-784.5) and hospitalizations from 61.7 (95% CI 60.9-62.7) to 15.7(14.7-16.7) per 100 person-years. The majority of HF-related healthcare resource costs per patient were due to hospitalizations (year 1-4: 63.3-38.2%), followed by indirect costs (year 1-4: 12.2-29.0%), pharmacy (year 1-4: 11.9-19.9%), and outpatient care (year 1-4: 12.6-12.9%). Mean (SD) per patient HF-related costs decreased from 2509.6 (3518.5) to 1234.6 (1534.1) Euros (50% cost reduction). At baseline, 70.1% were taking beta-blockers, 56.3% renin-angiotensin system inhibitors, 11.8% mineralocorticoid receptor antagonists and 8.9% SGLT2 inhibitors. At 12 months, these numbers were 72.3%, 65.4%, 18.9% and 9.8%, respectively. CONCLUSIONS: Although the economic burden of HF decreased over time since diagnosis, it is still substantial. This reduction could be partially related to a survival bias (sick patients died early), but also to a better HF management. Despite that, there is still much room for improvement.

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.

Burden of Illness beyond Mortality and Heart Failure Hospitalizations in Patients Newly Diagnosed with Heart Failure in Spain According to Ejection Fraction.

OBJECTIVE: The objective of this study was to describe the rates of adverse clinical outcomes, including all-cause mortality, heart failure (HF) hospitalization, myocardial infarction, and stroke, in patients newly diagnosed with HF to provide a comprehensive picture of HF burden. METHODS: This was a retrospective and observational study, using the BIG-PAC database in Spain. Adults, newly diagnosed with HF between January 2013 and September 2019 with ≥1 HF-free year of enrolment prior to HF diagnosis, were included. RESULTS: A total of 19,961 patients were newly diagnosed with HF (43.5% with reduced ejection fraction (EF), 26.3% with preserved EF, 5.1% with mildly reduced EF, and 25.1% with unknown EF). The mean age was 69.7 ± 19.0 years; 53.8% were men; and 41.0% and 41.5% of patients were in the New York Heart Association functional classes II and III, respectively. The baseline HF treatments included beta-blockers (70.1%), renin-angiotensin system inhibitors (56.3%), mineralocorticoid receptor antagonists (11.8%), and SGLT2 inhibitors (8.9%). The post-index incidence rates of all-cause mortality, HF hospitalization, and both combined were 102.2 (95% CI 99.9-104.5), 123.1 (95% CI 120.5-125.7), and 182 (95% CI 178.9-185.1) per 1000 person-years, respectively. The rates of myocardial infarction and stroke were lower (26.2 [95% CI 25.1-27.4] and 19.8 [95% CI 18.8-20.8] per 1000 person-years, respectively). CONCLUSIONS: In Spain, patients newly diagnosed with HF have a high risk of clinical outcomes. Specifically, the rates of all-cause mortality and HF hospitalization are high and substantially greater than the rates of myocardial infarction and stroke. Given the burden of adverse outcomes, these should be considered targets in the comprehensive management of HF. There is much room for improving the proportion of patients receiving disease-modifying therapies.

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.

Healthcare resource utilization and costs among patients with heart failure with preserved, mildly reduced, and reduced ejection fraction in Spain.

AIMS: To describe healthcare resource utilization (HCRU) of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain.  METHODS: Adults with ≥ 1 HF diagnosis and ≥ 1 year of continuous enrolment before the corresponding index date (1/January/2016) were identified through the BIG-PAC database. Rate per 100 person-years of all-cause and HF-related HCRU during the year after the index date were estimated using bootstrapping with replacement. RESULTS: Twenty-one thousand two hundred ninety-seven patients were included, of whom 48.5% had HFrEF, 38.6% HFpEF and 4.2% HFmrEF, with the rest being of unknown EF. Mean age was 78.8 ± 11.8 years, 53.0% were men and 83.0% were in NYHA functional class II/III. At index, 67.3% of patients were taking renin angiotensin system inhibitors, 61.2% beta blockers, 23.4% aldosterone antagonists and 5.2% SGLT2 inhibitors. Rates of HF-related outpatient visits and hospitalization were 968.8 and 51.6 per 100 person-years, respectively. Overall, 31.23% of patients were hospitalized, mainly because of HF (87.88% of total hospitalizations); HF hospitalization length 21.06 ± 17.49 days (median 16; 25th, 75th percentile 9-27). HF hospitalizations were the main cost component: inpatient 73.64%, pharmacy 9.67%, outpatient 9.43%, and indirect cost 7.25%. Rates of all-cause and HF-related HCRU and healthcare cost were substantial across all HF subgroups, being higher among HFrEF compared to HFmrEF and HFpEF patients. CONCLUSIONS: HCRU and cost associated with HF are high in Spain, HF hospitalizations being the main determinant. Medication cost represented only a small proportion of total costs, suggesting that an optimization of HF therapy may reduce HF burden.

Prevalence, Characteristics, Management and Outcomes of Patients with Heart Failure with Preserved, Mildly Reduced, and Reduced Ejection Fraction in Spain.

Objective: To estimate the prevalence, incidence, and describe the characteristics and management of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain. Methods: Adults with ≥1 inpatient or outpatient HF diagnosis between 1 January 2013 and 30 September 2019 were identified through the BIG-PAC database. Annual incidence and prevalence by EF phenotype were estimated. Characteristics by EF phenotype were described in the 2016 and 2019 HF prevalent cohorts and outcomes in the 2016 HF prevalent cohort. Results: Overall, HF incidence and prevalence were 0.32/100 person-years and 2.34%, respectively, but increased every year. In 2019, 49.3% had HFrEF, 38.1% had HFpEF, and 4.3% had HFmrEF (in 8.3%, EF was not available). Compared with HFrEF, patients with HFpEF were largely female, older, and had more atrial fibrillation but less atherosclerotic cardiovascular disease. Among patients with HFrEF, 76.3% were taking renin-angiotensin system inhibitors, 69.5% beta-blockers, 36.8% aldosterone antagonists, 12.5% sacubitril/valsartan and 6.7% SGLT2 inhibitors. Patients with HFpEF and HFmrEF took fewer HF drugs compared to HFrEF. Overall, the event rates of HF hospitalization were 231.6/1000 person-years, which is more common in HFrEF patients. No clinically relevant differences were found in patients with HFpEF, regardless EF (50- < 60% vs. ≥60%). Conclusions: >2% of patients have HF, of which around 50% have HFrEF and 40% have HFpEF. The prevalence of HF is increasing over time. Clinical characteristics by EF phenotype are consistent with previous studies. The risk of outcomes, particularly HF hospitalization, remains high, likely related to insufficient HF treatment.

An Epidemiology Model for Estimating the Numbers of US Patients With Multiple Myeloma by Line of Therapy and Treatment Exposure.

OBJECTIVES: Estimates on the distribution of patients with multiple myeloma (MM) by line of therapy (LOT) are scarce and get outdated quickly as new treatments become available. The objective of this study was to estimate the number of patients with MM by LOT and the number of patients who have received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies (mAbs). METHODS: A compartmental model was developed to calculate the number of patients by LOT. Two pathways were considered based on stem cell transplant eligibility, and at each pathway, treatments were stratified in 2 types: anti-CD38 mAbs or other. The model population was stratified into 4 subgroups based on age and cytogenetic risk. Model inputs were informed from real-world evidence. RESULTS: The model estimated that, in 2020, 126 869 patients were living with MM in the United States. Of these, 105 701 received treatment in any LOT, with 56 959, 27 252, 11 258, and 5217 in lines 1 to 4, respectively, and 5015 in line 5 or beyond. The model estimated that 3497 patients received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 mAbs. The model overall prevalence predictions aligned well with publicly available estimates. CONCLUSIONS: This study proposes a novel framework to estimate MM prevalence. It can assist clinicians to understand future trends in MM epidemiology, healthcare systems to plan for future resource use allocation, and payers to quantify the budget impact of new treatments.

Linaclotide utilization and potential for off-label use and misuse in three European countries.

Introduction: Linaclotide is approved for adults with moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C). Linaclotide is not indicated for weight loss or for patients with inflammatory bowel disease (IBD); it is contraindicated in patients with mechanical bowel obstruction (MBO). Some patients with obesity or eating disorders (ED) may use linaclotide off-label for weight loss or as a laxative. Objectives: To describe the use of linaclotide in clinical practice, including patients with potential for off-label use or misuse. Methods: Post-authorization safety study conducted in three databases from the linaclotide launch date to 2017: the Clinical Practice Research Datalink in the United Kingdom (UK), the Information System for Research in Primary Care database in Spain and the linked Patient, Prescription and Causes of Death Registries in Sweden. Cohorts of patients were identified as having IBS using diagnostic and treatment codes; IBS subtypes were identified using symptoms and treatment codes; patients with obesity, ED, MBO, and IBD were identified using diagnostic codes or body mass index. Results: There were 1319, 1981, and 5081 linaclotide users from the United Kingdom, Spain, and Sweden with a median age of 45, 57, and 51 years, respectively; most were females. In the United Kingdom, Spain, and Sweden, respectively: 59.0%, 60.3%, and 31.3% of linaclotide users had an IBS diagnosis recorded, and among those, 68.8%, 61.3%, and 92.7% were classified as IBS-C. The proportions of linaclotide users considered at risk for potential off-label use for weight loss or as a laxative were 17.1%, 29.7%, and 1.7%, and the proportions of users considered at risk of misuse due to a history of MBO or IBD were 3.5%, 4.6%, and 5.7% in the United Kingdom, Spain, and Sweden, respectively. Conclusions: Potential linaclotide off-label use and misuse appears limited, as evidenced by the small sizes of the patient subgroups at risk for off-label use and misuse.

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.

Health-related quality of life in patients with type 2 diabetes initiating a second-line glucose-lowering therapy: The DISCOVER study.

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.

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.

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.

Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme.

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.

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.

Glycaemic control in patients with type 2 diabetes initiating second-line therapy: Results from the global DISCOVER study programme.

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.

Post-authorisation Safety Study of Pioglitazone Use and Safety Endpoints of Interest in Denmark After Direct Healthcare Professional Communication.

INTRODUCTION: A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values. METHODS: This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011-2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated. RESULTS: There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone. CONCLUSIONS: Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.

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.

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.