Association Between Change in Ambulatory Pulmonary Artery Pressures and Natriuretic Peptides in Patients with Heart Failure: Results From the EMBRACE-HF Trial.

BACKGROUND: Remote monitoring of pulmonary artery (PA) pressures and serial N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements guide heart failure (HF) treatment, but their association has yet to be described. METHODS AND RESULTS: In the Empagliflozin Evaluation by Measuring the Impact on Hemodynamics in Patients with Heart Failure (EMBRACE-HF) trial, patients with HF and a remote PA pressure monitoring device were randomized to empagliflozin vs placebo. PA diastolic pressures (PADP) and NT-proBNP levels were obtained at baseline and 6 and 12 weeks. We used linear mixed models to examine the association between change in PADP and change in NT-proBNP, adjusting for baseline covariates. Of 62 patients, the mean patient age was 66.2 years, and 63% were male. The mean baseline PADP was 21.8 ± 6.4 mm Hg, and the mean NT-proBNP was 1844.6 ± 2767.7 pg/mL. The mean change between baseline and averaged 6- and 12-week PADP was -0.4 ± 3.1 mm Hg, and the mean change between baseline and averaged 6- and 12-week NT-proBNP was -81.5 ± 878.6 pg/mL. In adjusted analyses, every 2-mm Hg decrease in PADP was associated with an NT-proBNP reduction of 108.9 pg/mL (95% confidence interval -4.3 to 222.0, P = .06). CONCLUSIONS: We observed that short-term decreases in ambulatory PADP seem to be associated with decreases in NT-proBNP. This finding may provide additional clinical context when tailoring treatment for patients with HF.

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.

Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial.

BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors) prevent heart failure (HF) hospitalizations in patients with type 2 diabetes and improve outcomes in those with HF and reduced ejection fraction, regardless of type 2 diabetes. Mechanisms of HF benefits remain unclear, and the effects of SGLT2 inhibitor on hemodynamics (filling pressures) are not known. The EMBRACE-HF trial (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) was designed to address this knowledge gap. METHODS: EMBRACE-HF is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of ejection fraction, with or without type 2 diabetes) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary end point was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8-12). Secondary end points included health status (Kansas City Cardiomyopathy Questionnaire score), natriuretic peptides, and 6-min walking distance. RESULTS: Overall, 93 patients were screened, and 65 were randomized (33 to empagliflozin, 32 to placebo). The mean age was 66 years; 63% were male; 52% had type 2 diabetes; 54% were in New York Heart Association class III/IV; mean ejection fraction was 44%; median NT-proBNP (N-terminal pro B-type natriuretic peptide) was 637 pg/mL; and mean PADP was 22 mm Hg. Empagliflozin significantly reduced PADP, with effects that began at week 1 and amplified over time; average PADP (weeks 8-12) was 1.5 mm Hg lower (95% CI, 0.2-2.8; P=0.02); and at week 12, PADP was 1.7 mm Hg lower (95% CI, 0.3-3.2; P=0.02) with empagliflozin versus placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in Kansas City Cardiomyopathy Questionnaire scores, natriuretic peptide levels, and 6-min walking distance. CONCLUSIONS: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03030222.

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.

Factors associated with weight loss in people with overweight or obesity living with type 2 diabetes mellitus: Insights from the global DISCOVER study.

AIMS: To estimate real-world change in weight over 3 years and the factors influencing it in participants who are overweight and live with type 2 diabetes. MATERIALS AND METHODS: DISCOVER is a multinational prospective observational study that enrolled participants with type 2 diabetes between December 2014 and June 2016 at the time of initiation of a second-line glucose-lowering medication (GLM). Demographic, anthropometric, and quality-of-life data were collected at baseline, and after 6, 12, 24 and 36 months of follow-up. Using a hierarchical, repeated-measures linear regression model, we examined factors associated with weight change over time. RESULTS: Of 10 675 participants with type 2 diabetes who were overweight/obese (mean age 57.1 ± 11.1 years, 46% women), 21% lost ≥5% weight over 3 years, which was associated with modestly improved physical and mental health. Advancing age, female sex, and higher baseline weight were associated with weight loss. Most importantly, the type of GLM prescribed at previous visit had the strongest impact on weight change over time independent of participant factors, with use of a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist associated with 1.0% weight loss versus a 0.6% weight gain with sulphonylureas, thiazolidinediones, meglitinides or insulin. CONCLUSION: In this large contemporary prospective study, approximately one in five participants with early-stage type 2 diabetes and overweight/obesity lost ≥5% weight over 3 years. The type of GLM has the most impact on weight loss over time, highlighting the need for a careful selection of agents that takes baseline weight into consideration.

Unifying the analysis of continuous and categorical measures of weight loss and incorporating group effect: a secondary re-analysis of a large cluster randomized clinical trial using Bayesian approach.

BACKGROUND: Although frequentist paradigm has been the predominant approach to clinical studies for decades, some limitations associated with the frequentist null hypothesis significance testing have been recognized. Bayesian approaches can provide additional insights into data interpretation and inference by deriving posterior distributions of model parameters reflecting the clinical interest. In this article, we sought to demonstrate how Bayesian approaches can improve the data interpretation by reanalyzing the Rural Engagement in Primary Care for Optimizing Weight Reduction (REPOWER). METHODS: REPOWER is a cluster randomized clinical trial comparing three care delivery models: in-clinic individual visits, in-clinic group visits, and phone-based group visits. The primary endpoint was weight loss at 24 months and the secondary endpoints included the proportions of achieving 5 and 10% weight loss at 24 months. We reanalyzed the data using a three-level Bayesian hierarchical model. The posterior distributions of weight loss at 24 months for each arm were obtained using Hamiltonian Monte Carlo. We then estimated the probability of having a higher weight loss and the probability of having greater proportion achieving 5 and 10% weight loss between groups. Additionally, a four-level hierarchical model was used to assess the partially nested intervention group effect which was not investigated in the original REPOWER analyses. RESULTS: The Bayesian analyses estimated 99.5% probability that in-clinic group visits, compared with in-clinic individual visits, resulted in a higher percent weight loss (posterior mean difference: 1.8%[95% CrI: 0.5,3.2%]), a greater probability of achieving 5% threshold (posterior mean difference: 9.2% [95% CrI: 2.4, 16.0%]) and 10% threshold (posterior mean difference: 6.6% [95% CrI: 1.7, 11.5%]). The phone-based group visits had similar result. We also concluded that including intervention group did not impact model fit significantly. CONCLUSIONS: We unified the analyses of continuous (the primary endpoint) and categorical measures (the secondary endpoints) of weight loss with one single Bayesian hierarchical model. This approach gained statistical power for the dichotomized endpoints by leveraging the information in the continuous data. Furthermore, the Bayesian analysis enabled additional insights into data interpretation and inference by providing posterior distributions for parameters of interest and posterior probabilities of different hypotheses that were not available with the frequentist approach. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02456636 ; date of registry: May 28, 2015.

Global use of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Results from DISCOVER.

BACKGROUND: Despite strong evidence of benefit, uptake of newer glucose-lowering medications that reduce cardiovascular risk has been low. We sought to examine global trends and predictors of use of SGLT2i and GLP-1 RA in patients with type 2 diabetes. METHODS: DISCOVER is a global, prospective, observational study of patients with diabetes enrolled from 2014-16 at initiation of second-line glucose-lowering therapy and followed for 3 years. We used hierarchical logistic regression to examine factors associated with use of either an SGLT2i or GLP-1 RA at last follow-up and to assess country-level variability. RESULTS: Among 14,576 patients from 37 countries, 1579 (10.8%) were started on an SGLT2i (1275; 8.7%) or GLP-1 RA (318; 2.2%) at enrollment, increasing to 16.1% at end of follow-up, with large variability across countries (range 0-62.7%). Use was highest in patients treated by cardiologists (26.1%) versus primary care physicians (10.4%), endocrinologists (16.9%), and other specialists (22.0%; p < 0.001). Coronary artery disease (OR 1.29, 95% CI 1.08-1.54) was associated with greater use of SGLT2i or GLP-1 RA while peripheral artery disease (OR 0.73, 95% CI 0.54-1.00) and chronic kidney disease (OR 0.73, 95% CI 0.58-0.94) were associated with lower use (OR 0.73, 95% CI 0.54-1.00). The country-level median odds ratio was 3.48, indicating a very large amount of variability in the use of SGLT2i or GLP-1 RA independent of patient demographic and clinical factors. CONCLUSIONS: Global use of glucose-lowering medications with established cardiovascular benefits has increased over time but remains suboptimal, particularly in sub-groups most likely to benefit. Substantial country-level variability exists independent of patient factors, suggesting structural barriers may limit more widespread use of these medications.

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study.

AIM: To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy. MATERIALS AND METHODS: Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses. RESULTS: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU. CONCLUSIONS: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores.

What are the factors associated with long-term glycaemic control in patients with type 2 diabetes and elevated glycated haemoglobin (≥7.0%) at initiation of second-line therapy? Results from the DISCOVER study.

AIMS: Glycaemic control is a cornerstone of type 2 diabetes (T2D) management. We assessed factors associated with good long-term glycaemic control in patients with glycated haemoglobin (HbA1c) ≥7.0% at initiation of second-line glucose-lowering therapy, using data from DISCOVER, a global, prospective, 3-year observational study of patients with T2D. MATERIALS AND METHODS: This analysis included patients with HbA1c ≥7.0% at baseline (initiation of second-line therapy). Multivariable regression models assessed factors associated with having HbA1c <7.0% at 3 years in two distinct groups: patients with (a) HbA1c ≥7.0% and <9.0%, and (b) HbA1c ≥9.0% at baseline. RESULTS: In total, 7575 patients with baseline HbA1c ≥7.0% were included (2233 with baseline HbA1c ≥9.0%). At 6 months, 43.7% and 24.2% of patients had an HbA1c level <7.0% in groups a and b, respectively; the corresponding proportions at 3 years were 45.8% and 29.3%. Having HbA1c <7.0% at 6 months (vs. ≥7.0%) was the strongest predictor of having HbA1c <7.0% at 3 years in both group a and group b [odds ratio (95% confidence interval): 2.01 (1.77-2.27) and 2.68 (2.10-3.41), respectively]. Longer T2D duration was associated with a decreased likelihood of having HbA1c <7.0% at 3 years. CONCLUSIONS: In patients with poor glycaemic control at initiation of second-line therapy, early attainment of HbA1c <7.0% appears predictive of long-term glycaemic control, suggesting that timely modification of treatment strategies in patients with elevated HbA1c after 6 months is important to minimize therapeutic inertia.

Prevalence and progression of chronic kidney disease among patients with type 2 diabetes: Insights from the DISCOVER study.

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/1.73 m2 ), 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/1.73 m2 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.

Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction: Results from the DEFINE-HF trial.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE-HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin-treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin-treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits.

Meta-analysis of dose selection for budesonide in the treatment of Chinese patients with AECOPD.

OBJECTIVE: To systematically observe the curative efficacy and safety of budesonide inhalation in the treatment of acute exacerbation of chronic obstructive pulmonary disease, and to find a suitable dose of aerosolized budesonide for Chinese patients. METHODS: The meta-analysis study was conducted at Wenjiang District People's Hospital, Chengdu City, Sichuan Province, China from May 2019 to August 2019 and comprised randomised controlled trials of glucocorticoids for acute exacerbation of chronic obstructive pulmonary disease on the databases of the China National Knowledge Infrastructure, Wanfang Medical Network, PubMed, Medline, Embase, Cochrane Library and Google Scholar. Data extraction and quality evaluation of the studies was done and meta-analysis was then performed using RevMan 5.3. RESULTS: There were 25 studies identified that comprised 1959 patients. When the budesonide dose was 6mg/d and the methylprednisolone dose was 40mg/d, no significant difference was found in partial pressure of carbon dioxide and oxygen post-treatment (p>0.05). When the nebulized budesonide dose was <6mg/d, methylprednisolone was more effective than budesonide (p<0.05), while >6mg/d was not significantly more effective (p>0.05). At 4mg/d, the difference in the dyspnoea score post-treatment was significant (p<0.05). No significant difference was found in dyspnoea scores after intravenous glucocorticoid treatment when the dose was greater than or equal to 4mg/d. In terms of adverse reactions, the response rate of blood glucose, blood pressure, excitement, insomnia and stomach discomfort in the intravenous group was higher than that in the nebulised group (p<0.05). Oropharyngeal discomfort in the nebulized group was higher than that the intravenous group (p<0.05). CONCLUSIONS: The optimal dose for the inhalation of budesonide in Chinese patients was between 4mg/d and 6mg/d. The adverse reactions of nebulised budesonide were lower than those of intravenous methylprednisolone.

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

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.

Associations of fear of hypoglycemia with second-line use of insulin secretagogues or insulin and subsequent glycemic control in patients with type 2 diabetes: An analysis using data from the DISCOVER study.

BACKGROUND: Associations of fear of hypoglycemia with prescription of second-line insulin secretagogues (IS) or insulin and subsequent glycemic control in patients with type 2 diabetes were analysed using data from the DISCOVER study-a large, prospective, observational study. METHODS: Patients with type 2 diabetes initiating a second-line treatment after a first-line oral therapy were enrolled. Fear of hypoglycemia was assessed using baseline Hypoglycemia Fear Survey (HFS) worry score. Glycemic control was assessed using glycated haemoglobin (HbA1c) levels at 6-month and 1-year follow-up, and HbA1c change from baseline was analysed. To examine the association of baseline HFS worry scores with second-line use of IS or insulin, a hierarchical logistic model with country as random effect was used. RESULTS: A total of 6217 patients were analysed. The mean HFS worry score was 6.9 ± 11.4, while patients in the upper quartile had an HFS worry score ≥9. We divided patients into three groups according to their baseline HFS worry score (0, 1-8, ≥9). HFS worry score was associated with the use of first-line IS, but not the second-line treatment. Compared to treatments with no IS and insulin, a better HbA1c response to second-line IS or insulin was noted in patients with a baseline HFS worry score of 0 or 1-8, but not in patients with a baseline HFS worry score ≥9. CONCLUSION: HFS worry score was associated with the use of first-line IS and glycemic response to second-line IS or insulin in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02322762. Registered 23 December 2014.

Eligibility of patients with type 2 diabetes for sodium-glucose co-transporter-2 inhibitor cardiovascular outcomes trials: An assessment using the Diabetes Collaborative Registry.

Generalizability of findings from cardiovascular outcomes trials (CVOTs) to patients with type 2 diabetes (T2D) in clinical practice is unknown. We assessed the proportions of patients in the Diabetes Collaborative Registry who would have met enrolment criteria for pivotal CVOTs of sodium-glucose co-transporter-2 inhibitors (SGLT-2is): EMPA-REG OUTCOME, CANVAS, DECLARE and VERTIS CV. In 172 643 patients, mean [standard deviation (SD)] age and HbA1c were 68.1 (11.8) years and 7.8% (2.2), respectively; 56.8% of patients were men and SGLT-2i use was 4.4%. Atherosclerotic cardiovascular disease (ASCVD) prevalence was 64.3% and mean 10-year ASCVD risk was 28.6% in patients without ASCVD. Proportions of patients eligible for CVOTs ranged from 26% (EMPA-REG OUTCOME) to 44% (DECLARE); 48% of patients were ineligible for all CVOTs. Mean (SD) ASCVD risk was 25.4% (22.6), 32.1% (20.6) and 37.7% (19.4) in patients eligible for no, one or two CVOTs, respectively. SGLT-2i use was low in patients eligible for no CVOTs (3.5%) and at least one CVOT (5.2%). In conclusion, applicability of CVOT results to patients with T2D in clinical practice varies based on trial eligibility criteria.

Real-world opportunity of empagliflozin to improve blood pressure control in African American patients with type 2 diabetes: A National Cardiovascular Data Registry "research-to-practice" project from the diabetes collaborative registry.

The 1245.29 Trial recently showed that empaglifozin improved both blood pressure and glucose control in African American (AA) patients with type 2 diabetes (T2D) and hypertension. Using the Diabetes Collaborative Registry, a large-scale US registry of outpatients with diabetes recruited from primary care, cardiology and endocrinology practices, we sought to understand the potential impact of these observations in routine clinical practice. Among 74 290 AA patients with T2D from 368 US clinics, 60.4% had hypertension, of whom 34.5% had systolic blood pressure ≥ 140 mm Hg (20.8% of the total AA T2D population). Only 1.7% of this eligible population had been prescribed a sodium-glucose co-transporter two inhibitor. The mean estimated 5-year risk of cardiovascular death was 7.7%, which could be reduced to 6.2% when modelling the antihypertensive effect of empagliflozin across the eligible population (based on an 8-mm Hg blood pressure reduction). These findings may represent a potential opportunity for better management of cardiovascular risk factors and improved outcomes in this vulnerable cohort.

Management of patients with diabetes and heart failure with reduced ejection fraction: An international comparison.

AIMS: To compare the management of patients with diabetes and heart failure with reduced ejection fraction (HFrEF) in the United States and Asia to understand variations in treatment patterns across different healthcare systems. MATERIALS AND METHODS: Our cohort included patients with diabetes and HFrEF (ejection fraction <40%) from a US-based registry of adults with diabetes (2013-2016, electronic health records) and a multi-national Asian registry of adults with heart failure (2010-2016, prospective registry). Asian countries were categorized as high income (HI) or low income (LI), according to the United Nations classification. Rates of use of guideline-directed medical therapies (determined through review of active medication lists) were compared across regions. RESULTS: Patients with diabetes and HFrEF in the United States (n = 28 877) were older, had higher body mass indices, and were more likely to have coronary disease than those in Asia (n = 2235). Compared with US patients, the use of guideline-directed medical therapy for HFrEF was lower in patients in LI Asian countries (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers: patients in the United States, 77% vs. patients in HI Asian countries, 76% vs patients in LI Asian countries, 69%; ß-blockers: patients in the United States, 91% vs. patients in HI Asian countries, 87% vs. patients in LI Asian countries, 69%; P < 0.001 for both). Insulin was used more commonly in the United States (44% vs. 24% vs. 25%, respectively; P < 0.001), whereas sulphonylureas were more often prescribed in Asian countries (42% vs. 52% vs. 54%; respectively, P < 0.001). Thiazolidinediones were prescribed in 6% of US patients compared with <1% of patients in Asia. The use of newer diabetes medications was <5% in all. CONCLUSION: In both the United States and Asia, opportunities for improvement in the use of evidence-based therapies exist for patients with both diabetes and HFrEF. Effective tools to guide medication choices for these complex, high-risk patients could have substantial impact on quality and outcomes.

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.

Patterns of glucose-lowering medication use in patients with type 2 diabetes and heart failure. Insights from the Diabetes Collaborative Registry (DCR).

BACKGROUND: Optimal glucose-lowering strategies in patients with both heart failure (HF) and type 2 diabetes mellitus (T2D) are not well defined, particularly as novel medication classes emerge.We sought to evaluate current patterns of glucose-lowering medication use in adults with T2D with and without HF. METHODS: The DCR is a US-based outpatient registry of adults with diabetes; currently includes 3074 providers in 203 practices. We used hierarchical, modified Poisson regression models to examine the relationship between concomitant HF with use of each glucose-lowering medication class, adjusting for other factors that could impact selection of one medication class over another: age, chronic kidney disease (CKD), coronary artery disease (CAD), number of glucose-lowering medications, and insurance. RESULTS: Among 456,106 adults with T2D, 125,161 (27%) had a diagnosis of HF (30% HFrEF, 15%HFmrEF, 55% HFpEF). Patients with T2D and HF were more likely to be older and male, and to have CAD, atrial fibrillation, and CKD. In the multivariable models, HF was associated with a greater use of insulin (RR 1.39, 95% CI 1.36-1.42) and lower use of thiazolidinediones (RR 0.79, 95% CI 0.74-0.83), SGLT2 inhibitors (RR 0.83, 95% CI 0.79-0.89), and metformin (RR 0.84, 95% CI 0.82-0.86). Among the subgroup of patients with HF, thiazolidinediones, GLP-1 receptor agonists, and SGLT2 inhibitors were used even less often in patients with lower ejection fraction, indicating that both the diagnosis of clinical HF and ejection fraction may influence the choice of glucose-lowering medications. CONCLUSION: In a large US-based outpatient registry, we found that a quarter of adults with T2D had a diagnosis of HF, which was predominantly HFpEF. Although certain T2D medication use in patients with HF appeared consistent with evidence (less use of thiazolidinediones), others appeared contrary to evidence (less use of metformin and SGLT2 inhibitors).