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1.
Diabetes Obes Metab ; 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32115840

RESUMO

AIM: To perform post-hoc analyses of the EMPA-REG OUTCOME trial examining the degree to which empagliflozin-induced changes in conventional cardiovascular (CV) risk factors might explain the observed CV benefits. MATERIALS AND METHODS: We estimated 3-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL cholesterol, LDL cholesterol, systolic blood pressure, glycated haemoglobin, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate, and histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk reductions were compared. RESULTS: Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for all-cause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). CONCLUSIONS: Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and all-cause death reductions observed. Alternative risk-reduction mechanisms need to be explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.

2.
Diabetes Ther ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32086768

RESUMO

INTRODUCTION: To date, research is lacking on the development of a cardiovascular disease (CVD) risk assessment tool for people with diabetes mellitus, in general, and for Chinese patients with diabetes in particular. We have explored CVD risk assessment tools for Chinese patients with diabetes. Here, we report our investigation of cardiovascular risk assessment using the improved Framingham Risk Score (I-FRS) in patients with type 2 diabetes mellitus (T2DM) in Beijing communities. METHODS: A total of 3232 patients with T2DM attending Beijing community health centers were enrolled in this study. FRS were used to predict CVD risk in all patients at baseline using the following risk scores for glycated hemoglobin (HbA1c) categories: 0 = HbA1c ≤ 7.0%; 1 = 7.0% < HbA1c ≤ 7.9%;      2 = 8.0% < HbA1c ≤ 8.9%; and 3 = HbA1c > 9.0%. The I-FRS was use to stratify all patients into low (I-FRS < 10%), medium (I-FRS 10-20%), and high (I-FRS > 20%) FRS strata. All treatments administered in the Beijing Communities Diabetes Study were in accordance with national guidelines for T2DM in China, and patients regularly attended clinical consultations with professors in endocrinology, who were experts in their respective speciality, from top tier hospitals. After 10 years, patients were followed-up to assess the long-term effects of the multifactorial interventions. Statistical analysis was performed using SAS® software (SAS Institute, Inc., Cary, NC, USA). RESULTS: The receiver operating characteristic curve of the I-FRS showed significant prediction accuracy for the actual incidence of CVD events. At baseline, subjects in the high FRS stratum for diabetes were more prone to be elderly and to have a longer duration of T2DM, higher systolic blood pressure, and higher lipid profiles. Subjects in the medium and high FRS strata had a higher incidence of CVD events than those in the no-complications group (DM group with no blood pressure issues) (P < 0.001). The 10-year hazard ratios for CVD events in diabetic patients with I-FRS score > 20% was 12.5-fold higher than that of patients with I-FRS score < 10%. Multifactorial intervention significantly reduced the I-FRS of the three FRS strata in patients with T2DM. The post-intervention I-FRS for the hypertension and CVD groups of patients were significantly lower than the respective baseline I-FRS. Cox multivariate analyses revealed that patients in the medium and high FRS strata had higher incidences of endpoint events than those in the low FRS stratum. CONCLUSIONS: The I-FRS plays an important role in predicting CVD in patients with T2DM. Multifactorial interventions for CVD risk factors over 10-year follow-up lowered the estimated 10-year risk for CVD events in persons with diabetes. We suggest the use of the I-FRS score to stratify a patient's risk of CVD when analyzing the efficacy of diabetes management. Aggressive risk reduction should be focused on those individuals with a high I-FRS score. TRIAL REGISTRATION: ChiCTR-TRC-13003978 and ChiCTR-OOC-15006090.

3.
Lancet Diabetes Endocrinol ; 8(3): 206-215, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032540

RESUMO

BACKGROUND: Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status. METHODS: We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. FINDINGS: Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p<0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbA1c seen in adults with latent autoimmune diabetes than in those with type 2 diabetes explained entirely their subsequent increased risk for the composite microvascular outcome (adjusted HR 0·99 [95% CI 0·80-1·23], p=0·93). INTERPRETATION: At diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes. FUNDING: European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).

4.
Circulation ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32098501

RESUMO

Background: The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14,752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% vs. 28.8%), with metformin (6.1% vs. 4.9%), sulfonylurea (8.7% vs. 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% vs. 7.5%), SGLT-2i (10.3% vs. 8.1%), GLP1 RA (3.4% vs. 2.4%), and insulin (13.8% vs. 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (p=0.061) to 0.85 (p=0.008) and the ACM HR from 0.86 (p=0.016) to 0.81 (p=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or pvalues, although simulations of substantially greater use of drop-in cardioprotective glucoselowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01144338.

5.
Circulation ; 141(10): 843-862, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31992065

RESUMO

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

6.
Diabetes Obes Metab ; 22(5): 798-806, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31912603

RESUMO

AIM: To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. MATERIALS AND METHODS: Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. RESULTS: Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. CONCLUSIONS: Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL.

7.
Am Heart J ; 219: 47-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707324

RESUMO

BACKGROUND: Obesity is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whether obesity affects outcomes among those with T2D and atherosclerotic CVD (ASCVD) remains uncertain. Our objective was to investigate the relationship between body mass index (BMI) and ASCVD outcomes among TECOS participants with T2D and ASCVD. METHODS: BMI categories were defined as underweight/normal weight (BMI <25 kg/m2), overweight (25-29.9 kg/m2), obese class I (30-34.9 kg/m2), obese class II (35-39.9 kg/m2), and obese class III (≥ 40 kg/m2). Asian-specific BMI categories were applied to Asian participants. Kaplan-Meier survival analysis and Cox proportional hazards models were used to examine associations between baseline BMI and a composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina). RESULTS: For 14,534 TECOS patients with available BMI, mean age was 65.5 years; 29.3% were female, 32.0% non-White, and 23.1% insulin-treated, with median 3 years' follow-up. At baseline, 11.6% (n = 1686) were underweight/normal weight, 38.1% (n = 5532) overweight, 32.2% (n = 4683) obese class I, 12.4% (n = 1806) obese class II, and 5.7% (n = 827) obese class III. The composite CV outcome occurred in 11.4% (n = 1663) of participants; the outcome risk was lower, compared with under/normal weight, in overweight (HR 0.83, 95% CI 0.71-0.98) and obese class I (HR 0.79, 95% CI 0.67-0.93) individuals. Obesity was not associated with worse glycemic control. CONCLUSIONS: The majority of TECOS participants with ASCVD and T2D were overweight or obese, yet overweight or obese class I individuals had lower CV risk than those who were under/normal weight. These results suggest the presence of an obesity paradox, but this paradox may reflect an epidemiological artifact rather than a true negative association between normal weight and clinical outcomes.

8.
Diabetes Care ; 43(2): 374-381, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31806653

RESUMO

OBJECTIVE: To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS: Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.S. Medicare payments and wholesale acquisition costs, respectively. Secondary analyses used English costs. RESULTS: Patients were followed for an average of 3.3 years, during which time those randomized to EQW experienced 0.41 fewer inpatient days (7.05 vs. 7.46 days; relative rate ratio 0.91; P = 0.05). Rates of outpatient medical visits were similar, as were total inpatient and outpatient costs. Mean costs for nonstudy diabetes medications over the study period were ∼$1,600 lower with EQW than with placebo (P = 0.01). Total within-study costs, excluding study medication, were lower in the EQW arm than in the placebo arm ($28,907 vs. $30,914; P ≤ 0.01). When including the estimated cost of EQW, total mean costs were significantly higher in the EQW group than in the placebo group ($42,697 vs. $30,914; P < 0.01). With English costs applied, mean total costs, including exenatide costs, were £1,670 higher in the EQW group than the placebo group (£10,874 vs. £9,204; P < 0.01). There were no significant differences in EQ-5D health utilities between arms over time. CONCLUSIONS: Medical costs were lower in the EQW arm than the placebo arm, but total costs were significantly higher once the cost of branded exenatide was incorporated.

9.
Am Heart J ; 220: 82-88, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790905

RESUMO

BACKGROUND: Type 2 diabetes (T2D) patients are at increased risk for cardiovascular (CV) events. Most guidelines recommend treating low-density lipoprotein cholesterol (LDL-C) levels to ≤70 mg/dL (1.8 mM) for patients with T2D and established atherosclerotic CV disease, and some a more aggressive target of ≤55 mg/dL (1.4 mM). Our objective was to assess the degree to which these LDL-C targets are achieved in routine practice. METHODS: Using data from TECOS, an international pragmatic CV outcomes trial of sitagliptin vs placebo, we assessed lipid-lowering treatment among patients with T2D and CV disease, baseline lipid values, and the association between baseline LDL-C and 5-year risk for major adverse cardiac events (MACE; ie, CV death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 11,066 of 14,671 TECOS participants (75.4%) had LDL-C measured at baseline. Median age was 65 years, 72% were male, and median T2D duration was 10 years. Overall, 82.5% of patients were on statins; only 5.8% were on ezetimibe. At baseline, 14.3% had LDL-C ≤55 mg/dL, 18.4% between 55.1 and 70 mg/dL, 35% between 70.1 and 100 mg/dL, and 32.3% >100 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a higher risk of MACE (HR 1.05, 95% CI 1.03-1.07) or CV death (HR 1.06, 95% CI 1.04-1.09). CONCLUSIONS: Although most high-risk patients with T2D and CV disease were on lipid-lowering therapy, only 1:3 had LDL-C <70 mg/dL and 1:6 had LDL-C <55 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a 5% and 6% higher 5-year incidence of MACE and CV death, respectively. (TECOS, NCT00790205).

10.
Diabetes Care ; 43(2): 446-452, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757838

RESUMO

OBJECTIVE: To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS: Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS: EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI -0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70-1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74-0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58-0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85-1.38]; P for interaction = 0.031). CONCLUSIONS: EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity.

11.
Diabetes Care ; 43(3): 643-652, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31882409

RESUMO

OBJECTIVE: We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. RESEARCH DESIGN AND METHODS: In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. RESULTS: SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94-1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38-2.42], P < 0.001), CV death (1.60 [1.11-2.30], P = 0.012), and hHF (2.09 [1.37-3.17], P = 0.001), while nonfatal MI (2.02 [1.35-3.01], P = 0.001), nonfatal stroke (2.30 [1.25-4.23], P = 0.007), hACS (2.00 [1.39-2.90], P < 0.001), and hHF (3.24 [1.98-5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. CONCLUSIONS: These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

12.
Am Heart J ; 218: 57-65, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707329

RESUMO

International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. ß-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials.

13.
Diabetes Care ; 42(6): 1136-1146, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31666233

RESUMO

Technological progress in the past half century has greatly increased our ability to collect, store, and transmit vast quantities of information, giving rise to the term "big data." This term refers to very large data sets that can be analyzed to identify patterns, trends, and associations. In medicine-including diabetes care and research-big data come from three main sources: electronic medical records (EMRs), surveys and registries, and randomized controlled trials (RCTs). These systems have evolved in different ways, each with strengths and limitations. EMRs continuously accumulate information about patients and make it readily accessible but are limited by missing data or data that are not quality assured. Because EMRs vary in structure and management, comparisons of data between health systems may be difficult. Registries and surveys provide data that are consistently collected and representative of broad populations but are limited in scope and may be updated only intermittently. RCT databases excel in the specificity, completeness, and accuracy of their data, but rarely include a fully representative sample of the general population. Also, they are costly to build and seldom maintained after a trial's end. To consider these issues, and the challenges and opportunities they present, the editors of Diabetes Care convened a group of experts in management of diabetes-related data on 21 June 2018, in conjunction with the American Diabetes Association's 78th Scientific Sessions in Orlando, FL. This article summarizes the discussion and conclusions of that forum, offering a vision of benefits that might be realized from prospectively designed and unified data-management systems to support the collective needs of clinical, surveillance, and research activities related to diabetes.

14.
Am Heart J ; 218: 92-99, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715435

RESUMO

BACKGROUND: The effects of ß-blocker therapy in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. We sought to evaluate associations between ß-blocker use in T2D with ASCVD and cardiovascular (CV) outcomes. METHODS: In patients with T2D and ASCVD enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), an inverse probability of treatment-weighted Cox proportional hazards model was used to examine the association between baseline ß-blocker therapy (at randomization) and the primary CV composite (defined as CV death, non-fatal myocardial infarction [MI], non-fatal stroke, or hospitalization for unstable angina), including in subgroups with prior MI and heart failure (HF); other outcomes evaluated included individual components of the primary composite, hospitalization for HF, and severe hypoglycemic events. RESULTS: Of the 14,671 patients randomized, 9322 (64%) were on a ß-blocker at baseline; these patients were more likely to have prior MI or HF. Over a median 3.0 (25th, 75th percentile: 2.2, 3.6) years, the risk of the primary CV composite was significantly higher with baseline ß-blocker use versus no ß-blocker use (4.5 vs. 3.4 events/100-patient years, adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05-1.29); no significant interaction was noted for patients with versus without prior MI or HF. Baseline ß-blocker use was not associated with risks for severe hypoglycemic events (HR 1.14, 95% CI 0.88-1.48). CONCLUSIONS: In this observational analysis of T2D and ASCVD, baseline ß-blocker use was not associated with risks for severe hypoglycemia yet also was not associated with CV risk reduction over 3 years of follow-up, supporting a randomized examination of chronic ß-blocker therapy in this patient population. (TECOS ClinicalTrials.gov number, NCT00790205).

15.
Circ Cardiovasc Interv ; 12(12): e008018, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752517

RESUMO

BACKGROUND: Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering). METHODS: EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD. RESULTS: EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27]; P=0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20-1.60]; P<0.001) and more frequent LEA (adjusted hazard ratio 5.48 [95% CI, 4.16-7.22]; P<0.001). Patients treated with exenatide or placebo had similar rates of MACE and LEA, regardless of PAD status. CONCLUSIONS: EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

16.
Cardiovasc Diabetol ; 18(1): 138, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640705

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS: In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS: In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS: This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

17.
Cardiovasc Diabetol ; 18(1): 135, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623625

RESUMO

BACKGROUND: Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. METHODS: We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. RESULTS: Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. CONCLUSIONS: Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

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Circulation ; 140(20): 1613-1622, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31542942

RESUMO

BACKGROUND: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. METHODS: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. RESULTS: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77-0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80-0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85-1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68-0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71-0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89-1.29]; interaction P=0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68-0.99]; P=0.038). CONCLUSIONS: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

19.
Cardiovasc Diabetol ; 18(1): 116, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481069

RESUMO

BACKGROUND: To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. RESULTS: During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. CONCLUSIONS: In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.

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