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Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies.In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 mAmong 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbAA validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes.BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.

AimsSodium–glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking.Methods and resultsIn this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757–2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) −4.4% to −23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2–2.9%, P = 0.029), mean E/e′ reduction was 6.8% (95% CI 1.3–11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4–11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7–15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups.ConclusionIn patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters.ClinicalTrials.gov registration NCT03087773.

BackgroundEjection fraction (EF) is a key component of heart failure (HF) classification, including the increasingly codified HF with mildly reduced EF (HFmrEF) category. However, the biologic basis of HFmrEF as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF) has not been well characterized.MethodsThe EXSCEL trial randomized participants with type 2 diabetes (T2DM) to once-weekly exenatide (EQW) vs. placebo. For this study, profiling of ∼5000 proteins using the SomaLogic SomaScan platform was performed in baseline and 12-month serum samples from N=1199 participants with prevalent HF at baseline. Principal component analysis (PCA) and ANOVA (FDR p55% [HFpEF], EF 40-55% [HFmrEF], EFResultsOf N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation,e.g.COL28A1 and tenascin C [TNC]; pi.e.HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (pConclusionsIn this HF substudy of a large clinical trial of people with T2DM, we found that serum levels of most proteins across multiple biologic domains were similar between HFmrEF and HFpEF. HFmrEF may be more biologically similar to HFpEF than HFrEF, and specific related biomarkers may offer unique data on prognosis and pharmacotherapy modification with variability by EF.

BACKGROUND: Sodium–glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr:ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr:ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin – placebo], –0.25 [95% CI, –0.58 to 0.09]; P =0.14) or HFpEF (adjusted mean treatment difference, –0.16 [95% CI, –0.60 to 0.29]; P =0.47]. Likewise, there were no changes in PCr:ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, –0.13 [95% CI, –0.35 to 0.09]; P =0.23) or HFpEF (adjusted mean treatment difference, –0.22 [95% CI, –0.66 to 0.23]; P =0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03332212.

BACKGROUND AND AIMS: Polyvascular disease is an independent predictor of major adverse cardiovascular events (MACE). The relationship between the number of diseased arterial beds and MACE is unknown. How MACE risk changes in individuals with type 2 diabetes (T2D) is also understudied. Furthermore, it is unknown whether heart failure (HF) status and hemoglobin A1c (HbA1c) levels influence outcomes in polyvascular disease. This analysis from the Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL) aimed to examine the risk associated with increasing number of diseased arterial beds on MACE and all-cause mortality (ACM). METHODS: Cox models were used to test associations between the number of diseased arterial beds and MACE and ACM. Prespecified interaction testing between number of diseased arterial beds with baseline HF, HbA1c (≤8% vs. >8%), and treatment assignment was performed. RESULTS: Overall, 14,751 participants were included; 26.5% were without atherosclerosis, 58.9% had 1-bed, 12.3% had 2-bed, and 2.3% had 3-bed disease. An increasing burden of atherosclerotic disease was associated with increasing risk of MACE (adjusted HR [aHR] 1.71 [95% CI 1.46–2.02]; 2.61 [2.17–3.15]; 3.46 [2.69–4.45] for 1, 2, and 3 beds, respectively, p < 0.001 for all) and ACM (1.94 [1.56–2.42]; 3.03 [2.33–3.95]; 3.66 [2.59–5.18] for 1, 2, and 3 beds, respectively, p < 0.001 for all). Prespecified interaction testing did not reveal any significant associations. CONCLUSIONS: In patients with T2D, compared to those without atherosclerotic vascular disease, risk of MACE and ACM increases incrementally with each additional diseased arterial bed.

Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. In this study, we tested two hypotheses: (1) individuals with body mass index (BMI) 30 kg/m

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c -statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a “universal” surrogate end point for cardiovascular risk.

Background: In a recent individual level meta-analysis, intensive versus standard blood pressure (BP) treatment reduced participants’ risk of orthostatic hypotension (OH). Whether OH modified the relationship between intensive treatment and risk of cardiovascular disease (CVD) or death is unknown. Methods: We performed an individual participant data meta-analysis, updating a previous systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022, which included randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) on CVD or death. CVD events were adjudicated and included coronary heart disease, stroke, and congestive heart failure. OH was defined as a drop in SBP ≥20 mmHg and/or DBP ≥10 mmHg after changing positions from sitting to standing. Ultimately, 8 trials were identified with OH and outcomes data. Effects were examined overall and by trial type (BP goal or active agent), using Cox proportional hazard models adjusted for age and sex. Results: There were 27,974 participants followed for median of 4 years (mean age 69.5±10.7 years; 48.5% female; 8.6% with OH). Baseline OH was associated with a higher risk of CVD or death (HR 1.24; 95% CI: 1.10, 1.39). More intensive BP treatment or active therapy lowered risk of CVD or death among those without OH at baseline (HR 0.82; 95% CI: 0.76, 0.88) and with OH at baseline (HR 0.79; 95% CI: 0.63, 0.98). Effects did not differ by baseline OH ( P -interaction 0.78) ( Table ). Conclusion: While baseline OH was associated with CVD or death, it did not increase the risk of CVD or death from intensive treatment. OH prior to the initiation of intensive therapy should not be viewed as a reason to avoid BP treatment.

Aims Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). Methods and results The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31Phosphorus-MRS. Conclusions EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

OBJECTIVE Type 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA1c values and explored the potential impact of instituting earlier, compared with delayed, glucose-lowering therapy. RESEARCH DESIGN AND METHODS Twenty-year ACM and MI hazard functions were estimated from diagnosis of type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of HbA1c values over time was analyzed by weighting them according to their influence on downstream ACM and MI risks. RESULTS Hazard ratios for a one percentage unit higher HbA1c for ACM were 1.08 (95% CI 1.07–1.09), 1.18 (1.15–1.21), and 1.36 (1.30–1.42) at 5, 10, and 20 years, respectively, and for MI was 1.13 (1.11–1.15) at 5 years, increasing to 1.31 (1.25–1.36) at 20 years. Imposing a one percentage unit lower HbA1c from diagnosis generated an 18.8% (95% CI 21.1–16.0) ACM risk reduction 10–15 years later, whereas delaying this reduction until 10 years after diagnosis showed a sevenfold lower 2.7% (3.1–2.3) risk reduction. Corresponding MI risk reductions were 19.7% (22.4–16.5) when lowering HbA1c at diagnosis, and threefold lower 6.5% (7.4–5.3%) when imposed 10 years later. CONCLUSIONS The glycemic legacy effects seen in type 2 diabetes are explained largely by historical HbA1c values having a greater impact than recent values on clinical outcomes. Early detection of diabetes and intensive glucose control from the time of diagnosis is essential to maximize reduction of the long-term risk of glycemic complications.

We estimate health-related quality of life and the impact of four cardiovascular events (myocardial infarction [MI], stroke, congestive heart failure, angina) and gastrointestinal events in 6522 Chinese patients with coronary heart disease (CHD) and impaired glucose tolerance (IGT) participating in the Acarbose Cardiovascular Evaluation (ACE) trial.Health-related quality of life was captured using the EuroQol-5 Dimension-3 Level (EQ-5D-3L), with data collected at baseline and throughout the trial. Multilevel mixed-effects linear regression with random effects estimated health-related quality of life over time, capturing variation between hospital sites and individuals, and a fixed-effects linear model estimated the impact of cardiovascular and gastrointestinal events.Patients were followed for a median of 5 years (interquartile range 3.4-6.0). The average baseline EQ-5D score of 0.930 (SD 0.104) remained relatively unchanged over the trial period with no evidence of statistically significant differences in EQ-5D score between randomized treatment groups. The largest decrement in the year of an event was estimated for stroke (-0.107, P .001), followed by heart failure (-0.039, P = .022), MI (-0.021, P = .047), angina (-0.012, P = .047), and gastrointestinal events (-0.005, P = .430). MI and stroke reduced health-related quality of life beyond the year in which the event occurred (-0.031, P = .006, and -0.067, P .001, respectively).Acarbose treatment had no impact on health-related quality of life in ACE trial participants with CHD and IGT. Events such as MI, stroke, heart failure, and angina reduce health-related quality of life around the time they occurred, but only MI and stroke impacted on longer-term health-related quality of life.背景: 我们评估了参加阿卡波糖心血管评估(ACE)试验的6,522名中国冠心病(CHD)和糖耐量异常(IGT)患者的健康相关生活质量，以及四种心血管事件(心肌梗死(MI)、中风、充血性心力衰竭、心绞痛)和胃肠道事件的影响。 方法: 使用EuroQol-5 Dimension-3 Level(EQ-5D-3L)获取与健康相关的生活质量信息，收集基线和整个试验过程中的数据。运用具有随机效应的多水平混合效应线性回归估计随时间进展的与健康相关的生活质量，并记录医院和个人之间的差异，使用固定效应线性模型估计心血管和胃肠道事件的影响。 结果: 患者平均随访5年(四分位差3.4~6.0)。在试验期间，平均基线EQ-5D得分为0.930(SD 0.104)保持相对不变，没有证据表明随机治疗组之间的EQ-5D得分在统计学上有显著差异。在事件发生的一年中，使健康相关的生活质量下降幅度最大的是中风(-0.107，p0.001)，其次是心力衰竭(-0.039，p=0.022)、心肌梗塞(-0.021，p=0.047)、心绞痛(-0.012，p=0.047)和胃肠道事件(-0.005，p=0.430)。心肌梗死和中风降低了事件发生后一年与健康相关的生活质量(分别为0.031，p=0.006和-0.067，p0.001)。 结论: 阿卡波糖治疗对患有冠心病和糖耐量异常的ACE试验参与者的健康相关生活质量没有影响。心肌梗死、中风、心力衰竭和心绞痛等事件在发生时会降低与健康相关的生活质量，但只有心肌梗死和中风会对长期的健康相关生活质量产生影响。.

Background The WATCH‐DM (weight [body mass index], age, hypertension, creatinine, high‐density lipoprotein cholesterol, diabetes control [fasting plasma glucose], ECG QRS duration, myocardial infarction, and coronary artery bypass grafting) and TRS‐HF DM (Thrombolysis in Myocardial Infarction [TIMI] risk score for heart failure in diabetes) risk scores were developed to predict risk of heart failure (HF) among individuals with type 2 diabetes. WATCH‐DM was developed to predict incident HF, whereas TRS‐HF DM predicts HF hospitalization among patients with and without a prior HF history. We evaluated the model performance of both scores to predict incident HF events among patients with type 2 diabetes and no history of HF hospitalization across different cohorts and clinical settings with varying baseline risk. Methods and Results Incident HF risk was estimated by the integer‐based WATCH‐DM and TRS‐HF DM scores in participants with type 2 diabetes free of baseline HF from 2 randomized clinical trials (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin], N=12 028; and Look AHEAD [Look Action for Health in Diabetes] trial, N=4867). The integer‐based WATCH‐DM score was also validated in electronic health record data from a single large health care system (N=7475). Model discrimination was assessed by the Harrell concordance index and calibration by the Greenwood‐Nam‐D’Agostino statistic. HF incidence rate was 7.5, 3.9, and 4.1 per 1000 person‐years in the TECOS, Look AHEAD trial, and electronic health record cohorts, respectively. Integer‐based WATCH‐DM and TRS‐HF DM scores had similar discrimination and calibration for predicting 5‐year HF risk in the Look AHEAD trial cohort (concordance indexes=0.70; Greenwood‐Nam‐D’Agostino P >0.30 for both). Both scores had lower discrimination and underpredicted HF risk in the TECOS cohort (concordance indexes=0.65 and 0.66, respectively; Greenwood‐Nam‐D’Agostino P P =0.96). TRS‐HF DM score could not be validated in the electronic health record because of unavailability of data on urine albumin/creatinine ratio in most patients in the contemporary clinical practice. Conclusions The WATCH‐DM and TRS‐HF DM risk scores can discriminate risk of HF among intermediate‐risk populations with type 2 diabetes.

Background and aims: Mechanisms underlying weight loss induced remission of type 2 diabetes (T2DM) have been reported only in people with BMI >27kg/m2. The Personal Fat Threshold hypothesis postulated that the same mechanisms in people with BMI Methods: People with T2DM (13/20 female, mean (±1SD) 59.3±7.1 years, BMI 24.8±1.7kg/m2) were studied before and after up to three 5% weight loss cycles, each comprising a 2-4 week low energy diet (800kcal/day formula meal replacements plus non starchy vegetables) , followed by 4-6 weeks of weight maintenance. All hypoglycemic agents were stopped before weight loss. Studies were repeated at 12 months. Outcomes were compared to normoglycemic matched controls (n=20) . Intrahepatic and intrapancreatic fat was quantified by magnetic resonance, and a standard meal test assessed insulin secretion by Disposition Index (DI) . Results: 70% achieved remission (HbA1c Conclusion: Mechanistic changes underpinning remission after weight loss in non-obese people with T2DM are the same as in obese people. T2DM occurs if a person becomes too heavy for their own constitution, irrespective of BMI. Weight loss of ∼10% can bring about T2DM remission in people classified as having a ‘normal’ BMI. Disclosure R. Taylor: Speaker's Bureau; Janssen Global Services, LLC, Lilly Diabetes, Nestlé Health Science, Novartis AG. C. Cobelli: None. K. M. Irvine: None. A. C. Barnes: None. T. L. Kelly: None. L. G. Clark: None. K. G. Hollingsworth: None. A. Al-mrabeh: None. R. R. Holman: Advisory Panel; Anji Pharmaceuticals, Novartis AG, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. D. Romeres: None. Funding Diabetes UK (17/0005645)

Aim To provide evidence on the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 to 4. Materials and methods This post hoc analysis compared participants with an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73m2 in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR-TIMI 53) trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed-model repeated measures analysis, and the number of lactic acidosis events was tabulated. Results No strong trend for lower metformin doses with lower eGFR values was observed in either the EXSCEL or SAVOR-TIMI 53 trials. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.76-1.08; P = 0.28) and ACM (HR 0.86, 95% CI 0.70-1.07; P = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR-TIMI 53, but not in other groups. Conclusions This analysis of participants with CKD stages 3 to 4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin, but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population.

The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR.

Background Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. Methods We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from Findings We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. Interpretation Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. Funding British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.

Objectives We applied principles for conducting economic evaluations of factorial trials to a trial-based economic evaluation of a cluster-randomized 2 × 2 × 2 factorial trial. We assessed the cost-effectiveness of atorvastatin, omega-3 fish oil, and an action-planning leaflet, alone and in combination, from a UK National Health Service perspective. Methods The Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes (AFORRD) Trial randomized 800 patients with type 2 diabetes to atorvastatin, omega-3, or their respective placebos and randomized general practices to receive a leaflet-based action-planning intervention designed to improve compliance or standard care. The trial was conducted at 59 UK general practices. Sixteen-week outcomes for each trial participant were extrapolated for 70 years using the United Kingdom Prospective Diabetes Study Outcomes Model v2.01. We analyzed the trial as a 2 × 2 factorial trial (ignoring interactions between action-planning leaflet and medication), as a 2 × 2 × 2 factorial trial (considering all interactions), and ignoring all interactions. Results We observed several qualitative interactions for costs and quality-adjusted life-years (QALYs) that changed treatment rankings. However, different approaches to analyzing the factorial design did not change the conclusions. There was a ≥99% chance that atorvastatin is cost-effective and omega-3 is not, at a £20 000/QALY threshold. Conclusions Atorvastatin monotherapy was the most cost-effective combination of the 3 trial interventions at a £20 000/QALY threshold. Omega-3 fish oil was not cost-effective, while there was insufficient evidence to draw firm conclusions about action planning. Recently-developed methods for analyzing factorial trials and combining parameter and sampling uncertainty were extended to estimate cost-effectiveness acceptability curves within a 2x2x2 factorial design with model-based extrapolation., Highlights • Methods have been developed for conducting economic evaluations on 2 × 2 factorial trials, but the impact of more complex designs and studies with model-based extrapolation has not yet been explored. • Atorvastatin has been shown to be cost-effective for patients with type 2 diabetes, whereas omega-3 is not recommended. • We are not aware of any previous studies exploring interactions between statins, omega-3, and interventions to improve compliance in type 2 diabetes. • We applied methods for analyzing factorial trials to a trial with a 2 × 2 × 2 design and a model-based extrapolation. • We observed large interactions between the 3 interventions, although the methods for analyzing the factorial trial did not change the conclusions about which treatment was the best value for the money. • We extended recent work on combining sampling uncertainty and parameter uncertainty to estimate cost-effectiveness acceptability curves and the value of perfect information. • We confirmed that atorvastatin is cost-effective, but omega-3 is not. • Further research on action-planning interventions to improve compliance is likely to be good value for money.

OBJECTIVE To estimate using the UK Prospective Diabetes Study Outcomes Model Version 2 (UKPDS-OM2) the impact of delaying type 2 diabetes onset on costs and quality-adjusted life expectancy using trial participants who developed diabetes in the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) study. RESEARCH DESIGN AND METHODS We simulated the impact of delaying diabetes onset by 1–9 years, utilizing data from the 3,058 of 9,306 NAVIGATOR trial participants who developed type 2 diabetes. Costs and utility weights associated with diabetes and diabetes-related complications were obtained for the U.S. and U.K. settings, with costs expressed in 2017 values. We estimated discounted lifetime costs and quality-adjusted life years (QALYs) with 95% CIs. RESULTS Gains in QALYs increased from 0.02 (U.S. setting, 95% CI 0.01, 0.03) to 0.15 (U.S. setting, 95% CI 0.10, 0.21) as the imposed time to diabetes onset was increased from 1 to 9 years, respectively. Savings in complication costs increased from $1,388 (95% CI $1,092, $1,669) for a 1-year delay to $8,437 (95% CI $6,611, $10,197) for a delay of 9 years. Interventions costing up to $567–$2,680 and £201–£947 per year would be cost-effective at $100,000 per QALY and £20,000 per QALY thresholds in the U.S. and U.K., respectively, as the modeled delay in diabetes onset was increased from 1 to 9 years. CONCLUSIONS Simulating a hypothetical diabetes-delaying intervention provides guidance concerning the maximum cost and minimum delay in diabetes onset needed to be cost-effective. These results can inform the ongoing debate about diabetes prevention strategies and the design of future intervention studies.

Aims Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA1c ) and cardiovascular outcomes in a placebo-controlled randomized trial which demonstrated no cardiovascular effect of sitagliptin in patients with T2D and atherosclerotic vascular disease. Methods and results Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3-3.8) year follow-up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non-HF cardiovascular event (cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time-varying HbA1c and cardiovascular outcomes were U-shaped, with the lowest risk when HbA1c was around 7%. Each one-unit increase in the time-varying HbA1c above 7% was associated with an adjusted hazard ratio (HR) of 1.21 [95% confidence interval (CI) 1.11-1.33] for first HF hospitalization, 1.11 (1.03-1.21) for all-cause death, 1.18 (1.09-1.26) for death or HF hospitalization, and 1.10 (1.02-1.17) for non-HF cardiovascular events. Each one-unit decrease in the time-varying HbA1c below 7% was associated with an adjusted HR of 1.35 (95% CI 1.12-1.64) for first HF hospitalization, 1.37 (1.16-1.61) for death, 1.42 (1.23-1.64) for death or HF hospitalization, and 1.22 (1.06-1.41) for non-HF cardiovascular events. Conclusion Glycated haemogobin exhibits a U-shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%. Clinical trial registration ClinicalTrials.gov Identifier: NCT00790205.

OBJECTIVE We examined the impact of acarbose, an α-glucosidase inhibitor, on incident diabetes and regression to normoglycemia in 6,522 Acarbose Cardiovascular Evaluation (ACE) trial participants in China who had impaired glucose tolerance (IGT) and coronary heart disease (CHD). RESEARCH DESIGN AND METHODS Participants were randomly assigned to acarbose or placebo and followed with four monthly fasting plasma glucose (FPG) tests and annual oral glucose tolerance tests. Incident diabetes was defined as two successive diagnostic FPG levels ≥7 mmol/L or 2-h plasma glucose (PG) levels ≥11.1 mmol/L while taking study medication or a masked adjudicated confirmation of this diagnosis. Regression to normoglycemia was defined as FPG RESULTS Incident diabetes was less frequent with acarbose compared with placebo (3.2 and 3.8 per 100 person-years, respectively; rate ratio 0.82 [95% CI 0.71, 0.94], P = 0.005), with no evidence of differential effects within the predefined subgroups after accounting for multiple testing. Regression to normoglycemia occurred more frequently in those randomized to acarbose compared with placebo (16.3 and 14.1 per 100 person-years, respectively; 1.16 [1.08, 1.25], P < 0.0001). This effect was greater in participants not taking an ACEi or ARB (1.36 [1.21, 1.53], Pinteraction = 0.0006). The likelihood of remaining in normoglycemic regression did not differ between the acarbose and placebo groups (P = 0.41). CONCLUSIONS Acarbose reduced the incidence of diabetes and promoted regression to normoglycemia in Chinese people with IGT and CHD.