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1.
CMAJ ; 191(35): E955-E961, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481423

RESUMO

BACKGROUND: The evolving clinical burden of limb loss secondary to diabetes and peripheral artery disease remains poorly characterized. We sought to examine secular trends in the rate of lower-extremity amputations related to diabetes, peripheral artery disease or both. METHODS: We included all individuals aged 40 years and older who underwent lower-extremity amputations related to diabetes or peripheral artery disease in Ontario, Canada (2005-2016). We identified patients and amputations through deterministic linkage of administrative health databases. Quarterly rates (per 100 000 individuals aged ≥ 40 yr) of any (major or minor) amputation and of major amputations alone were calculated. We used time-series analyses with exponential smoothing models to characterize secular trends and forecast 2 years forward in time. RESULTS: A total of 20 062 patients underwent any lower-extremity amputation, of which 12 786 (63.7%) underwent a major (above ankle) amputation. Diabetes was present in 81.8%, peripheral artery disease in 93.8%, and both diabetes and peripheral artery disease in 75.6%. The rate of any amputation initially declined from 9.88 to 8.62 per 100 000 between Q2 of 2005 and Q4 of 2010, but increased again by Q1 of 2016 to 10.0 per 100 000 (p = 0.003). We observed a significant increase in the rate of any amputation among patients with diabetes, peripheral artery disease, and both diabetes and peripheral artery disease. Major amputations did not significantly change among patients with diabetes, peripheral artery disease or both. INTERPRETATION: Lower-extremity amputations related to diabetes, peripheral artery disease or both have increased over the last decade. These data support renewed efforts to prevent and decrease the burden of limb loss.

4.
Diabetes Obes Metab ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31379119

RESUMO

People with diabetes mellitus are at higher risk of ischaemic stroke and worse outcomes thereafter. However, whether it is better to prescribe intensive glucose-lowering treatment compared with conventional treatment in people with diabetes to prevent recurrent stroke is debated. It is also crucial to consider whether specific antidiabetic agents are more efficacious and safer than others for prevention of stroke. In this review, we provide an overview of the efficacy of intensive and conventional glucose-lowering treatment in post-stroke management. Our conclusion is that the overall evidence for a beneficial effect of intensive glycaemic control on risk of stroke is limited. We also discuss evidence from recent large clinical trials of thiazolidinediones and new antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 inhibitors. On the basis of the findings of these trials, our conclusion is that pioglitazone and the GLP-1RA class (other than short-acting lixisenatide) are likely to lessen the occurrence of cerebrovascular disease (by mechanisms not dependent on glucose-lowering per se), whereas there is no consistent evidence for other drug classes.

6.
Menopause ; 26(9): 1002-1009, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31453962

RESUMO

OBJECTIVE: We sought to examine the association of menopausal hot flashing with vascular reactivity in two different vascular beds in the same cohort of postmenopausal women and explore the relationship between hot flashing and cardiovascular disease (CVD) risk profile. METHODS: A cross-sectional study of 79 healthy postmenopausal women, 23 of whom have never had menopausal hot flashes and 56 of whom have reported hot flashes. Endothelial function at a microvascular level was measured with Laser Doppler Imaging with Iontophoresis which assesses the response to both acetylcholine (Ach, endothelium dependent) and sodium-nitroprusside (SNP, endothelium independent). Reactive Hyperemia Index (RHI) was measured with peripheral arterial tonometry as a marker of endothelial function mainly at a macrovascular level. Metabolic biomarkers including insulin sensitivity were assessed. RESULTS: Women with hot flashes had enhanced microvascular response to Ach by ∼30% (P = 0.04) and to SNP by ∼31% (P = 0.02), but lower RHI by ∼13% (P = 0.05) compared with women without flashes. Hot flashing was associated with enhanced response to SNP and lower RHI after adjustment for confounders and conventional CVD risk factors. Women with hot flashes were more insulin resistant than nonflashers (HOMAIR: 1.9 (1.2-2.6) vs 1.4 (0.8-1.9), P = 0.03). CONCLUSIONS: Our data support the association of hot flashing with greater insulin resistance and lower macrovascular response. The paradoxical enhanced microvascular response in hot flashers could be the result of the net effect of thermoregulatory and nonnitric oxide-related pathways rather than of endothelial integrity.

7.
Nat Commun ; 10(1): 3346, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

8.
Arthritis Rheumatol ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469238

RESUMO

OBJECTIVE: To compare the risk for major adverse cardiovascular events (MACE) in RA patients treated with tocilizumab versus the tumor necrosis factor inhibitor etanercept. METHODS: This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (N=3080), inadequate responses to conventional synthetic disease-modifying antirheumatic drugs, and at least one cardiovascular risk factor. Patients were randomly assigned 1:1 to open-label tocilizumab 8 mg/kg/month or etanercept 50 mg/week and followed up for an average of 3.2 years. The primary end point was comparison of time-to-first MACE. The trial was powered to exclude a 1.8 or higher relative hazard of MACE for tocilizumab versus etanercept. RESULTS: By week 4, serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were 11.1%, 5.7%, and 13.6% higher, respectively, for patients allocated to tocilizumab compared with etanercept (all P<.001). During follow-up, 83 MACE occurred in the tocilizumab group compared with 78 in the etanercept group. The estimated hazard of MACE for tocilizumab relative to etanercept was 1.05 (95% confidence interval=0.77, 1.43). Result were similar in sensitivity analyses and the on-treatment analysis. Adverse events that occurred more frequently in the tocilizumab group included serious infection and gastrointestinal perforation. CONCLUSION: The trial, which provides insights into the cardiovascular safety of tocilizumab versus etanercept, excluded a relative risk for MACE of 1.43 or higher. This result should be interpreted in the context of the clinical efficacy and the non-cardiovascular safety of tocilizumab. This article is protected by copyright. All rights reserved.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31422062

RESUMO

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. METHODS: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. FINDINGS: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.

10.
Heart ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366573

RESUMO

BACKGROUND: There are known risk factors associated with the development of heart failure (HF), but it is not fully understood whether these differ by sex. OBJECTIVES: To investigate sex differences in risk factors for HF incidence and mortality. METHODS: 468 941 participants (55.9% women, age range 37-73 years) were included. Established CVD risk factors (hypertension, hypercholesterolaemia, diabetes type 1 and 2, adiposity, smoking, physical activity and poor diet) and novel risk factors (grip strength, fitness, TV viewing and sleep duration) were the exposures of interest. HF incidence and mortality were the outcomes. RESULTS: Over a mean follow-up of 9.0 years, 1812 participants developed HF and 763 died due to HF. Women with type 1 diabetes (T1DM), type 2 diabetes (T2DM), hypertension, hypercholesterolaemia, low levels of physical activity and fitness, low strength, high levels of TV viewing, sleep duration <7 hours/day, smokers; those who were underweight and who were obese, had high body surface area and those who drink >14 units of alcohol were at higher risk of HF incidence. However, in women T2DM, hypercholesterolaemia, >3 hours/day of TV and sleep <7 hours/day, low level of physical activity and high level of TV viewing were more strongly associated with HF incidence compared with men. CONCLUSION: Several modifiable risk factors (in particular diabetes) appear more strongly associated with HF in women compared with men. The relevance of these findings to HF characteristics and future outcomes needs to be established.

11.
Curr Atheroscler Rep ; 21(10): 41, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31350612

RESUMO

PURPOSE OF REVIEW: We summarize the best evidence for statins in the prevention and treatment of heart failure. RECENT FINDINGS: In patients with cardiovascular risk factors or established atherosclerotic cardiovascular disease (but without heart failure), statins reduce the risk of incident heart failure-mainly by preventing myocardial infarction although an additional benefit from reducing myocardial ischemia cannot be excluded. However, in patients with established heart failure, statins do not reduce the risk of cardiovascular death, which is mainly caused by pump failure and ventricular arrhythmias. Retrospective analyses, however, suggest that statins may reduce the rate of heart failure hospitalization and atherosclerotic events (which are proportionately much less common in these patients than heart failure hospitalization or death). Statin therapy should probably be continued in patients with coronary artery disease developing heart failure, although the weak evidence and small benefit may not justify the use of this treatment in very elderly patients with a short life expectancy and in which polypharmacy is a problem.

12.
Diabet Med ; 36(9): 1072-1074, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271670
13.
Diabetes Care ; 42(9): 1792-1799, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292141

RESUMO

OBJECTIVE: Microvascular complications are common among patients with diabetes mellitus (DM). The presence of heart failure (HF) is presumed to be due to macrovascular disease (typically HF with reduced ejection fraction [HFrEF] following myocardial infarction). We hypothesized that HF with preserved ejection fraction (HFpEF) in patients with DM may be a manifestation of microvascular disease compared with HFrEF. The objective of this study was to examine the prevalence and association with clinical outcome of microvascular complications in patients with HF and DM. RESEARCH DESIGN AND METHODS: We investigated the prevalence, association with clinical outcome, and cardiac structure and function of microvascular (neuropathy, nephropathy, and retinopathy) complications of DM in 2,800 prospectively enrolled participants with HF and DM (561 with HFpEF) from the Asian Sudden Cardiac Death In Heart Failure (ASIAN-HF) registry. RESULTS: A total of 601 (21.5%) participants with DM had microvascular complications. Participants with DM and any (one or more) microvascular complications were more likely to have HFpEF (odds ratio 1.70 [95% CI 1.15-2.50]; P = 0.008). Furthermore, the likelihood of having HFpEF increased with an increasing number of microvascular complications (P trend < 0.001). Microvascular complications were associated with more left ventricular (LV) hypertrophy and a greater reduction in quality of life in HFpEF than HFrEF (P interaction < 0.001 for all). Compared with participants with DM and without microvascular complications, the adjusted hazard ratio for the composite outcome of all-cause death or HF hospitalization was 1.35 (95% CI 1.04-1.76) for participants with DM and microvascular complications regardless of HF type (P interaction = 0.112). CONCLUSIONS: Diabetic microvascular disease is more common, and related to greater LV remodeling, more impairment of quality in life, and similar adverse outcomes, in participants with HFpEF compared with HFrEF. HFpEF may be a clinical manifestation of microvascular disease in DM.

14.
Eur J Endocrinol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325907

RESUMO

OBJECTIVE: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). DESIGN AND METHODS: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). RESULTS: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, body mass index, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR 1.28 per 1 SD higher cortisol, 95% CI 1.06-1.54). In the meta-analysis of prospective studies the equivalent result was OR 1.18, 95% CI 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR 1.06, 95% CI 0.98-1.15. CONCLUSIONS: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

15.
Nat Rev Rheumatol ; 15(8): 461-474, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292564

RESUMO

Cardiometabolic comorbidities present a considerable burden for patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Both RA and PsA are associated with an increased risk of cardiovascular disease (CVD). PsA more often exhibits an increased risk of metabolically linked comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Although both RA and PsA are characterized by a state of chronic inflammation, the mechanisms that contribute to CVD risk in these conditions might not be identical. In RA, systemic inflammation is thought to directly contribute to CVD risk, whereas in PsA, adiposity is thought to contribute to a notable metabolic phenotype that, in turn, contributes to CVD risk. Hence, appropriate management strategies that consider the increased risk of cardiometabolic comorbidities in patients with inflammatory arthropathy are important. In RA, such strategies should focus on the prediction of CVD risk and its management through targeting chronic inflammation and traditional CVD risk factors. In PsA, management strategies should additionally focus on targeting metabolic components, including weight management, which might not only help improve disease activity in the joints, entheses and skin, but also reduce the risk of metabolic comorbidities and improve the quality of life of patients.

16.
Int J Obes (Lond) ; 43(8): 1526-1538, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168053

RESUMO

OBJECTIVE: To investigate whether the association between a genetic profile risk score for obesity (GPRS-obesity) (based on 93 SNPs) and body mass index (BMI) was modified by physical activity (PA), cardiorespiratory fitness, commuting mode, walking pace and sedentary behaviours. METHODS: For the analyses we used cross-sectional baseline data from 310,652 participants in the UK Biobank study. We investigated interaction effects of GPRS-obesity with objectively measured and self-reported PA, cardiorespiratory fitness, commuting mode, walking pace, TV viewing, playing computer games, PC-screen time and total sedentary behaviour on BMI. Body mass index (BMI) was the main outcome measure. RESULTS: GPRS-obesity was associated with BMI (ß:0.54 kg.m-2 per standard deviation (SD) increase in GPRS, [95% CI: 0.53; 0.56]; P = 2.1 × 10-241). There was a significant interaction between GPRS-obesity and objectively measured PA (P[interaction] = 3.3 × 10-11): among inactive individuals, BMI was higher by 0.58 kg.m-2 per SD increase in GPRS-obesity (p = 1.3 × 10-70) whereas among active individuals the relevant BMI difference was less (ß:0.33 kg.m-2, p = 6.4 × 10-41). We observed similar patterns for fitness (Unfit ß:0.72 versus Fit ß:0.36 kg.m-2, P[interaction] = 1.4 × 10-11), walking pace (Slow ß:0.91 versus Brisk ß:0.38 kg.m-2, P[interaction] = 8.1 × 10-27), discretionary sedentary behaviour (High ß:0.64 versus Low ß:0.48 kg.m-2, P[interaction] = 9.1 × 10-12), TV viewing (High ß:0.62 versus Low ß:0.47 kg.m-2, P[interaction] = 1.7 × 10-11), PC-screen time (High ß:0.82 versus Low ß:0.54 kg.m-2, P[interaction] = 0.0004) and playing computer games (Often ß:0.69 versus Low ß:0.52 kg.m-2, P[interaction] = 8.9 × 10-10). No significant interactions were found for commuting mode (car, public transport, active commuters). CONCLUSIONS: Physical activity, sedentary behaviours and fitness modify the extent to which a set of the most important known adiposity variants affect BMI. This suggests that the adiposity benefits of high PA and low sedentary behaviour may be particularly important in individuals with high genetic risk for obesity.

17.
Circulation ; 140(7): 542-552, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31216866

RESUMO

BACKGROUND: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. METHODS: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non-HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). RESULTS: ApoB, LDL-C, and non-HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non-HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non-HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non-HDL-C did not further improve discrimination. CONCLUSIONS: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

18.
Age Ageing ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31204772

RESUMO

BACKGROUND: higher grip strength is associated with better health outcomes. The optimal way to report grip strength (i.e. absolute vs. relative) for prediction, however, remains to be established. METHODS: in participants (aged 37-73 at baseline) from the UK Biobank, we examined the associations of grip strength, expressed in absolute terms (kilograms) and relative to anthropometric variables, with mortality and disease incidence, after exclusion of the first 2 years of follow-up, and compared risk predictions scores of handgrip strength when differentially expressed. RESULTS: of the 356 721 participants included in the analysis 6,234 died (1.7%) and 4,523 developed CVD (1.3%) over a mean follow-up of 5.0 years (ranging from 3.3 to 7.8) for mortality and 4.1 years (ranging from 2.4 to 7.0) for disease incidence data. As expected, baseline higher grip strength was associated with lower risk of all-cause and cause specific mortality and incidence. These associations did not meaningfully differ when grip-strength was expressed in absolute terms, vs. relative to height, weight, fat-free mass, BMI, fat-free mass index and fat-free mass, or as z-scores. Similarly the different ways of expressing grip strength had little effect on the ability of grip strength to improve risk prediction, based on C-index change, of an office-based risk score. CONCLUSIONS: the ability of grip strength to predict mortality is not altered by changing how it is expressed.

19.
Diabetologia ; 62(8): 1337-1348, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201437

RESUMO

AIMS/HYPOTHESIS: Individuals of South Asian origin have a high risk of type 2 diabetes and of dying from a diabetes-attributable cause. Lifestyle modification intervention trials to prevent type 2 diabetes in high-risk South Asian adults have suggested more modest effects than in European-origin populations. The strength of the evidence of individual studies is limited, however. We performed an individual participant data meta-analysis of available RCTs to assess the effectiveness of lifestyle modification in South Asian populations worldwide. METHODS: We searched PubMed, EMBASE, Cochrane Library and Web of Science (to 24 September 2018) for RCTs on lifestyle modification interventions incorporating diet and/or physical activity in South Asian adults. Reviewers identified eligible studies and assessed the quality of the evidence. We obtained individual participant data on 1816 participants from all six eligible trials (four from Europe and two from India). We generated HR estimates for incident diabetes (primary outcome) and mean differences for fasting glucose, 2 h glucose, weight and waist circumference (secondary outcomes) using mixed-effect meta-analysis overall and by pre-specified subgroups. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence of the estimates. The study is registered with the International Prospective Register of Systematic Reviews ([PROSPERO] CRD42017078003). RESULTS: Incident diabetes was observed in 12.6% of participants in the intervention groups and in 20.0% of participants in the control groups. The pooled HR for diabetes incidence was 0.65 (95% CI 0.51, 0.81; I2 = 0%) in intervention compared with control groups. The absolute risk reduction was 7.4% (95% CI 4.0, 10.2), with no interactions for the pre-specified subgroups (sex, BMI, age, study duration and region where studies were performed). The quality of evidence was rated as moderate. Mean difference for lifestyle modification vs control groups for 2 h glucose was -0.34 mmol/l (95% CI -0.62, -0.07; I2 = 50%); for weight -0.75 kg (95% CI -1.34, -0.17; I2 = 71%) and for waist -1.16 cm (95% CI -2.16, -0.16; I2 = 75%). No effect was found for fasting glucose. Findings were similar across subgroups, except for weight for European vs Indian studies (-1.10 kg vs -0.08 kg, p = 0.02 for interaction). CONCLUSIONS/INTERPRETATION: Despite modest changes for adiposity, lifestyle modification interventions in high-risk South Asian populations resulted in a clinically important 35% relative reduction in diabetes incidence, consistent across subgroups. If implemented on a large scale, lifestyle modification interventions in high-risk South Asian populations in Europe would reduce the incidence of diabetes in these populations.

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