GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. Methods: We searched MEDLINE and Embase databases from inception until July 12, 2024 for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events ([MACE] nonfatal myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50 % reduction in estimated glomerular filtration rate (eGFR ), kidney failure or death due to kidney failure, and annualized rate of decline in eGFR (eGFR slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on PROSPERO (CRD42024565765). Results: We identified three trials with 1,743/17,072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of MACE by 21% (HR 0.79, 95% CI 0.71-0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR 0.77, 95% CI 0.54-1.09 and HR 0.79, 95% CI 0.71-0.87, respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR 0.58, 95% CI 0.36-0.93 and HR 0.73, 95% CI 0.63-0.85; P-heterogeneity=0.26). Effects on the composite kidney outcome (RR 0.79, 95% CI 0.66-0.95 ) and eGFR slope (0.78 mL/min/1.73m2/year, 95% CI 0.57-0.98) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). Conclusions: In persons with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

Arm and ankle blood pressure indices, and peripheral artery disease, and mortality: a cohort study.

BACKGROUND AND AIMS: Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials. METHODS: Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death. RESULTS: Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3%, diabetes 50.2%) from 53 countries, 1071 (2.6%) developed PAD, and 4955 (12.2%) died during 5 years of follow-up. Incident PAD progressively rose with higher arm BP indices and fell with ankle BP indices. The strongest relationships were noted for ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, adjusted hazard ratios (95% confidence interval) for each lower fourth were 1.64 (1.31-2.04), 2.59 (2.10-3.20), and 4.23 (3.44-5.21) for ankle SBP; 1.19 (0.95-1.50), 1.66 (1.34-2.05), and 3.34 (2.75-4.06) for ABI; and 1.41 (1.11-1.78), 2.04 (1.64-2.54), and 3.63 (2.96-4.45) for APPD. Similar patterns were observed for mortality. Ankle BP indices provided the highest c-statistics and classification indices in predicting future PAD beyond established risk factors. CONCLUSIONS: Ankle BP indices including the ankle SBP and the APPD best predicted PAD and mortality.

Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.

BACKGROUND: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. METHODS: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. RESULTS: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. CONCLUSIONS: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial.

BACKGROUND: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain. METHODS: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ2 statistic for trend. RESULTS: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5-0.86]; P=0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63-1.06]; P=0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P=0.011; HR, 0.85 for 4 mg, P=0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P<0.0001; HR, 0.73 for 4 mg, P=0.0009), MACE or any death (HR, 0.67 for 6 mg, P=0.0021; HR, 0.81 for 4 mg, P=0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P=0.0072; HR, 0.97 for 4 mg, P=0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P=0.0002; HR, 0.81 for 4 mg, P=0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018). CONCLUSIONS: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03496298.

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

BACKGROUND: Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain. METHODS: In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m2 of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes). RESULTS: A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo. CONCLUSIONS: In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).

Relationships between ankle blood pressure indices and major adverse cardiovascular events in people with and without type 2 diabetes.

BACKGROUND: The relationship between ankle blood pressure (BP) and cardiovascular disease remains unclear. We examined the relationships between known and new ankle BP indices and major cardiovascular outcomes in people with and without type 2 diabetes. METHODS: We used data from 3 large trials with measurements of ankle systolic BP (SBP), ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). The primary outcome was a composite of cardiovascular mortality, myocardial infarction, hospitalization for heart failure, or stroke. Secondary outcomes included death from cardiovascular causes, total (fatal and non-fatal) myocardial infarction, hospitalization for heart failure, and total stroke. RESULTS: Among 42,929 participants (age 65.6 years, females 31.3%, type 2 diabetes 50.1%, 53 countries), the primary outcome occurred in 7230 (16.8%) participants during 5 years of follow-up (19.4% in people with diabetes, 14.3% in those without diabetes). The incidence of the outcome increased with lower ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, multivariable-adjusted hazard ratios (HRs, 95% CI) of the outcome for each lower fourth were 1.05 (0.98-1.12), 1.17 (1.08-1.25), and 1.54 (1.54-1.65) for ankle SBP; HR 1.06 (0.99-1.14), 1.26 (1.17-1.35), and 1.48 (1.38-1.58) for ABI; and HR 1.02 (0.95-1.10), 1.15 (1.07-1.23), and 1.48 (1.38-1.58) for APPD. The largest effect size was noted for ankle SBP (HRs 1.05 [0.90-1.21], 1.21 [1.05-1.40], and 1.93 [1.68-2.22]), and APPD (HRs 1.08 [0.93-1.26], 1.30 [1.12-1.50], and 1.97 [1.72-2.25]) with respect to hospitalization for heart failure, while only a marginal association was observed for stroke. The relationships were similar in people with and without diabetes (all p for interaction > 0.05). CONCLUSIONS: Inverse and independent associations were observed between ankle BP and cardiovascular events, similarly in people with and without type 2 diabetes. The largest associations were observed for heart failure and the smallest for stroke. Including ankle BP indices in routine clinical assessments may help to identify people at highest risk of cardiovascular outcomes.

Effect of basal insulin and omega 3 fatty acids on cognitive impairment in dysglycaemia: An exploratory analysis of the ORIGIN trial.

AIM: The outcomes reduction with an initial glargine intervention (ORIGIN) trial reported that, allocation to insulin glargine-mediated normoglycaemia versus standard care, and to omega 3 fatty acids versus placebo had a neutral effect on cognitive test scores when analysed as continuous variables. Analyses of these scores as standardized categorical variables using a previously validated strategy may yield different results. MATERIALS AND METHODS: The ORIGIN trial recruited participants with dysglycaemia and additional cardiovascular risk factors from 573 sites in 40 countries. They completed a mini mental state examination and a subset completed the digit symbol substitution test at baseline and up to three subsequent visits. The effect of the interventions on country-standardized substantive cognitive impairment, defined as the first occurrence of a baseline-adjusted follow-up mini mental state examination or digit symbol substitution test score ≥1.5 standard deviations below the baseline mean score in each participant's country was assessed using Cox proportional hazards models. RESULTS: During a median follow-up of 6.2 years, 2627 of 11 682 people (22.5%) developed country-standardized substantive cognitive impairment. The hazard of this outcome was reduced by 9% (hazard ratio 0.91, 95% confidence interval 0.85, 0.99; p = .023) in participants assigned to insulin glargine (21.6%) versus standard care (23.3%). Conversely, the hazard of this outcome was not affected by assignment to omega 3 fatty acid versus placebo (hazard ratio 0.93, 95% confidence interval 0.86, 1.01; p = .074). CONCLUSIONS: In this post hoc exploratory analysis, insulin glargine-mediated normoglycaemia but not omega 3 fatty acids reduced the hazard of substantive cognitive impairment in people with dysglycaemia and additional cardiovascular risk factors.

Determinants of serious health outcome-free status in middle-aged and older people with dysglycaemia: Exploratory analysis of the ORIGIN trial.

AIM: To assess clinical and biochemical measurements that can identify people with dysglycaemia (i.e. diabetes or pre-diabetes) who remain free of serious outcomes during follow-up. MATERIALS AND METHODS: We conducted exploratory analyses using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study to identify independent determinants of outcome-free status in 12 537 middle-aged and older adults with prediabetes and early type 2 diabetes from 40 countries. Serious outcome-free status was defined as the absence of major cardiovascular outcomes, kidney or retinal outcomes, peripheral artery disease, dementia, cancer, any hospitalization, or death during follow-up. RESULTS: In total, 3328 (26.6%) participants remained free of serious outcomes during a median follow-up of 6.2 years (IQR 5.8, 6.7). Independent clinical determinants of outcome-free status included younger age, female sex, non-White ethnicity, shorter diabetes duration, absence of previous cardiovascular disease, current or former smokers, higher grip strength, Mini-Mental State Examination score, and ankle-brachial index, lower body mass index and kidney disease index, and non-use of renin-angiotensin system drugs and beta-blockers. In a subset of 8401 people with baseline measurements of 238 biomarkers, growth differentiation factor 15, kidney injury molecule-1, N-terminal pro-brain natriuretic peptide, uromodulin, C-reactive protein, factor VII and ferritin were independent determinants. The combination of clinical determinants and biomarkers best identified participants who remained outcome-free (C-statistics 0.71, 95% confidence interval 0.70-0.73; net reclassification improvement 0.55, 95% confidence interval 0.48-0.58). CONCLUSIONS: A set of routinely measured clinical characteristics and seven protein biomarkers identify middle-aged and older people with prediabetes or early type 2 diabetes as least likely to experience serious outcomes during follow-up.

Development and first-stage validation of a digital version of the Digit Symbol Substitution test for use in assessing cognitive function in older people with diabetes.

AIMS: To describe the development and report the first-stage validation of a digital version of the digit symbol substitution test (DSST), for assessment of cognitive function in older people with diabetes. MATERIALS AND METHODS: A multidisciplinary team of experts was convened to conceptualize and build a digital version of the DSST and develop a machine-learning (ML) algorithm to analyse the inputs. One hundred individuals with type 2 diabetes (aged ≥ 60 years) were invited to participate in a one-time meeting in which both the digital and the pencil-and-paper (P&P) versions of the DSST were administered. Information pertaining to demographics, laboratory measurements, and diabetes indices was collected. The correlation between the digital and P&P versions of the test was determined. Additionally, as part of the validation process, the performance of the digital version in people with and without known risk factors for cognitive impairment was analysed. RESULTS: The ML model yielded an overall accuracy of 89.1%. A strong correlation was found between the P&P and digital versions (r = 0.76, p < 0.001) of the DSST, as well as between the ML model and the manual reading of the digital DSST (r = 0.99, p < 0.001). CONCLUSIONS: This study describes the development of and provides first-stage validation data for a newly developed digital cognitive assessment tool that may be used for screening and surveillance of cognitive function in older people with diabetes. More studies are needed to further validate this tool, especially when self-administered and in different clinical settings.

Cardiovascular and renal outcomes with varying degrees of kidney disease in high-risk people with type 2 diabetes: An epidemiological analysis of data from the AMPLITUDE-O trial.

AIMS: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices. MATERIALS AND METHODS: AMPLITUDE-O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed. RESULTS: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow-up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high- versus low-risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26). CONCLUSIONS: In high-risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney-related risk category.

Evaluating remission of type 2 diabetes using a metabolic intervention including fixed-ratio insulin degludec and liraglutide: A randomized controlled trial.

AIM: To evaluate the effect on type 2 diabetes remission of short-term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed-ratio insulin degludec/liraglutide. METHODS: In a multicentre open-label randomized controlled trial, insulin-naïve participants within 5 years of diabetes diagnosis were assigned to a 16-week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose-lowering drugs. RESULTS: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m2, and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16-week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. CONCLUSIONS: An intensive remission-induction intervention including fixed-ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.

The Effects of Diabetes on Gas Transfer Capacity, Lung Volumes, Muscle Strength, and Cardio-pulmonary Responses During Exercise.

BACKGROUND: Diabetes is a risk factor for the development of vascular disease, chronic kidney disease, retinopathy, and neuropathy. Diabetes is a co-morbid condition commonly present in patients with respiratory disorders but the extent to which it influences ventilatory capacity, gas exchange, and functional capacity is not well known. Research question Does the presence of diabetes contribute to impairment in spirometry, gas transfer, and exercise capacity? METHODS: Retrospective analysis of all subjects who performed incremental cardio-pulmonary exercise testing (CPET) between 1988 and 2012 at McMaster University Medical Centre. The impact of diabetes on physiological outcomes and maximum power output (MPO) was assessed using stepwise multiple additive linear regression models including age, height, weight, sex, muscle strength, and previous myocardial infarct as co-variates, and was also stratified based on BMI categories. RESULTS: 40,776 subjects were included in the analysis; 1938 (5%, 66% male) had diabetes. Diabetics were older (59 vs. 53 years), heavier (88.3 vs.78.0 kg), and had a higher BMI (31 vs. 27 kg/m2). The presence of diabetes was independently associated with a reduction in FEV1 (- 130 ml), FVC (- 220 ml), DLCO (- 1.52 ml/min/mmHg), and VA (- 340ml) but not KCO. Patients with diabetes achieved a lower % predicted MPO[diabetic subjects 70% predicted (670 kpm/min ± 95% CI 284) vs. 80% in non-diabetics (786 kpm/min ± 342), p < 0.001]. With the exception of KCO, these differences persisted across BMI categories and after adjusting for MI. CONCLUSION: The presence of diabetes is independently associated with weaker muscles, lower ventilatory and gas transfer capacity and translates to a lower exercise capacity. These differences are independent of age, height, weight, sex, and previous MI.

Diet, cardiovascular disease, and mortality in 80 countries.

AIMS: To develop a healthy diet score that is associated with health outcomes and is globally applicable using data from the Prospective Urban Rural Epidemiology (PURE) study and replicate it in five independent studies on a total of 245 000 people from 80 countries. METHODS AND RESULTS: A healthy diet score was developed in 147 642 people from the general population, from 21 countries in the PURE study, and the consistency of the associations of the score with events was examined in five large independent studies from 70 countries. The healthy diet score was developed based on six foods each of which has been associated with a significantly lower risk of mortality [i.e. fruit, vegetables, nuts, legumes, fish, and dairy (mainly whole-fat); range of scores, 0-6]. The main outcome measures were all-cause mortality and major cardiovascular events [cardiovascular disease (CVD)]. During a median follow-up of 9.3 years in PURE, compared with a diet score of ≤1 points, a diet score of ≥5 points was associated with a lower risk of mortality [hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.63-0.77)], CVD (HR 0.82; 0.75-0.91), myocardial infarction (HR 0.86; 0.75-0.99), and stroke (HR 0.81; 0.71-0.93). In three independent studies in vascular patients, similar results were found, with a higher diet score being associated with lower mortality (HR 0.73; 0.66-0.81), CVD (HR 0.79; 0.72-0.87), myocardial infarction (HR 0.85; 0.71-0.99), and a non-statistically significant lower risk of stroke (HR 0.87; 0.73-1.03). Additionally, in two case-control studies, a higher diet score was associated with lower first myocardial infarction [odds ratio (OR) 0.72; 0.65-0.80] and stroke (OR 0.57; 0.50-0.65). A higher diet score was associated with a significantly lower risk of death or CVD in regions with lower than with higher gross national incomes (P for heterogeneity <0.0001). The PURE score showed slightly stronger associations with death or CVD than several other common diet scores (P < 0.001 for each comparison). CONCLUSION: A diet comprised of higher amounts of fruit, vegetables, nuts, legumes, fish, and whole-fat dairy is associated with lower CVD and mortality in all world regions, especially in countries with lower income where consumption of these foods is low.

Identifying blood biomarkers for type 2 diabetes subtyping: a report from the ORIGIN trial.

AIMS/HYPOTHESIS: Individuals with diabetes can be clustered into five subtypes using up to six routinely measured clinical variables. We hypothesised that circulating protein levels might be used to distinguish between these subtypes. We recently used five of these six variables to categorise 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into these subtypes: severe autoimmune diabetes (SAID, n=241), severe insulin-deficient diabetes (SIDD, n=1594), severe insulin-resistant diabetes (SIRD, n=914), mild obesity-related diabetes (MOD, n=1595) and mild age-related diabetes (MARD, n=2673). METHODS: Forward-selection logistic regression models were used to identify a subset of 233 cardiometabolic protein biomarkers that were independent determinants of one subtype vs the others. We then assessed the performance of adding identified biomarkers (one after one, from the most discriminant to the least) to predict each subtype vs the others using area under the receiver operating characteristic curve (AUC ROC). Models were adjusted for age, sex, ethnicity, C-peptide level, diabetes duration and glucose-lowering medication usage at blood collection. RESULTS: A total of 25 biomarkers were independent determinants of subtypes, including 13 for SIDD, 2 for SIRD, 7 for MOD and 11 for MARD (all p<4.3 × 10-5). The performance of the biomarker sets (comprising 1 to 25 biomarkers), assessed through the AUC ROC, ranged from 0.611 to 0.734, 0.723 to 0.861, 0.672 to 0.742, and 0.651 to 0.751, for SIDD, SIRD, MOD and MARD, respectively. No biomarkers other than GAD antibodies were determinants of SAID. CONCLUSIONS/INTERPRETATION: We identified 25 serum biomarkers, as independent determinants of type 2 diabetes subtypes, that could be combined into a diagnostic test for subtyping. TRIAL REGISTRATION: ORIGIN trial, ClinicalTrials.gov NCT00069784.

Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial.

BACKGROUND: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. METHODS: Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. RESULTS: The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. CONCLUSIONS: The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.

Influence of Genetic Ancestry on Human Serum Proteome.

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10-6). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10-8) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

High BMI and the risk for incident type 1 Diabetes Mellitus: a systematic review and meta-analysis of aggregated cohort studies.

BACKGROUND: There is uncertainty regarding the role of obesity in type 1 diabetes development. The aim of this systematic review and meta-analysis was to collect and synthesize evidence regarding BMI and the risk of developing type 1 diabetes. METHODS: A systematic review and meta-analysis were conducted to assess the association between BMI and incident type 1 diabetes. Databases were searched up to June 2022. Cohort studies were included reporting the association between overweight and/or obesity, as measured by BMI after age 2 years, with incident type 1 diabetes. Independent reviewers extracted data and assessed study quality. Risk estimates were pooled using a random-effects model. RESULTS: Ten cohort studies met the inclusion criteria. The seven studies that classified BMI into categories were of high quality and involved 1,690,660 individuals and 1979 incident type 1 diabetes cases. The pooled risk ratio (RR) for type 1 diabetes was 1.35 (95% CI 0.93-1.97) among people with overweight (3 studies); 2.17 (95% CI 1.75-2.69) among people with obesity (5 studies); and 1·87 (95% CI 1.52-2.29) among people with overweight/obesity (two studies merged the categories). These point estimates persisted in sensitivity analyses that addressed the duration of follow-up, variability in baseline risk for incident type 1 diabetes, and potential misclassifications related to exposure or outcome definitions. People with overweight/obesity had a 2.55 (95% CI 1.11-5.86) greater risk for incident type 1 diabetes with positive islet autoantibodies. CONCLUSION: This systematic review and meta-analysis of high-quality observational cohort studies indicated an association between high BMI and the risk of type 1 diabetes, in a graded manner.

General versus central adiposity as risk factors for cardiovascular-related outcomes in a high-risk population with type 2 diabetes: a post hoc analysis of the REWIND trial.

BACKGROUND: In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D). METHODS: Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m2. Cox proportional hazard models were used to investigate if BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were significant risk factors for major adverse CV events (MACE)-3, CVD-related mortality, all-cause mortality, and heart failure (HF) requiring hospitalization. Models were adjusted for age, sex, and additional baseline factors selected by LASSO method. Results are presented for one standard deviation increase of the respective anthropometric factor. RESULTS: Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p < 0.001; HR for BMI: 1.33 [95% CI 1.17 to 1.50]; p < 0.001). No significant interaction with sex was observed. CONCLUSIONS: In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk.

Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial.

AIM: Non-surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short-term intensive glucose-lowering therapy. METHODS: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time-to-event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. RESULTS: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40-0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14-3.24) and 1.83 (1.03-3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00-3.53) at 48 weeks and 2.05 (0.98-4.29) at 64 weeks. CONCLUSIONS: A 12-week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.