Diabetes, Obesity and Metabolism

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Our focus was a 12-week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 g) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 g) or placebo, and a drug-drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 g dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed. For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5-22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800-6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements. In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development.

AimSGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes - including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. MethodsCanagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including drug-induced increases in urinary excretion of glucose, sodium, and uric acid. ResultsThis pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6x10), serum creatinine (+0.05 mg/dL; p=8x10-4), and serum uric acid (-0.90 mg/dL; p=5x10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males responses were [~]60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2. ConclusionsNormalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function. RegistrationNCT02462421 (clinicaltrials.gov) FundingResearch grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by either ineffective activation or undesirable off-target secondary effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a {beta}3-adrenergic receptor ({beta}3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this too has been accompanied by undesirable cardiovascular effects. Combining mirabegron with a cardio-selective {beta}1-AR antagonist could not only suppress these unwanted effects, but potentially increase the sensitivity of the {beta}3-AR and {beta}2-AR in WAT and BAT. Here we report that co-ingesting a high dose of the {beta}1-AR antagonist bisoprolol with mirabegron suppresses the increase in heart rate, systolic blood pressure and myocardial oxygen consumption. However, it also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis and glucose uptake. Whether the attenuation in BAT blood flow induced by the large dose of bisoprolol limited BAT thermogenesis remains to be determined. clinicaltrials.gov (NCT04823442)

BackgroundParalytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management. MethodsTo investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (ncases/controls=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (ncases/controls=517/182,423) using GWAS data from the FinnGen project. ResultsBased on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally. ConclusionsOur studys findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are among the safest and most effective medications for diabetes and weight loss and are currently used by millions of individuals worldwide. While their cardiometabolic benefits are well established, emerging observational reports have raised concerns about a potential association between GLP-1 RA use and new-onset non-arteritic anterior ischemic optic neuropathy (NAION). ObjectiveTo emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide, a GLP-1RA, compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for type 2 diabetes in a nationwide cohort of U.S. Veterans. DesignActive-comparator, new-user, target trial emulation. Marginal cause-specific hazard ratios (HRs) were estimated using overlap weighting to account for confounding. Data analysis was conducted from July 2025 to September 2025. SettingThe Veterans Health Administration (VHA) nationwide health care system between March 1, 2018 and March 1, 2025. ParticipantsU.S. Veterans with a diagnosis of type 2 diabetes who were current metformin users and had no prior exposure to GLP-1RAs or SGLT2is. ExposureInitiation of semaglutide or any SGLT2i. Main Outcome and MeasureIncident NAION, identified using ICD-10 and SNOMED diagnosis codes. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.7] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White; 20.7% Black; 8.1% Hispanic). Over a median follow-up of 2.1 years, 153 total incident NAION events occurred. The incidence rate of NAION was 123 per 100,000 person-years among semaglutide initiators and 67 per 100,000 person-years among SGLT2i initiators. Patients who initiated semaglutide had a 2.33-fold higher risk than patients who initiated SGLT2i (HR, 2.33; 95% CI, 1.54-3.54; P<.001). Conclusions and RelevanceIn this nationwide cohort of U.S. Veterans with type 2 diabetes, patients who initiated semaglutide had over a 2-fold increased risk of NAION compared to patients who initiated SGLT2i.

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for obesity and type 2 diabetes, yet substantial variability in weight-loss response remains poorly understood. MethodsWe conducted a retrospective cohort study using de-identified electronic health records and performed 1:1 propensity matching on age, sex, type 2 diabetes status, baseline BMI and weight, index year, and follow-up duration. The matched cohorts included 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients. Patients were categorized by maximum weight loss over two years into five response groups. Adverse events were identified through AI-enabled curation of clinical notes. Weight-loss trajectories, demographic patterns, adverse-event profiles, and pre- to post-treatment disease-prevalence changes were compared across drugs. ResultsPatients treated with tirzepatide lost more weight than those treated with semaglutide (mean reduction, 14.7% vs. 10.8%; p<0.001). High-response rates ([&ge;]15% weight loss in year 1) were nearly doubled with tirzepatide (42.6% vs. 21.6%; p<0.001), accompanied by faster monthly weight-loss velocity (2.54% vs. 2.18%). AI-enabled curation showed that tirzepatide was associated with lower prevalence of gastrointestinal and systemic adverse events. For both tirzepatide and semaglutide, women were more represented among high responders than the minimal weight-loss group (<5% weight loss) and White patients were more represented among high responders, whereas Black and Hispanic patients were more represented among the minimal weight loss group. ConclusionsIn this large, propensity-matched real-world cohort, tirzepatide was associated with greater and faster weight loss than semaglutide. Marked demographic disparities highlight the need for precision approaches to obesity treatment.

BackgroundGlucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, are widely prescribed to treat type 2 diabetes mellitus and obesity. Recent anecdotal reports have suggested these agents might be associated with allodynia, a neuropathic pain syndrome, but large-scale epidemiologic evidence is lacking. MethodsTo investigate this potential link, a retrospective cohort study was conducted using the IQVIA PharMetrics(R) Plus database. Adults aged 18 and older who initiated liraglutide, semaglutide, or bupropion-naltrexone between 2006 and 2020 were included, excluding those with prior diabetes or antihyperglycemic therapy. Incident allodynia was identified via ICD-9/10 codes as the primary outcome. ResultsAmong 20,504 new users, those on GLP-1 receptor agonists had an allodynia incidence of 35 per 1,000 person-years, compared to 15 per 1,000 person-years for bupropion-naltrexone users. Adjusted analyses demonstrated over a twofold increased risk of allodynia with GLP-1 receptor agonists (aHR 2.15, 95% CI 1.57-2.96). ConclusionThese findings emphasize the need for heightened clinical vigilance and further research into mechanisms and management.

The Fasting for Brain and Heart Health Study was a prospective, single-center, observational study examining the effects of medically supervised, water-only fasting followed by an exclusively whole-plant-food refeeding diet on accepted measures of cardiovascular risk and metabolic health. The study enrolled 48 overweight/obese, non-diabetic participants of which 26 completed the full study protocol. The participants fasted according to an established protocol at an independent medical center that reported mean fast and refeed lengths of 17 and 7 days, respectively. The primary endpoint was to describe mean glucose tolerance as indicated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores at baseline, end-of-fast (EOF), and end-of-refeed (EOR) visits. Secondary endpoints were to describe the effects of fasting and refeeding on accepted markers of cardiovascular risk. Here we show that medically supervised, water-only fasting and/or whole-plant-food refeeding reduced resting systolic blood pressure (SBP), abdominal circumference, low-density lipoprotein (LDL), and high-sensitivity C-reactive protein (hsCRP) after refeeding. An increase in HOMA-IR scores at EOR was also observed.

Prescription of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with guideline-directed indications remains limited with substantial inter-prescriber variability. In this prospective study of US adults, we used administrative claims database of individuals with type 2 diabetes and compelling indications for SGLT-2i and GLP-1RA to evaluate the impact of healthcare visits with certain specialty providers on the initiation of these medications. These specialties included family medicine, internal medicine, cardiology, endocrinology, and nephrology. Overall, 294,988 individuals eligible for SGLT-2i and 198,525 for GLP-1RA were identified. In 2019-2020, SGLT-2i and GLP-1RA were initiated in 10.4% and 16.7% of eligible individuals, respectively. After accounting for patient characteristics and comorbidities, healthcare visit with endocrinologists was associated with the highest rate of initiation of either drug across specialties (OR=2.16 [2.08-2.24] for SGLT-2i, and 2.76 [2.64-2.88] for GLP-1RA). Healthcare visits with cardiologists and with family medicine and internal medicine physicians were only modestly associated with initiation of SGLT-2i and GLP-1RA. The study highlights the need for broad education for expansion of the use of these medications rather than focus on dedicated specialty clinics.

BackgroundGlucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents. However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation. In this systematic review, we aimed to characterise the trajectory of weight regain after GLP-1RA cessation. MethodsThis systematic review and meta-regression analysis followed Cochrane and PRISMA guidelines. We searched MEDLINE, Embase, Cochrane Library, Scopus and Web of Science from inception to December 26, 2024 for randomised controlled trials and observational studies reporting weight outcomes after cessation of GLP-1RAs in adults with overweight or obesity. Weight regain was the primary outcome and was modelled using nonlinear regression. Secondary outcomes included HbA1c and systolic blood pressure. The study protocol is registered with PROSPERO (CRD420250631751). FindingsWe identified 44 relevant studies. Weight, HbA1c and systolic blood pressure consistently rebounded after cessation of GLP-1RAs. Six trials with 3,236 participants were included in the exponential recovery model. Weight regain was estimated to plateau at 75.6% (95% CI 68.5-82.7) of the weight lost on treatment. The rate constant was 0.0302 per week (95% CI 0.0204-0.0399), corresponding to a half-life of 23.0 weeks. At 1 year after cessation, an estimated 40.2% of the on-treatment weight loss remained. Most studies were assessed to have moderate risk of bias. InterpretationGLP-1RA cessation is associated with a predictable and decelerating pattern of weight regain, which appears to plateau below pre-treatment levels, suggesting that partial weight-loss benefit may persist long-term but is substantially attenuated. FundingNone.

IntroductionSemaglutide is an effective intervention for weight loss, but the relative contributions of fat and fat-free mass (FFM) to total weight loss remain unclear. MethodsThis was a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating semaglutide use in adults living with overweight or obesity. Searches were performed in PubMed, Web of Science, Embase, and Scopus through April 2025. Eligible trials reported baseline and post-treatment measures of body mass, fat mass, and FFM. Data extraction followed PRISMA guidelines, and risk of bias and certainty of evidence were assessed. Random-effects models were applied, with linear or quadratic functions fitted as appropriate. ResultsSeven RCTs involving 452 participants (259 semaglutide, 193 placebo) met the inclusion criteria. Semaglutide produced significant non-linear weight loss (0.04 kg/day; 95% CI 0.03-0.05; p<0.0001), primarily due to fat mass reduction (0.03 kg/day; 95% CI 0.01-0.05; p=0.007). FFM declined linearly at a smaller rate (0.007 kg/day; 95% CI 0.003-0.010; p=0.0001). Certainty of evidence was moderate. ConclusionSemaglutide induces substantial reductions in body and fat mass, with modest FFM loss. Clinical strategies combining semaglutide with resistance exercise and nutritional support may help preserve lean mass and optimize long-term outcomes.

OBJECTIVETo assess the dose-response effects of exercise in combination with a diet-induced weight loss on fat mass (FM) percentage (FM%) in persons with diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODSIn this secondary analysis of a four-armed randomized trial (Clinicaltrials.gov NCT03769883) 82 persons (35% females, mean age and standard deviation (SD) 58.2 (9.8) years) living with type 2 diabetes were randomly allocated to the control group (N=21, CON), diet control (25% energy restriction; N=20, DCON), diet control and exercise three times/week (two sessions of aerobic and one session combining resistance and aerobic training; N=20, MED), or diet control and exercise six times/week (four sessions of aerobic and two sessions combining resistance and aerobic training; N=21, HED) for 16 weeks. The primary outcome was the change in FM percentage points (pp). Secondary outcomes included fat-free mass and visceral adipose tissue volume. RESULTSType 2 diabetes duration was 4.0 years (interquartile range 1.9 to 5.5), body weight (SD) 101.4 kg (14.6), FM% (SD) 39.4 (6.7). FMpp decreased compared to standard care -3.5 pp (95% CI -5.6 to -1.4) p=0.002, -6.3 pp (CI -8.4 to -4.1) p<0.001, and -8.0 pp (95% CI -10.2 to -5.8) p<0.001, for DCON, MED, and HED, respectively. The difference between HED and MED was -1.8 pp [95% CI -3.9 to 0.4]; p=0.11). CONCLUSIONSAll interventions were superior in reducing FMpp compared to standard care in a dose-dependent manner. Adding three or six sessions of exercise to a low-calorie diet was superior in reducing FM compared to a low-calorie diet alone. Article HighlightsO_LIWhy did we undertake this study? Exercise and weight loss are recommended for persons with type 2 diabetes. It is unclear if adding exercise, and which amount of exercise, to a low-calorie diet supports additional fat mass loss. C_LIO_LIWhat is the specific question(s) we wanted to answer? What is the dose-response effect of exercise combined with a moderate caloric restriction on changes in fat mass? C_LIO_LIWhat did we find? Adding exercise to a diet-induced weight loss reduced fat mass and preserved fat-free mass in a dose-dependent manner. C_LIO_LIWhat are the implications of our findings? Adding exercise to a moderate caloric restriction dose-dependently facilitates reductions in fat mass by enlarging weight loss and fat loss. C_LI

BackgroundThe SELECT trial showed cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in obese patients with cardiovascular disease; however, real-world data (RWD) on this benefit remain limited. This study used an artificial intelligence (AI)-generated algorithm and multimodal RWD to evaluate the impact of GLP-1 RAs on cardiovascular disease risk in a population of obese patients with and without preexisting cardiovascular disease. MethodsUsing data from the Dandelion Health RWD library, an Emulated SELECT Cohort was created to include obese patients similar to those in the SELECT trial, but with and without preexisting cardiovascular disease. An AI algorithm developed by Pheiron that used 12-lead electrocardiograms (ECGs) as a predictive biomarker for the risk of major adverse cardiovascular events (MACE) was validated and used to derive MACE risk scores for the Emulated SELECT Cohort. These outcomes were compared over time between patients who used GLP-1 RAs and non-users using inverse-probability weighted linear regression models, adjusting for key covariates. ResultsOut-of-sample validation showed high predictive accuracy of the AI algorithm, with ROC AUCs of 0.81 for myocardial infarction (MI) and 0.75 for stroke. Increased risk scores from the algorithm were correlated with higher MACE incidence in RWD. In the Emulated SELECT Cohort of 20,795 patients, GLP-1 RA use was associated with significant attenuation of MACE risk, with reductions observed in percentile risk score for MI (4%; p<0.001) and stroke (3.6%; p<0.001) per year of use. Differences in GLP-1 RA and non-GLP-1 users were evident as early as 1.7 years, with a 15-20% difference in absolute MACE risk scores between GLP-1 RA users and non-users observed by the end of the study. ConclusionAn AI algorithm using 12-lead ECGs accurately predicted MACE risk and could be used to model risk attenuation associated with GLP-1 RA use. Using this outcome, we find that GLP-1 RA use was associated with significant reductions in MI and stroke risk, in a broader population and within a shorter timeframe than the SELECT trial. These findings suggest potentially significant cardioprotective benefits of GLP-1 RAs in real-world settings and demonstrate a proof-of-concept for utilizing clinical AI to understand these benefits.

In the medical management of obesity, treating physicians observe significant heterogeneity in responses to pharmacotherapy. Indeed one of the most important clinical questions in obesity medicine is whether we can predict how an individual will respond to a particular pharmacotherapeutic agent. The present study examines patterns and predictors of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment. 182 women were assigned using single-blind randomization to either treatment with twice daily exenatide injections or to matched placebo injections with dietary counseling. Women who demonstrated > 5% weight loss after 12 weeks of treatment were deemed high responders and remained on study treatment for up to 52 weeks; women who lost < 5% body weight at 12 weeks were deemed low responders and stopped study treatment. We additionally characterized individuals who lost > 10% of body weight as super responders. Our primary outcome was change in body weight; secondary outcomes included changes in metabolic parameters including lipids, waist circumference, resting energy expenditure, and response to a meal tolerance test. We also performed an exploratory metabolomic analysis. Consistent with published literature, we observed individual heterogeneity in the weight loss response to exenatide and diet/placebo. Although there was no significant difference between treatment groups in the percentage of participants who achieved > 5% weight loss (56% of exenatide group and 76% of diet/placebo group), or those who achieved > 10% weight loss (43% of exenatide group and 55% of diet/placebo group), in both cases there was a trend toward a higher response rate in the group that received placebo with dietary counseling. In addition to achieving similar average weight loss, both treatment groups also demonstrated similar maximum weight loss. The range of maximum weight loss was greater in the diet/placebo group and there was more weight regain among individuals in the exenatide group compared to the diet/placebo group. In our exploratory metabolomic analysis, we observed lower baseline circulating cysteine concentrations in the exenatide responder group and we also found a trend toward higher baseline levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group. We did not identify any metabolic predictors of weight loss in either the exenatide or the diet/placebo treatment group.

BackgroundGLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited. ObjectivesTo compare the cardiovascular effectiveness of individual GLP-1RAs and SGLT2Is. MethodsWe conducted a multi-national, retrospective, new-user active-comparator cohort study using 10 US and non-US administrative claims and electronic health record databases. The study included 1,245,211 adults with T2DM receiving metformin who initiated second-line therapy with one of six GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or one of four SGLT2Is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin). Empagliflozin (393,499; 31.6%), semaglutide (235,585; 18.9%), dapagliflozin (208,666; 16.8%), and dulaglutide (207,348; 16.8%) were most commonly used. A secondary subgroup analysis included 316,242 patients with established cardiovascular diseases (CVD). Primary outcomes were 3-point major adverse cardiovascular events (MACE: acute myocardial infarction, stroke, sudden cardiac death) and 4-point MACE (adding hospitalization/ER visit with heart failure). Secondary outcomes included the individual components. Hazard ratios (HRs) were estimated for pairwise agent comparisons while on-treatment (per-protocol) and over total follow-up using Cox proportional hazards models, with propensity score adjustments, negative control calibration, and pre-specified study diagnostics to guard against potential confounding. Random-effects meta-analysis produced summary HR estimates across data sources that passed diagnostics. ResultsAcross the study cohort, individual GLP-1RAs and SGLT2Is demonstrated broadly similar cardiovascular effectiveness, both within and across drug classes. For example, semaglutide and empagliflozin showed comparable risks for 3-point MACE (meta-analytic HR 1.05; 95% CI 0.79-1.39) and 4-point MACE (meta-analytic HR 0.95; 95% CI 0.81-1.12), with consistent findings in the CVD subgroup. Study diagnostics confirmed adequate equipoise, covariate balance and statistical power to detect similarity in HRs between 0.8 and 1.2 for commonly used agents. ConclusionsIn this large-scale real-world study, individual GLP-1RAs and SGLT2Is exhibited largely comparable cardiovascular benefits, including in patients with established CVD. These findings align with network meta-analytic estimates from major cardiovascular outcome trials and broadly support current treatment guidelines. Clinical choices should be guided by relevant factors such as safety, adherence, tolerability, cost, and patient preference, where further work is needed.

ImportanceSodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP1ra) and dipeptidyl peptidase-4 inhibitors (DPP4i) improve hyperglycaemia and, in the case of SGLT2i and GLP1ra, reduce the risk of major adverse cardiovascular events (MACE) in type 2 diabetes. It is not clear whether efficacy varies by age or sex. ObjectiveAssess whether age or sex are associated with differences in efficacy of SGL2i, GLP1ra and DPP4i. Data sourcesMedline, Embase and clinical trial registries. Study selectionTwo independent reviewers screened for randomised controlled trials of SGLT2i/GLP1ra/DPP4i, compared to placebo/active comparator, in adults with type 2 diabetes. Data extraction and synthesisWe sought individual participant data (IPD) all eligible studies. Where IPD were available, we modelled age- and sex-treatment interactions for each trial. Otherwise, we assessed age- sex distributions along with results from aggregate trial data. IPD and aggregate findings were combined in a Bayesian network meta-analysis. Main outcome measuresHbA1c and MACE. ResultsWe identified 616 eligible trials (604 reporting HbA1c, 23 reporting MACE) and obtained IPD for 75 trials (6 reporting MACE). Mean age was 59.0 (10.7) years and 64.0 (8.6) in HbA1c and MACE trials, respectively. Proportions of female were 43.1% and 44.0% in HbA1c and MACE trials, respectively. SGLT2i reduced HbA1c by 0.5-1.0% overall compared to placebo. This reduction versus placebo was attenuated in older participants (change in HbA1c 0.25 percentage-points less for 75-year-olds compared to 45-year-olds). SGLT2i showed greater relative efficacy in MACE risk reduction among older than younger people. This finding was sensitive to the exclusion of one of the IPD MACE trials, however, in all sensitivity analyses, SGLT2i were either as efficacious or more efficacious in older participants. There was no consistently significant difference in efficacy by age for GLP1ra or DPP4i for HbA1c or MACE, nor were there consistent significant sex differences for any class. ConclusionNewer glucose-lowering drugs are efficacious across age and sex groups. SGLT2i are more cardioprotective in older than younger people despite smaller HbA1c reductions. Age alone should not be a barrier to treatments with proven cardiovascular benefit providing they are well tolerated align with patient priorities.

BackgroundCurcumin, which is derived from turmeric root and is widely utilized in Asian cuisines, exhibits notable anti-inflammatory effects. Its consumption has proven beneficial in alleviating inflammation-related disorders such as ulcerative colitis, rheumatoid arthritis, and esophagitis. These anti-inflammatory properties might also provide advantages in reducing cardiovascular complications, such as atherosclerosis, which is particularly prevalent among diabetic individuals. This study aimed to evaluate the efficacy of curcumin in decreasing the risk of atherogenesis in obese patients with type 2 diabetes. MethodsThe study employed a rigorous randomized, double-blind, placebo-controlled trial design with 265 participants who were diagnosed with type 2 diabetes. Subjects were randomly assigned to receive either curcumin capsules or a placebo over 12 months. The key metrics used to assess atherogenic risk reduction included pulse wave velocity and various metabolic profiles. These profiles included low-density lipoprotein cholesterol, small dense low-density lipoprotein cholesterol, apolipoprotein B, triglyceride to high-density lipoprotein ratio, uric acid, waist circumference, total body fat, and visceral fat. Measurements were recorded at baseline and at 3-, 6-, 9-, and 12-month intervals throughout the treatment phase. ResultsAfter 12 months, participants receiving curcumin exhibited a significant reduction in pulse wave velocity (P < 0.001). Furthermore, this group also showed significantly reduced levels of various cardiometabolic risk biomarkers. These included low-density lipoprotein cholesterol, small dense low-density lipoprotein cholesterol, apolipoprotein B, the triglyceride to high-density lipoprotein ratio, uric acid, waist circumference, and total body fat, all with P values less than 0.001. Additionally, visceral fat levels were reduced, with a P value of 0.01. Markers of inflammation (high-sensitivity C-reactive protein, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) were also significantly lower in the curcumin group than in the placebo group, with P values less than 0.001. ConclusionsThe 12-month administration of curcumin to patients with type 2 diabetes and obesity significantly reduced pulse wave velocity and improved cardiometabolic risk profiles. It also demonstrated substantial anti-inflammatory effects with minimal adverse outcomes. These findings suggest that curcumin treatment may effectively reduce atherogenic risks in obese patients with type 2 diabetes. Trial registrationThai Clinical Trials Registry: TCTR20140303003 Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIndividual patient data from randomized trials of curcumin extract versus placebo, spanning a 12-month period and including a rather large sample size (n=227), are analyzed collectively. C_LIO_LICurcumin extract use resulted in a significant reduction in pulse wave velocity and showed a significant improvement in cardiometabolic risk profiles. C_LI What Are the Clinical Implications?O_LIThe efficacy and safety data from randomized clinical trials supports the use of curcumin extract over placebo for mitigating inflammation and improving cardiometabolic risk factors. C_LIO_LICurcumin supplementation shows promise in protecting against atherosclerosis and related cardiovascular diseases in patients with T2DM and obesity. C_LI

PurposeTo investigate the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and nonarteritic anterior ischaemic optic neuropathy (NAION) in type 2 diabetes, examining treatment recency and cumulative duration. MethodsThis nationwide registry-based nested case-control study utilised Danish health registries (1996-2023). Among 201,776 metformin-treated adults initiating second-line antihyperglycaemic therapy, 123 incident NAION cases were matched to 4,920 controls by birth year and sex (incidence-density sampling). Conditional logistic regression estimated adjusted hazard rate ratios (HRs) for GLP-1RA exposure by recency (current 0-90 days; recent 91-365 days) and cumulative duration, adjusting for socioeconomic factors, hypertension, hypercholesterolaemia, sleep apnoea, and diabetes duration. ResultsGLP-1RA use occurred in 63/123 cases (51.2%) and 1,688/4,920 controls (34.3%). Ever use was associated with a higher NAION rate than other second-line therapies (HR 2.13, 95% CI 1.43-3.18). Current use was associated with elevated rates (HR 2.28, 95% CI 1.49-3.48), whereas the estimate for recent use was imprecise (HR 1.69, 95% CI 0.88-3.25). By cumulative duration, no clear evidence of an increase was seen within 0-[1/2] years (HR 0.80, 95% CI 0.32-2.05), and rates were highest at [1/2]-1 year (HR 3.63, 95% CI 2.06-6.40) and 1-1[1/2] years (HR 3.52, 95% CI 1.73-7.17). Findings were consistent after HbA1c adjustment and in a new-user analysis. ConclusionGLP-1RA use is associated with a higher NAION rate in type 2 diabetes. This association appears time-dependent, being most pronounced during current treatment and peaking after 6-18 months of cumulative exposure.

Objectiveto assess the incremental efficacy of a four-drug (POLYCHEM: metformin/pioglitazone/sitagliptin/empagliflozin) regimen vs standard diabetes care (SDC) in inducing remission in patients with newly diagnosed type 2 diabetes. Research Design and MethodsA multicenter, open-label, pragmatic, phase III, randomized clinical trial was conducted in 6 Italian Diabetes Outpatient Clinics. Major inclusion criteria were age 35-75 years, HbA1c <10% (97 mmol/mol), fasting C-peptide >0.3 nmol/l, GAD-antibody negative. Patients were randomized (visit 1) to receive POLYCHEM or SDC for 16 weeks, after which, if there was regression of diabetic hyperglycemia (visit 2), drug therapy was suspended. The primary endpoint was remission (HbA1c < 6.5 %; 48 mmol/mol) assessed at least 12 weeks (visit 3) after ceasing any glucose-lowering pharmacotherapy. Results108 patients (80% males, age: 58{+/-}9 yrs), were enrolled in the study, of whom 60 were randomized to POLYCHEM and 48 to SDC treatment. After 16 weeks, 54 (90.0%) and 37 (77.1%) patients achieved regression of diabetic hyperglycemia in the POLYCHEM and SDC arm, respectively (p=0.002). At visit 3, 23 (38.3%) and 21 (43.8%) patients achieved diabetes remission in the POLYCHEM and SDC arm, respectively (p=0.59). The difference between the upper 95% CI in POLYCHEM (50.9%) and the lower 95% CI in SDC (30.4%) of diabetes remission was 20.5%. ConclusionA four-drug regimen with minimal to null weight-lowering effect is not superior to current SDC in achieving remission in patients with newly diagnosed type 2 diabetes. If a superiority of POLYCHEM over SDC exists, it is expected to be less than 21%. Trial registrationClinicalTrials.gov number: NCT04271189

This decentralized, double-blind, randomized, placebo-controlled trial investigated the impact of a novel fasting mimetic "Mimio" on hunger, satiety, digestive symptoms, metabolism, cognition and wellbeing in overweight older adults with elevated HbA1c. Participants collected 2 weeks of baseline subjective data along with a fasted metabolic blood panel. The Mimio fasting mimetic, containing spermidine, nicotinamide, palmitoylethanolamide (PEA) and oleoethanolamide (OEA), or a placebo capsule was then taken before the first meal of the day for 8 weeks. Subjective measures were repeatedly collected throughout the study and metabolic bloodwork was repeated at the end of 8 weeks. 42 Participants were evaluated (47.6% female, BMI 27.6 (0.2) kg/m2, aged 62 {+/-} 4, HbA1c 6.0 {+/-} 0.1, n=23 intervention and n=19 placebo). Mimio improved more over time in all hunger and satiety metrics than placebo (Hunger and Satiety Composite Score Mann-Kendall p=2.2*10-16). More participants in the Mimio group improved daily ratings of hunger and appetite compared to placebo, including 91% vs. 47% of participants improving mealtime appetite across the study (Fishers Exact Test p=0.003). The Mimio cohort reported significantly less abdominal pain and bloating than the placebo group (Mann-Whitney U p<0.05). Mimio significantly reduced total cholesterol, LDL cholesterol, LDL particle number, oxidized LDL, non-HDL cholesterol and fasting glucose compared to placebo (Mann-Whitney U p<0.05). Changes in quality of life, three-factor eating questionnaire and cognitive failures did not differ significantly between Mimio and placebo. There were no significant differences in any adverse effects between Mimio and placebo. Mimio, a daily fasting mimetic supplement, improves daily hunger and satiety, reduces oxidative stress, symptoms of indigestion and improves cardiometabolic health markers in overweight older adults with elevated HbA1c. This is the first study to show that fasting mimetic supplementation can recreate clinical fasting-like cardiometabolic benefits without lifestyle changes or the need to fast. Trial RegistrationThe trial was IRB approved and registered with ClinicalTrials.gov (Pro00080269).