BACKGROUND:SGLT2 inhibitors increase the risk of ketoacidosis, but data from routine clinical practice are scarce. We used nationwide registers with the aim of assessing the incidence, risk factors, and prognosis of ketoacidosis during SGLT2 inhibitor treatment in patients with type 2 diabetes. METHODS:In this cohort and nested case-control study we used data from three Scandinavian countries. In a cohort of SGLT2 inhibitor-treatment episodes among patients with type 2 diabetes aged at least 18 years in Sweden, Denmark, and Norway, we estimated ketoacidosis incidence. Using a nested case-control design (matched on age, sex, region of birth, calendar time, and time since treatment initiation), we assessed risk factors and precipitating or co-occurring events. Changes in diabetes medications were evaluated. FINDINGS:The study period was Jan 1, 2013, to Dec 31, 2021, in Denmark and Sweden, and Jan 1, 2013, to Dec 31, 2022, in Norway. We included 322 597 treatment episodes among 282 282 patients with type 2 diabetes (mean age 63 years, 116 521 [36·1%] of 322 597 women). During a median (IQR) follow-up of 1·3 (0·7-2·8) years, 1452 ketoacidosis events occurred (incidence 2·43 per 1000 person-years). Although highest shortly after initiation, risk persisted throughout follow-up. Strong risk factors included high HbA1c (≥83 vs ≤52 mmol/mol: odds ratio [OR] 15·37 [95% CI 11·50-20·53]), malnutrition (OR 10·54 [7·32-15·18]), previous ketoacidosis (OR 10·40 [7·09-15·24]), low BMI (<20 kg/m2vs 20 to <25 kg/m2: OR 9·98 [5·68-17·53]), and recent hypoglycaemia (OR 5·22 [2·60-10·49]). Infection was the most common precipitating or co-occurring event (454 [31·8%] of 1428 vs 862 [6·1%] of 14 233 for ketoacidosis cases vs controls; OR 7·60 [6·62-8·71]). The strongest associations were observed for alcohol intoxication, acute renal events, acute abdomen, stroke, and major surgery, although associations for some transient exposures, particularly milder conditions, might have been overestimated because of under-registration among controls. Exploratory analyses suggested that the observed associations were largely general to patients with type 2 diabetes rather than specific to SGLT2 inhibitor use. At 1 year after ketoacidosis, 211 (25·1%) of 842 remained on SGLT2 inhibitors and insulin use increased from 269 (31·9%) of 842 to 615 (73·0%) of 842. INTERPRETATION:Ketoacidosis risk with SGLT2 inhibitors varies greatly by patient characteristics and is not confined to early in treatment. Risk should be assessed throughout treatment, and patients should be instructed to pause treatment during acute illness and stress. FUNDING:Region Stockholm, Swedish Society of Medicine, Karolinska Institutet.
Obesity (ie, excess adiposity) is a major driver of multisystem morbidity, spanning musculoskeletal (eg, osteoarthritis), metabolic (eg, type 2 diabetes), cardiovascular (eg, heart failure), mental health (eg, depression), respiratory (eg, obstructive sleep apnoea), and gastrointestinal and hepatic (eg, metabolic dysfunction-associated steatotic liver disease) disorders. However, the extent to which weight-loss interventions can prevent or modify these conditions varies considerably. In this Review, we synthesise evidence from epidemiological studies, genetic analyses (including Mendelian randomisation), observational weight-change studies, and randomised trials, using a triangulation framework to assess causal links between adiposity and common diseases. Although robust trial evidence supports weight loss as a disease-modifying strategy in some conditions, including but not limited to type 2 diabetes and heart failure with preserved ejection fraction, many other conditions, including musculoskeletal, respiratory, cardiovascular, and mental health disorders, remain under-investigated. Incretin-based therapies, in particular the glucagon-like peptide 1 receptor agonist semaglutide and the dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide, now achieve average weight losses of approximately 14-20% in people without diabetes and have generated the first large-scale randomised evidence of disease modification across several of these conditions. We highlight key gaps and propose priorities for future trials, including the need for studies across different disease stages, incorporation of mechanistic and mediation analyses, and evaluation of the impact on disease outcomes of varying magnitudes of weight loss with differing agents. Future research should also consider multimorbidity, individualised treatment targets, and long-term outcomes-including potential legacy effects. Addressing global access gaps and conducting trials in diverse populations will be essential to inform scalable and equitable obesity care.
BACKGROUND:Therapies targeting GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) receptors have provided efficacious weight reduction in adults with obesity. Mazdutide, a glucagon and GLP-1 receptor dual agonist, presents a novel opportunity for differentiated weight reduction. We aimed to evaluate the efficacy, safety, and tolerability of once-weekly mazdutide across a dose range up to 16 mg in adults with obesity or overweight without type 2 diabetes in the USA. METHODS:In this randomised, double-blind, placebo-controlled phase 2 trial at 24 centres in the USA, adults aged 18-75 years without type 2 diabetes and with a BMI of 30 kg/m2 and higher-or of 27 kg/m2 to less than 30 kg/m2 with at least one weight-related comorbidity-were randomly allocated (3:2:3:3) to receive once-weekly subcutaneous injections of placebo or mazdutide (3-6 mg, 10 mg, or 16 mg) for 48 weeks. Participants assigned to 3-6 mg mazdutide maintained 3 mg from week 4 to week 32 before escalating to 6 mg at 32 weeks to assess 3 mg and 6 mg as potential maintenance doses. The primary endpoint was percentage change in bodyweight from baseline to 32 weeks, evaluated using the efficacy (hypothetical) estimand. Efficacy analyses included all randomly allocated participants, and safety analyses included all randomly allocated participants who received at least one treatment dose. This study is registered at ClinicalTrials.gov, NCT06124807, and is completed. FINDINGS:Between Nov 17, 2023, and July 9, 2025, 179 participants were randomly allocated to receive mazdutide (32 participants to 3-6 mg, 48 to 10 mg, and 51 to 16 mg) or placebo (48 participants). The mean age was 47·7 years (SD 12·3), and 118 (66%) participants were female and 61 (34%) were male. At 32 weeks, the least-squares mean percentage change from baseline in bodyweight was -7·3% (SE 0·9) with mazdutide 3-6 mg, -15·6% (0·7) with 10 mg, and -18·1% (1·0) with 16 mg, versus -0·9% (0·8) with placebo. Estimated treatment differences versus placebo ranged from -6·5% to -17·2% (p<0·0001, all comparisons). Additional bodyweight reductions were observed at 48 weeks. The most common adverse events with mazdutide were gastrointestinal-related and mostly mild to moderate in severity; discontinuation of study treatment due to adverse events occurred most frequently with 16 mg (20%), associated primarily with gastrointestinal disorders. INTERPRETATION:Once-weekly, subcutaneous mazdutide showed clinically meaningful bodyweight reduction in adults with obesity or overweight across all studied doses, with higher doses (10 mg and 16 mg) showing additional weight reduction. FUNDING:Eli Lilly and Company.
BACKGROUND:Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes. METHODS:This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA1c (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J). FINDINGS:Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies. INTERPRETATION:Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes. FUNDING:Eli Lilly. TRANSLATION:For the Japanese translation of the abstract see Supplementary Materials section.
BACKGROUND:Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications. METHODS:COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100. The titration target was 3·9-5·0 mmol/L (70-90 mg/dL). The primary endpoint was change in HbA1c and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants. Adverse events were recorded during weeks 0-45. This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete. FINDINGS:Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100. Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82). For HbA1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001). From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001). Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59 episodes per person-year of exposure; estimated rate ratio 0·56 [95% CI 0·32 to 0·97]; p=0·04). Gastrointestinal disorders were the most frequently reported adverse events with IcoSema. INTERPRETATION:Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications. FUNDING:Novo Nordisk.
BACKGROUND:Semaglutide 2·4 mg is a GLP-1 receptor agonist that reduces bodyweight, and provides other cardiometabolic benefits, among people with a BMI at least 30 kg/m2 or at least 27 kg/m2 and with weight-related comorbidities. This trial aimed to evaluate the efficacy, tolerability, and safety of semaglutide 2·4 mg in adults from mainland China and Taiwan with overweight or obesity according to locally defined, BMI thresholds. METHODS:This completed randomised, double-blind, placebo-controlled, multicentre, two-armed, parallel-group, phase 3b trial (STEP 12) was conducted at 19 sites across mainland China and Taiwan. Adults with a BMI of 24-<28 kg/m2 and at least one weight-related comorbidity, or a BMI of 28-<30 kg/m2, with or without type 2 diabetes, were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo, plus lifestyle intervention, for 44 weeks. Randomisation was performed by the study sponsor using the Randomisation Trial Supplies Management System. Coprimary endpoints were percentage change in bodyweight and the proportion of participants achieving at least 5% bodyweight reduction. Safety was analysed descriptively in all participants who received the trial intervention. Missing data at week 44 were imputed with washout multiple imputation. This study is registered with ClinicalTrials.gov, NCT06041217, and is completed. FINDINGS:Between Sept 15, 2023, and May 7, 2025, of 254 screened participants, 161 (66·5%) of 242 participants were randomly assigned to semaglutide 2·4 mg and 81 (33·5%) to placebo; 121 (50·0%) participants were female, and 47 (19·4%) participants had type 2 diabetes. Bodyweight reduction was greater with semaglutide versus placebo (-12·1% [SE 0·6] vs -2·2% [0·8]; estimated treatment difference -9·9 percentage points [95% CI -11·8 to -8·0]; p<0·0001), with a greater proportion of participants achieving at least 5% bodyweight reduction (80·5% vs 24·4%; odds ratio [OR] 14·8 [95% CI 7·4 to 29·6]; p<0·0001). Adverse events were reported in 141 (87·6%) of 161 participants in the semaglutide 2·4 mg group and 61 (75·3%) of 81 participants in the placebo group, with gastrointestinal disorders being the most common. INTERPRETATION:Semaglutide 2·4 mg provided a superior reduction in bodyweight versus placebo in Chinese adults with overweight or obesity. The safety profile was consistent with the known profile of semaglutide. FUNDING:Novo Nordisk A/S. TRANSLATION:For the Mandarin translation of the abstract see Supplementary Materials section.
BACKGROUND:The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. METHODS:Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1·0 mg [FLOW], once-weekly subcutaneous 2·4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1·73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. FINDINGS:The pooled participants from the trials (N=30 787) had a mean follow-up of 39·5-47·5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0·84 [95% CI 0·77-0·91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0·80 [0·69-0·92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. INTERPRETATION:Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. FUNDING:Novo Nordisk.
Over the last decade, goal-directed management of osteoporosis has been developed as a concept. In 2024, a working group of the American Society for Bone and Mineral Research (ASBMR) determined that this concept should include specific bone mineral density (BMD) targets during treatment, to ensure optimal fracture risk reduction. Two observations were key to this recommendation: that higher on-treatment BMDs are associated with lower fracture risks in several studies, and that, in a meta-regression of individual clinical trials, agents producing larger increases in BMD also produced greater reduction in fracture risk. However, the inferences drawn from these studies might be unsound. First, on-treatment BMD is the sum of baseline BMD and its change on therapy. In trials in which these variables have both been considered, it was found that the influence of on-treatment BMD is substantially a reflection of the effect of baseline BMD on fracture risk rather than an effect of on-treatment BMD change. Second, the meta-regression findings are heavily dependent on the inclusion of less effective treatments in the analysis. Among more effective antiresorptives, no such relationship is seen. For example, although denosumab has greater effects on BMD than zoledronate, these agents have similar anti-fracture efficacy in trials. Therefore, a key conclusion of the treat-to-BMD-target framework-that denosumab is needed for many patients to reach their BMD targets-has no clinical trial support, suggesting the framework is flawed. Thus, use of BMD treatment targets in osteoporosis management is not supported by available evidence, so the frequent BMD measurements required by the treat-to-target framework will increase costs without demonstrable benefit.
BACKGROUND:Mild autonomous cortisol secretion (MACS), the most common hormonal abnormality in adrenal incidentalomas, is associated with increased cardiometabolic risk. MACS is defined by cortisol concentrations higher than 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST). The prognostic value of a single test remains uncertain. We examined longitudinal changes in 1-mg DST results, cumulative cortisol exposure, and their associations with cardiometabolic outcomes and mortality. METHODS:In this retrospective cohort study conducted in 25 adrenal centres that are part of the European Network for the Study of Adrenal Tumours consortium across 14 countries with adults (aged ≥18 years) with benign adrenal incidentalomas diagnosed from Jan 1, 2000, to Dec 1, 2020, two or more 1-mg DSTs, and follow-up of at least 36 months, we used multivariable Cox models to assess associations between longitudinal 1-mg DST results and all-cause mortality and cardiovascular and thrombotic events. Patients with Cushing's syndrome, primary aldosteronism, phaeochromocytoma, or androgen-secreting tumour at baseline; active malignancy within 36 months of incidentaloma diagnosis; or suspicion of unreliable 1-mg DST results were excluded, along with patients taking oral glucocorticoids, strong CYP3A4 modulators, adrenal enzyme inhibitors, oral oestrogen, or selective oestrogen receptor modulators. Cumulative cortisol exposure was estimated from serial 1-mg DSTs. Restricted mean survival time (RMST) quantified differences in event-free time. Data were collected from the electronic health records of all eligible patients at each participating centre. FINDINGS:Among 2525 patients (median follow-up 80 months [IQR 49-122]), 563 (22·3%) had changes in 1-mg DST results leading to a change in diagnosis, most within 3 years of their baseline 1-mg DST. Patients with persistently abnormal 1-mg DST results (ie, MACS-to-MACS patients; n=839) were older and had a greater cardiometabolic burden than those with persistently normal results (ie, non-functioning adrenal tumours [NFAT]-to-NFAT patients; n=1103). MACS-to-MACS patients had a higher rate of worsening hypertension (adjusted hazard ratio 1·34 [95% CI 1·03-1·73]) and a shorter event-free time for worsening hypertension (10-year RMST 60·4 months [56·8-75·5] vs 86·1 months [79·1-93·4]) than NFAT-to-NFAT patients. In crude analyses, patients with higher baseline post-1-mg DST cortisol, patients with greater cumulative cortisol exposure, and MACS-to-MACS patients had shorter survival and event-free time; however, these associations were not independent of age and baseline cardiometabolic risk factors after multivariable adjustment. INTERPRETATION:Longitudinal 1-mg DST changes are common. MACS-to-MACS patients had worsening hypertension, but rates of mortality and cardiovascular or thrombotic events were not significantly associated with 1-mg DST trajectories after adjustment for age and cardiovascular risk factors. These findings identify patients with persistently abnormal 1-mg DST results as a group with high cardiometabolic risk that warrants closer attention to modifiable risk factors. Prospective studies are needed to establish the clinical significance of repeated 1-mg DSTs for risk stratification. FUNDING:National Institute for Health and Care Research Birmingham Biomedical Research Centre, Horizon Europe 2022, and Deutsche Forschungsgemeinschaft.
