Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.

BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. RESULTS: Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).

Chronic kidney disease in type 1 diabetes: translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes.

Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.

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.).

Incretin mimetics and acute pancreatitis: enemy or innocent bystander?

PURPOSE OF REVIEW: The incretin enhancers and mimetics, including dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists (GLP-1RA) and GLP-1/GIP co-agonists, have become mainstays in the treatment of type 2 diabetes (T2D). Recently, the approval of certain GLP-1RA and GLP-1/GIP co-agonists for the treatment of obesity has broadened their popularity and use. In this review, we summarize the evidence for an association of these drugs with acute pancreatitis and other adverse events of special interest to gastroenterologists. RECENT FINDINGS: In addition to pancreatic islets, GLP-1 receptors are expressed in the exocrine cells of the pancreas. There is inconsistent evidence for an association of DPP-4 inhibitors, GLP-1RA and co-agonists with risk for acute pancreatitis in individual trials. Meta-analyses of long-term randomized controlled trials indicate a small risk of acute pancreatitis associated with DPP-4 inhibitors but not GLP-1RA or co-agonists. Cholecystitis and cholelithiasis may be more common among those treated with GLP-1RA and GLP-1/GIP co-agonists. There is no evidence that any of these drugs are associated with an increased risk of pancreatic cancer. SUMMARY: While drugs that leverage the incretin system are increasingly being used for patients with T2D and obesity, caution in warranted in those with a history of pancreatitis and gallbladder disease.

Supporting the 'lived expertise' of older adults with type 1 diabetes: An applied focus group analysis to characterize barriers, facilitators, and strategies for self-management in a growing and understudied population.

INTRODUCTION: There is a growing number of older adults (≥65 years) who live with type 1 diabetes. We qualitatively explored experiences and perspectives regarding type 1 diabetes self-management and treatment decisions among older adults, focusing on adopting care advances such as continuous glucose monitoring (CGM). METHODS: Among a clinic-based sample of older adults ≥65 years with type 1 diabetes, we conducted a series of literature and expert informed focus groups with structured discussion activities. Groups were transcribed followed by inductive coding, theme identification, and inference verification. Medical records and surveys added clinical information. RESULTS: Twenty nine older adults (age 73.4 ± 4.5 years; 86% CGM users) and four caregivers (age 73.3 ± 2.9 years) participated. Participants were 58% female and 82% non-Hispanic White. Analysis revealed themes related to attitudes, behaviours, and experiences, as well as interpersonal and contextual factors that shape self-management and outcomes. These factors and their interactions drive variability in diabetes outcomes and optimal treatment strategies between individuals as well as within individuals over time (i.e. with ageing). Participants proposed strategies to address these factors: regular, holistic needs assessments to match people with effective self-care approaches and adapt them over the lifespan; longitudinal support (e.g., education, tactical help, sharing and validating experiences); tailored education and skills training; and leveraging of caregivers, family, and peers as resources. CONCLUSIONS: Our study of what influences self-management decisions and technology adoption among older adults with type 1 diabetes underscores the importance of ongoing assessments to address dynamic age-specific needs, as well as individualized multi-faceted support that integrates peers and caregivers.

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.

Effect of albiglutide on cardiovascular outcomes in older adults: A post hoc analysis of a randomized controlled trial.

AIM: To analyse the effects of albiglutide, a glucagon-like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). MATERIALS AND METHODS: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial-time to first occurrence of a major adverse cardiovascular event-in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. RESULTS: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53-0.82) in persons <65 and 0.86 (95% CI, 0.71-1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67-0.91) in <75 and 0.70 (95% CI, 0.48-1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. CONCLUSIONS: This post hoc analysis adds to the body of literature showing that glucagon-like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk-benefit profile was similar between younger and older age groups treated with albiglutide.

A comparative Proteomics Analysis Identified Differentially Expressed Proteins in Pancreatic Cancer-Associated Stellate Cell Small Extracellular Vesicles.

Human pancreatic stellate cells (HPSCs) are an essential stromal component and mediators of pancreatic ductal adenocarcinoma (PDAC) progression. Small extracellular vesicles (sEVs) are membrane-enclosed nanoparticles involved in cell-to-cell communications and are released from stromal cells within PDAC. A detailed comparison of sEVs from normal pancreatic stellate cells (HPaStec) and from PDAC-associated stellate cells (HPSCs) remains a gap in our current knowledge regarding stellate cells and PDAC. We hypothesized there would be differences in sEVs secretion and protein expression that might contribute to PDAC biology. To test this hypothesis, we isolated sEVs using ultracentrifugation followed by characterization by electron microscopy and Nanoparticle Tracking Analysis. We report here our initial observations. First, HPSC cells derived from PDAC tumors secrete a higher volume of sEVs when compared to normal pancreatic stellate cells (HPaStec). Although our data revealed that both normal and tumor-derived sEVs demonstrated no significant biological effect on cancer cells, we observed efficient uptake of sEVs by both normal and cancer epithelial cells. Additionally, intact membrane-associated proteins on sEVs were essential for efficient uptake. We then compared sEV proteins isolated from HPSCs and HPaStecs cells using liquid chromatography-tandem mass spectrometry. Most of the 1481 protein groups identified were shared with the exosome database, ExoCarta. Eighty-seven protein groups were differentially expressed (selected by 2-fold difference and adjusted p value ≤0.05) between HPSC and HPaStec sEVs. Of note, HPSC sEVs contained dramatically more CSE1L (chromosome segregation 1-like protein), a described marker of poor prognosis in patients with pancreatic cancer. Based on our results, we have demonstrated unique populations of sEVs originating from stromal cells with PDAC and suggest that these are significant to cancer biology. Further studies should be undertaken to gain a deeper understanding that could drive novel therapy.

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.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.

BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).

Associations of Dietary Intake with the Intestinal Microbiota and Short-Chain Fatty Acids Among Young Adults with Type 1 Diabetes and Overweight or Obesity.

BACKGROUND: Diet, a key component of type 1 diabetes (T1D) management, modulates the intestinal microbiota and its metabolically active byproducts-including SCFA-through fermentation of dietary carbohydrates such as fiber. However, the diet-microbiome relationship remains largely unexplored in longstanding T1D. OBJECTIVES: We evaluated whether increased carbohydrate intake, including fiber, is associated with increased SCFA-producing gut microbes, SCFA, and intestinal microbial diversity among young adults with longstanding T1D and overweight or obesity. METHODS: Young adult men and women with T1D for ≥1 y, aged 19-30 y, and BMI of 27.0-39.9 kg/m2 at baseline provided stool samples at baseline and 3, 6, and 9 mo of a randomized dietary weight loss trial. Diet was assessed by 1-2 24-h recalls. The abundance of SCFA-producing microbes was measured using 16S rRNA gene sequencing. GC-MS measured fecal SCFA (acetate, butyrate, propionate, and total) concentrations. Adjusted and Bonferroni-corrected generalized estimating equations modeled associations of dietary fiber (total, soluble, and pectins) and carbohydrate (available carbohydrate, and fructose) with microbiome-related outcomes. Primary analyses were restricted to data collected before COVID-19 interruptions. RESULTS: Fiber (total and soluble) and carbohydrates (available and fructose) were positively associated with total SCFA and acetate concentrations (n = 40 participants, 52 visits). Each 10 g/d of total and soluble fiber intake was associated with an additional 8.8 µmol/g (95% CI: 4.5, 12.8 µmol/g; P = 0.006) and 24.0 µmol/g (95% CI: 12.9, 35.1 µmol/g; P = 0.003) of fecal acetate, respectively. Available carbohydrate intake was positively associated with SCFA producers Roseburia and Ruminococcus gnavus. All diet variables except pectin were inversely associated with normalized abundance of Bacteroides and Alistipes. Fructose was inversely associated with Akkermansia abundance. CONCLUSIONS: In young adults with longstanding T1D, fiber and carbohydrate intake were associated positively with fecal SCFA but had variable associations with SCFA-producing gut microbes. Controlled feeding studies should determine whether gut microbes and SCFA can be directly manipulated in T1D.

More hypoglycemia not associated with increasing estimated adiposity in youth with type 1 diabetes.

BACKGROUND: Despite the widespread clinical perception that hypoglycemia may drive weight gain in youth with type 1 diabetes (T1D), there is an absence of published evidence supporting this hypothesis. METHODS: We estimated the body fat percentage (eBFP) of 211 youth (HbA1c 8.0-13.0%, age 13-16) at baseline, 6, and 18 months of the Flexible Lifestyles Empowering Change trial using validated equations. Group-based trajectory modeling assigned adolescents to sex-specific eBFP groups. Using baseline 7-day blinded continuous glucose monitoring data, "more" vs. "less" percent time spent in hypoglycemia was defined by cut-points using sample median split and clinical guidelines. Adjusted logistic regression estimated the odds of membership in an increasing eBFP group comparing youth with more vs. less baseline hypoglycemia. RESULTS: More time spent in clinical hypoglycemia (defined by median split) was associated with 0.29 the odds of increasing eBFP in females (95% CI: 0.12, 0.69; p = 0.005), and 0.33 the odds of stable/increasing eBFP in males (95% CI: 0.14, 0.78; p = 0.01). CONCLUSIONS: Hypoglycemia may not be a major driver of weight gain in US youth with T1D and HbA1c ≥8.0. Further studies in different sub-groups are needed to clarify for whom hypoglycemia may drive weight gain and focus future etiological studies and interventions. IMPACT: We contribute epidemiological evidence that hypoglycemia may not be a major driver of weight gain in US youth with type 1 diabetes and HbA1c ≥8.0% and highlight the need for studies to prospectively test this hypothesis rooted in clinical perception. Future research should examine the relationship between hypoglycemia and adiposity together with psychosocial, behavioral, and other clinical factors among sub-groups of youth with type 1 diabetes (i.e., who meet glycemic targets or experience a frequency/severity of hypoglycemia above a threshold) to further clarify for whom hypoglycemia may drive weight gain and progress etiological understanding of and interventions for healthy weight maintenance.

The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D. METHODS: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes. RESULTS: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression. CONCLUSION: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes.

AIM: Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively. MATERIALS AND METHODS: Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480). RESULTS: In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide. CONCLUSIONS: The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.

Cardiorenal outcomes by indices of liver steatosis and fibrosis in individuals with type 2 diabetes and atherosclerotic cardiovascular disease: Analyses from VERTIS CV, a randomized trial of the sodium-glucose cotransporter-2 inhibitor ertugliflozin.

AIM: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo). RESULTS: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m2 , HSI 44.0 and FIB-4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB-4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB-4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. CONCLUSION: In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.

Weight management in young adults with type 1 diabetes: The advancing care for type 1 diabetes and obesity network sequential multiple assignment randomized trial pilot results.

AIMS: Co-management of weight and glycaemia is critical yet challenging in type 1 diabetes (T1D). We evaluated the effect of a hypocaloric low carbohydrate, hypocaloric moderate low fat, and Mediterranean diet without calorie restriction on weight and glycaemia in young adults with T1D and overweight or obesity. MATERIALS AND METHODS: We implemented a 9-month Sequential, Multiple Assignment, Randomized Trial pilot among adults aged 19-30 years with T1D for ≥1 year and body mass index 27-39.9 kg/m2 . Re-randomization occurred at 3 and 6 months if the assigned diet was not acceptable or not effective. We report results from the initial 3-month diet period and re-randomization statistics before shutdowns due to COVID-19 for primary [weight, haemoglobin A1c (HbA1c), percentage of time below range <70 mg/dl] and secondary outcomes [body fat percentage, percentage of time in range (70-180 mg/dl), and percentage of time below range <54 mg/dl]. Models adjusted for design, demographic and clinical covariates tested changes in outcomes and diet differences. RESULTS: Adjusted weight and HbA1c (n = 38) changed by -2.7 kg (95% CI -3.8, -1.5, P < .0001) and -0.91 percentage points (95% CI -1.5, -0.30, P = .005), respectively, while adjusted body fat percentage remained stable, on average (P = .21). Hypoglycaemia indices remained unchanged following adjustment (n = 28, P > .05). Variability in all outcomes, including weight change, was considerable (57.9% were re-randomized primarily due to loss of <2% body weight). No outcomes varied by diet. CONCLUSIONS: Three months of a diet, irrespective of macronutrient distribution or caloric restriction, resulted in weight loss while improving or maintaining HbA1c levels without increasing hypoglycaemia in adults with T1D.

Associations of disordered eating with the intestinal microbiota and short-chain fatty acids among young adults with type 1 diabetes.

BACKGROUND AND AIMS: Disordered eating (DE) in type 1 diabetes (T1D) includes insulin restriction for weight loss with serious complications. Gut microbiota-derived short chain fatty acids (SCFA) may benefit host metabolism but are reduced in T1D. We evaluated the hypothesis that DE and insulin restriction were associated with reduced SCFA-producing gut microbes, SCFA, and intestinal microbial diversity in adults with T1D. METHODS AND RESULTS: We collected stool samples at four timepoints in a hypothesis-generating gut microbiome pilot study ancillary to a weight management pilot in young adults with T1D. 16S ribosomal RNA gene sequencing measured the normalized abundance of SCFA-producing intestinal microbes. Gas-chromatography mass-spectrometry measured SCFA (total, acetate, butyrate, and propionate). The Diabetes Eating Problem Survey-Revised (DEPS-R) assessed DE and insulin restriction. Covariate-adjusted and Bonferroni-corrected generalized estimating equations modeled the associations. COVID-19 interrupted data collection, so models were repeated restricted to pre-COVID-19 data. Data were available for 45 participants at 109 visits, which included 42 participants at 65 visits pre-COVID-19. Participants reported restricting insulin "At least sometimes" at 53.3% of visits. Pre-COVID-19, each 5-point DEPS-R increase was associated with a -0.34 (95% CI -0.56, -0.13, p = 0.07) lower normalized abundance of genus Anaerostipes; and the normalized abundance of Lachnospira genus was -0.94 (95% CI -1.5, -0.42), p = 0.02 lower when insulin restriction was reported "At least sometimes" compared to "Rarely or Never". CONCLUSION: DE and insulin restriction were associated with a reduced abundance of SCFA-producing gut microbes pre-COVID-19. Additional studies are needed to confirm these associations to inform microbiota-based therapies in T1D.

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

BACKGROUND: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function. METHODS: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease. RESULTS: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease. CONCLUSIONS: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).