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Richard E Pratley1–31Florida Hospital Diabetes Institute, 2Translational Research Institute for Metabolism and Diabetes, 3Sanford-Burnham Medical Research Institute, Orlando, FL, USAAbstract: Older people have the highest prevalence of type 2 diabetes mellitus (T2DM) of any age group and are thus frequent users of glucose-lowering agents. Because individuals 65 years or older are underrepresented in clinical studies, there is a lack of information regarding the efficacy and safety of available treatments in this population. Additionally, a high prevalence of comorbidities, polypharmacy, and frailty can make treatment of T2DM in this population challenging. Safety is an important consideration when choosing a treatment for older individuals. Renal impairment is quite common in older patients with T2DM and can contribute to hypoglycemia. Hypoglycemia can lead to serious consequences, such as falls and fractures, and cognitive changes. As such, hemoglobin A1c treatment targets, typically

Objective: To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes.Research Design and Methods: In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged.Results: Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA(1c)) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8 mg/day, -1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA(1c) <7% (from ∼30% to ∼50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA(1c) (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7 mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia.Conclusions: Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions. [ABSTRACT FROM AUTHOR]

Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese.Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity.Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time.Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery.Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation. [ABSTRACT FROM AUTHOR]

Enzymatic cleavage of amyloid-β protein precursor (AβPP) produces amyloid-β (Aβ) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AβPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AβPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AβPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AβPP and all three major isoforms (AβPP695, AβPP751, and AβPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AβPP and AβPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AβPP751 and AβPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AβPP695 (p = 0.051) and increased percentage AβPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AβPP and AβPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AβPP isoform transcripts by real-time PCR and confirm previous studies showing altered AβPP isoform expression patterns in AD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Managing elderly patients with type 2 diabetes poses particular challenges, so it is important to evaluate the efficacy and tolerability profile of antidiabetic therapies specifically in this patient population. OBJECTIVE: The aim of our study was to compare the efficacy and tolerability profile of liraglutide, a GLP-1 analog, in elderly (>=65 years) and younger (<65 years) patients with type 2 diabetes. METHODS: A pooled analysis of 6 randomized, placebo-controlled, multinational trials included data from 3967 patients aged18 to 80 years with type 2 diabetes and glycosylated hemoglobin (HbA(1c)) of 7% to 11%. Of these, 552 patients >=65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo; 2231 patients <65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo for 26 weeks. End points were: change in HbA(1c), fasting plasma glucose, body weight, and blood pressure: as marked to identify elements tracked for change from baseline; hypoglycemic episodes; and adverse events. RESULTS: Reduction in HbA(1c) from baseline was significantly greater with liraglutide 1.8 mg versus placebo (least squares mean difference: >=65 years, 0.91% [95% CI, 0.69-1.12]; <65 years, 1.17% [95% CI, 1.06-1.28]; both, P < 0.0001) and with liraglutide 1.2 mg versus placebo (>=65 years, 0.87% [95% CI, 0.64-1.11]; <65 years, 1.10% [95% CI, 0.98-1.22]; both, P < 0.0001). For fasting plasma glucose, comparable results were observed between liraglutide 1.8 mg or 1.2 mg and placebo for both age groups (P < 0.0001). No statistically significant difference in body weight change was seen with liraglutide between the age groups. The proportion of patients reporting minor hypoglycemia was low and appeared comparable between the >=65-year-old (4.3%-15.2%) and <65-year-old (8%-13.2%) groups. Likewise, adverse events appeared comparable in nature and frequency. CONCLUSION: Liraglutide provides effective glycemic control and is well tolerated in patients >=65 and <65 years of age with type 2 diabetes. These data suggest that liraglutide may be a suitable treatment option for older patients who may have additional age-related complications. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18-80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] 7.0-10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. MAIN OUTCOME MEASURES: The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG > or = 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia. RESULTS: Least squares (LS) mean change in HbA(1c) was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p < or = 0.016) larger proportion of patients achieved HbA(1c) < or = 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (-19.7 mg/dL [-1.09 mmol/L]) or 25 mg (-19.9 mg/dL [-1.10 mmol/L]) than with placebo (-5.7 mg/dL [-0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (< or =25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo. CONCLUSIONS: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety. CLINICAL TRIAL REGISTRATION: NCT00286494, clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Incretin-based therapies have features that are unique among antidiabetic therapies. DPP-4 inhibitors enhance both GIP and GLP-1, whereas GLP-1 agonists have a pure GLP-1 effect. DPP-4 inhibitors result in physiological or high physiological fluctuations in hormone levels, whereas pharmacological levels are achieved with GLP-1 agonists. DPP-4 inhibitors are limited by endogenous secretion of GLP-1 and GIP, which is not the case with GLP-1 agonists, where one is providing the exogenous hormone. Data from several clinical trials demonstrate the clinical efficacy and favorable safety profile of these agents. The DPP-4 inhibitors are comparable in efficacy to many oral agents, including thiazolidinediones and sulfonylureas. The longer-acting GLP-1 agonists in development (i.e., exenatide LAR and liraglutide) may have enhanced efficacy. This class of agents is associated with a low incidence of hypoglycemia.Incretin-based therapies are weight neutral (DPP-4 inhibitors) or promote weight loss (GLP-1 agonists). DPP-4 inhibitors may be most appropriate to use early in the course of type 2 diabetes, whereas GLP-1 agonists may be appropriate across the spectrum of disease progression. Their place in therapy remains to be more fully established, but consideration should be given for their use earlier in the treatment paradigm. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of vildagliptin in elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Efficacy data from five double-blind, randomized, placebo- or active-controlled trials of >or=24 weeks' duration were pooled. Effects of 24-week vildagliptin monotherapy (100 mg daily) were compared in younger (<65 years, n = 1,231) and older (>or=65 years, n = 238) patients. Safety data from eight controlled clinical trials of >or=12-weeks' duration were pooled; adverse event profiles in younger (n = 1,890) and older (n = 374) patients were compared. RESULTS: Mean baseline A1C and fasting plasma glucose (FPG) were significantly lower in older (70 years: 8.3 +/- 0.1% and 9.6 +/- 0.1 mmol/l, respectively) than in younger (50 years: 8.7 +/- 0.0% and 10.5 +/- 0.1 mmol/l, respectively) patients. Despite this, the adjusted mean change from baseline (AMDelta) in A1C was -1.2 +/- 0.1% in older and -1.0 +/- 0.0% in younger vildagliptin-treated patients (P = 0.092), and the AMDelta in FPG was significantly larger in older (-1.5 +/- 0.2 mmol/l) than in younger (-1.1 +/- 0.1 mmol/l, P = 0.035) patients. Body weight was significantly lower at baseline in older (83.4 +/- 1.0 kg) than in younger (92.0 +/- 0.6 kg) patients. Weight decreased significantly in the older subgroup (AMDelta -0.9 +/- 0.3 kg, P = 0.007), whereas smaller, nonsignificant decreases occurred in younger patients (AMDelta -0.2 +/- 0.1 kg). Adverse event rates were slightly higher in older than in younger subgroups but were lower among older, vildagliptin-treated subjects (63.6%) than in the pooled active comparator group (68.1%). Vildagliptin treatment did not increase adverse events among older patients with mild renal impairment (62.0%). Hypoglycemia was rare (0.8%) in the elderly patients, and no severe events occurred. CONCLUSIONS: Vildagliptin monotherapy was effective and well tolerated in treatment-naive elderly patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is epidemic in most developed and many developing countries. The associated morbidity, mortality and high costs of care, make type 2 diabetes an important global public health challenge and target for prevention. Patients at high risk for type 2 diabetes can be diagnosed by fasting glucose levels or responses to an oral glucose tolerance test (OGTT). Such patients are also at increased risk for cardiovascular disease (CVD). Since obesity and physical inactivity are important risk factors for type 2 diabetes, lifestyle interventions, emphasising modest weight loss and increases in physical activity, should be recommended for most patients with pre-diabetes. Such interventions are safe and effective and also reduce risk factors for CVD. Several oral antidiabetic agents have been shown to be effective at delaying onset of type 2 diabetes. Thiazolidinediones (TZDs) reduced incident diabetes by -60%, whilst metformin, acarbose and orlistat are only about half as effective as the TZDs. Pharmacological interventions may be appropriate for patients at particular risk for developing diabetes, but the benefits of treatment need to be balanced against the safety and tolerability of the intervention. If pharmacological treatment is warranted, metformin should be considered first because of its favourable overall safety, tolerability, efficacy, and cost profile. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by the enteroendocrine cells of the gut in response to the ingestion of nutrients. These incretin hormones, so called because they increase insulin secretion, are key modulators of pancreatic islet hormone secretion and, thus, glucose homeostasis. The glucoregulatory effects of incretins are the basis for new therapies currently being developed for the treatment of type 2 diabetes mellitus (T2DM). Drugs that inhibit dipeptidyl peptidase-4 (DPP-4), a ubiquitous enzyme that rapidly inactivates both GLP-1 and GIP, increase active levels of these hormones and, in doing so, improve islet function and glycemic control in T2DM.Scope: In this review, we briefly describe (1) the role of pancreatic islet dysfunction in the onset and progression of T2DM, (2) the rationale for developing drugs that enhance incretin activity, (3) the evidence that inhibition of DPP-4 is effective in ameliorating islet dysfunction and improving glycemic control in T2DM, (4) the efficacy, safety, and tolerability of DPP-4 inhibitors as monotherapy and in combination with other antidiabetic agents, and (5) the potential utility of DPP-4 inhibitors relative to existing oral antidiabetic agents and newer antidiabetic drugs in the pipeline. The review is based upon MEDLINE literature searches (1966-August 2006) and abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006). Basic science, preclinical, and clinical studies and review articles published in the English language were evaluated and selected based upon consideration of their originality, relevance, and frequency of citation.Findings: DPP-4 inhibitors are a new class of antidiabetogenic drugs that provide comparable efficacy to current treatments. They are effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. The DPP-4 inhibitors are well tolerated, carry a low risk of producing hypoglycemia, and are weight neutral. The long-term durability of effect on glycemic control and beta-cell morphology and function remain to be established.Conclusions: Islet cell dysfunction is central to the pathogenesis of T2DM. Incretin-based therapies, including GLP 1 analogues and DPP-4 inhibitors, have been shown to restore glucose homeostasis and improve glycemic control. The DPP-4 inhibitors, which can be used as monotherapy or in combination with other antidiabetic drugs, are a promising new treatment option, especially for patients with early-stage T2DM and more severe hyperglycemia. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a growing problem in most parts of the world. There is now good evidence that controlling hyperglycaemia can help prevent many of the serious complications associated with the disease. Despite this evidence and the availability of several classes of oral antidiabetic agents and insulin, many people with diabetes do not achieve adequate glycaemic control (i.e. HbA[1C]

Objective: We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain beta-cell function parameters from a meal test and examined the impact of the beta-cell improvement on glucose tolerance.Research Design and Methods: Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. Beta-cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment.Results: The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose-insulin secretion relationship), and insulin secretion at a fixed- reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes.Conclusions: The model-derived parameters are sensitive measures of beta-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sex differences in eating behavior are well documented, but it is not known whether these differences have neuroanatomical correlates. Recent neuroimaging studies have provided functional maps of the human cerebral areas activated in response to hunger and satiation. OBJECTIVE: The objective of this study was to assess whether the brain's response to a meal is sex-specific. DESIGN: Using positron emission tomography, we measured regional cerebral blood flow, a marker of neuronal activity, to investigate the functional neuroanatomy of hunger (36-h fast) and satiation (in response to a liquid meal) in 22 women and 22 men. RESULTS: We observed extensive similarities, as well as some differences, between the sexes. In response to hunger, the men tended to have greater activation in the frontotemporal and paralimbic areas than did the women (P < 0.005). In response to satiation, the women tended to have greater activation in the occipital and parietal sensory association areas and in the dorsolateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventromedial prefrontal cortex than did the women (P < 0.005). CONCLUSIONS: Despite extensive similarities in the brain responses to hunger and satiation between the men and women, our study showed sex-specific brain responses to a meal that indicate possible differences between men and women in the cognitive and emotional processing of hunger and satiation. This study provides a foundation for investigating the brain regions and cognitive processes that distinguish normal and abnormal eating behavior in men and women. Copyright © 2002 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: The sensation of taste provides reinforcement for eating and is of possible relevance to the clinical problem of obesity. Objective: Positron emission tomography (PET) was used to explore regions of the brain that were preferentially affected during the taste perception of a liquid meal by 11 right-handed, lean men in the fasting state. Design: After subjects had fasted for 36 h, 2 measurements of regional cerebral blood flow (rCBF) obtained immediately after subjects retained and swallowed 2 mL of a flavored liquid meal (the taste condition) were compared with 2 measurements of rCBF obtained immediately after subjects retained and swallowed 2 mL of water (the baseline condition). Results: Compared with the baseline condition, taste was associated with increased rCBF (P < 0.005) in the left dorsolateral prefrontal cortex and superior temporal gyrus, the right ventrolateral prefrontal cortex, supramarginal gyrus, and anterior thalamus; and bilaterally in the hippocampal formation, posterior cingulate, midbrain, occipital cortex, and cerebellum. Taste was also associated with decreased rCBF (P < 0.005) in the right dorsolateral prefrontal cortex, superior temporal gyrus, and supplementary motor area, and bilaterally in the medial prefrontal cortex and inferior parietal lobule. Conclusions: This exploratory study provides additional evidence that the temporal cortex, thalamus, cingulate cortex, caudate, and hippocampal formation are preferentially affected by taste stimulation. The asymmetric pattern of activity in the dorsolateral prefrontal cortex and superior temporal gyrus may contribute to the taste perception of a liquid meal perceived as pleasant. Additional studies are required to determine how these regions are affected in patients with obesity or anorexia. Copyright (c) 1999 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

The comprehensive longitudinal studies of diabetes conducted in the Pima Indians of Arizona over the last 30 years indicate that both genetic and environmental factors play a critical role in the pathogenesis of the disease. Pre- and postnatal exposures as well as diet and physical activity in adulthood markedly affect risk of developing NIDDM in this population. In addition, the high prevalence of diabetes in the Pimas relative to other populations and the familiality of the disease and its precursors, strongly suggest a substantial genetic basis. Interactions between genes and the environment are obviously important in the pathogenesis of NIDDM, but it remains unclear exactly how these interactions occur and how to adequately account for these effects when searching for genes contributing to diabetes. The realization that gene-environment interactions are significant, and may be the dominant mechanism increasing susceptibility to NIDDM, should encourage further investigations. Future progress in studying the genetics of NIDDM and other complex diseases will come not only from technical advances currently in development, but also from advances in understanding the pathophysiology of the disease and the role of gene-environment interactions, and a renewed emphasis on careful clinical characterization of subjects participating in these studies. [ABSTRACT FROM AUTHOR]

Purpose: Type 2 diabetes is characterized by multiple metabolic abnormalities including the dysfunction of pancreatic islet cells. Current treatment options have different mechanisms of action and are variably effective at lowering blood glucose levels. The newest pharmacologic treatments, incretin mimetics and dipeptidyl peptidase-IV (DPP-4) inhibitors, target the incretin system, and it is important to understand their role in current treatment paradigms and in addressing the basic pathophysiology of type 2 diabetes -- pancreatic islet cell dysfunction. Conclusion: This article discusses the pathophysiology of type 2 diabetes including impairment of the incretin effect, and explains how incretin mimetics and DPP-4 inhibitors are being incorporated into treatment algorithms to address pancreatic islet cell dysfunction and enable patients to achieve glycemic targets. [ABSTRACT FROM AUTHOR]

Aim: To conduct post hoc analyses of the VERTIS CV (NCT01986881) trial to explore the effects of ertugliflozin on serum uric acid (UA) and gout-related outcomes., Materials and Methods: Participants with type 2 diabetes and atherosclerotic cardiovascular disease were randomised (1:1:1) to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg. Mean UA over time (260 weeks) was evaluated for pooled ertugliflozin versus placebo overall, and by baseline quintile of UA (≤4.3 mg/dL [≤255.8 µmol/L], >4.3-5.1 mg/dL [>255.8-303.4 µmol/L], >5.1-5.8 mg/dL [>303.4-345.0 µmol/L], >5.8-6.9 mg/dL [>345.0-410.4 µmol/L] and >6.9 mg/dL [>410.4 µmol/L]), glycated haemoglobin level, albuminuria status, estimated glomerular filtration rate and KDIGO (Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease) risk category. The effect of ertugliflozin on a composite of gout onset or initiation of anti-gout medication was assessed., Results: The mean UA levels at baseline were 5.67 and 5.62 mg/dL in the placebo and ertugliflozin groups, respectively. Ertugliflozin reduced UA over Weeks 6-260 compared with placebo, with least squares mean (LSM) changes (95% confidence interval [CI]) from baseline at Week 260 of 0.07 mg/dL (-0.02, 0.15) and -0.19 mg/dL (-0.25, -0.13) in the placebo and pooled ertugliflozin groups, respectively. At Week 260, placebo-adjusted LSM change (95% CI) from baseline in UA was -0.26 mg/dL (-0.36, -0.16) with ertugliflozin. Ertugliflozin was associated with reductions in UA across baseline UA quintiles compared with placebo. The incidence of the composite of gout-related outcomes was 84/2539 (3.3%) for placebo and 133/5091 (2.6%) for ertugliflozin (hazard ratio for the composite 0.76 [95% CI 0.580, 1.002])., Conclusions: Ertugliflozin was generally associated with lowering UA overall and across subgroups compared with placebo, and numerically reduced rates of gout-related outcome events., (© 2024 Merck Sharp & Dohme LLC. Pfizer Inc and The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Rationale: Although recent evidence suggested that glucagon-like peptide 1 receptor agonists (GLP1RAs) might reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. Objectives: To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. Methods: We implemented an active-comparator, new-user design analysis using commercially ensured patients 18-65 years of age from MarketScan data for 2007-2019 and identified two cohorts: GLP1RAs versus thiazolidinediones and GLP1RAs versus sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department visit for asthma) within 180 days after initiation. We applied iterative causal forest, a novel causal machine learning subgrouping algorithm, to assess heterogeneous treatment effects. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences for the effect of GLP1RAs relative to comparators on asthma exacerbation using inverse probability treatment weighting in the propensity score-trimmed subpopulation. Results: Among 10,989 patients initiating GLP1RAs or thiazolidinediones and 17,088 patients initiating GLP1RAs versus sulfonylurea, GLP1RA initiators had fewer exacerbations, with adjusted risk differences of -0.5% (95% confidence interval [CI], -1.1% to 0.1%) and -1.6% (95% CI, -2.2% to -1.1%), respectively. In the GLP1RA versus sulfonylurea cohort, in which we observed a beneficial effect, our iterative causal forest analysis identified five subgroups with different treatment effects, defined by the number of emergency department visits, the number of prescriptions for short-acting β 2 -agonists, the number of prescriptions for inhaled steroids and long-acting β-agonists (either combination therapy or concurrent use), and age ≥ 50 years. Among these, patients with two or more emergency department visits during the 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RAs (95% CI, -4.8% to -0.9%). Conclusions: GLP1RAs demonstrated a beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Patients with asthma with two or more emergency department visits (a proxy for disease severity) benefit most from GLP1RAs. Emergency department visit frequency, the number of maintenance and reliever inhalers, and age might help individualize prediction of the short-term benefit of GLP1RAs on asthma exacerbation.

Background: People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m 2 , kidney replacement therapy, and kidney or CV death) by 24%., Objectives: This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population., Methods: Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee., Results: A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment., Conclusions: Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)., Competing Interests: Funding Support and Author Disclosures The FLOW trial was funded by Novo Nordisk A/S. Dr Pratley has received speaker fees paid to his employer, AdventHealth (through December 31, 2023) from Eli Lilly, Lilly USA LLC, and Novo Nordisk; has received consulting fees directed to his institution from AbbVie, AstraZeneca, Bayer AG, Bayer HealthCare Pharmaceuticals, Corcept Therapeutics, Dexcom, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Hanmi Pharmaceutical, Hengrui (USA) Ltd, Intas Pharmaceuticals, Eli Lilly, Lilly USA LLC, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals, Scholar Rock, and Sun Pharmaceutical Industries; has received grants directed to his institution from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi; and has received personal fees (from January 1, 2024) from AdventHealth, a nonprofit entity. Dr Tuttle has received support from National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and OT2OD032581, and from Centers for Disease Control and Prevention project numbers 75D301-21-P-12254 and 75D301-23-C-18264; has received investigator-initiated grant support from Travere, Bayer, and the Doris Duke Foundation outside of the submitted work; has received consulting fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and has received speaker fees from Novo Nordisk. Dr Rossing has received grants from Bayer, AstraZeneca, and Novo Nordisk; has received honoraria paid to the Steno Diabetes Centre Copenhagen from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer; and has received consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer. Dr Perkovic has received honoraria for steering committee, data monitoring committee, or advisory board roles or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UptoDate; and is Board Director for George Clinical, St Vincent’s Health Australia and several independent medical research institutes. Dr Mann has received grants from Novo Nordisk, the European Union, and McMaster University, Hamilton, Canada; has received consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; has received honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, as well as a leadership role in the Kidney Disease: Improving Global Outcomes group. Dr MacIsaac was a FLOW trial investigator and member of the FLOW global expert panel; has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program, and The National Health and Medical Research Council of Australia; has received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, MSD, Novartis, and Boehringer Ingelheim; has been on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, AstraZeneca, and MSD; has received travel support from Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca; and has been a principal investigator for industry-sponsored clinical trials run by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag, and AbbVie. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Kamenov has received speaker fees from Actavis, AstraZeneca, Bayer-Schering, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, KRKA, Merck, MLD, MSD (Merck), Mundipharma, Mylan, Novartis, Novo Nordisk, Pfizer, Sandoz, Sanofi, Servier, TEVA Pharmaceuticals, Valentis, Vedra, and Viatris. Dr Hadjadj has received grants from Asdia, Asten, AstraZeneca, Homeperf, LVL, Nestle Home Care, Pierre Fabre, and VitalAire; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Servier, and Valbiotis; has received speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Dino Santé, Eli Lilly, Novartis, Novo Nordisk, Pierre Fabre, Sanofi, Servier, and Valbiotis; and has received meeting invitations from AstraZeneca, Abbott, Dino Santé, Eli Lilly, and Novo Nordisk. Dr Bakris has received consulting fees from Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Novo Nordisk, and Dia Medica Therapeutics. Dr Mahaffey has received grants from the American Heart Association, Apple, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and has received consulting fees from Applied Therapeutics, Bayer, Bristol Myers Squibb, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, PhaseBio, Portola, Quidel, and Theravance; and holds equity in Human, Medeloop, Precordior and Regencor. Drs Rasmussen, Nielsen, Idorn, Hansen, and Baeres are employees of and shareholders in Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The TAS1R2 receptor, known for its role in taste perception, has also emerged as a key regulator of muscle physiology. Previous studies have shown that genetic ablation of TAS1R2 in mice enhances muscle fitness mimicking responses to endurance exercise training. However, the translational relevance of these findings to humans remains uncertain., Methods: We explored responses to endurance exercise training in mice and humans with genetic deficiency of TAS1R2. First, we assessed the effects of muscle-specific deletion of TAS1R2 in mice (mKO) or wild type controls (mWT) following 4 weeks of voluntary wheel running (VWR). Next, we investigated the effects of the TAS1R2 -Ile191Val (rs35874116) partial loss-of-function variant on responses to a 6-month diet-induced weight loss with exercise training (WLEX), weight loss alone (WL), or education control (CON) interventions in older individuals with obesity. Participants were retrospectively genotyped for the TAS1R2 -Ile191Val polymorphism and classified as conventional function (Ile/Ile) or partial loss-of-function (Val carriers: Ile/Val and Val/Val). Body composition, cardiorespiratory fitness, and skeletal muscle mitochondrial function were assessed before and after the intervention., Results: In response to VWR, mKO mice demonstrated enhanced running endurance and mitochondrial protein content. Similarly, TAS1R2 Val carriers exhibited distinctive improvements in body composition, including increased muscle mass, along with enhanced cardiorespiratory fitness and mitochondrial function in skeletal muscle following the WLEX intervention compared to Ile/Ile counterparts. Notably, every Val carrier demonstrated substantial responses to exercise training and weight loss, surpassing all Ile/Ile participants in overall performance metrics., Conclusions: Our findings suggest that TAS1R2 partial loss-of-function confers beneficial effects on muscle function and metabolism in humans in response to exercise training, akin to observations in TAS1R2 muscle-deficient mice. Targeting TAS1R2 may help enhancing exercise training adaptations in individuals with compromised exercise tolerance or metabolic disorders, presenting a potential avenue for personalized exercise interventions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Published by Elsevier Inc.)

People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P < 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min -1 /1.73 m 2 /year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use (P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 ., (© 2024. The Author(s).)

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes., Competing Interests: Declaration of competing interest None of the Task Force members received monetary renumeration for their contributions to the creation or writing of this consensus document. See the Supplementary Appendix for full declarations of competing interests for each author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) study demonstrated continuous glucose monitoring (CGM) reduced hypoglycemia over 6 months among older adults with type 1 diabetes (T1D) compared with blood glucose monitoring (BGM). We explored heterogeneous treatment effects of CGM on hypoglycemia by formulating a data-driven decision rule that selects an intervention (ie, CGM vs BGM) to minimize percentage of time <70 mg/dL for each individual WISDM participant., Method: The precision medicine analyses used data from participants with complete data (n = 194 older adults, including those who received CGM [n = 100] and BGM [n = 94] in the trial). Policy tree and decision list algorithms were fit with 14 baseline demographic, clinical, and laboratory measures. The primary outcome was CGM-measured percentage of time spent in hypoglycemic range (<70 mg/dL), and the decision rule assigned participants to a subgroup reflecting the treatment estimated to minimize this outcome across all follow-up visits., Results: The optimal decision rule was found to be a decision list with 3 steps. The first step moved WISDM participants with baseline time-below range >1.35% and no detectable C-peptide levels to the CGM subgroup (n = 139), and the second step moved WISDM participants with a baseline time-below range of >6.45% to the CGM subgroup (n = 18). The remaining participants (n = 37) were left in the BGM subgroup. Compared with the BGM subgroup (n = 37; 19%), the group for whom CGM minimized hypoglycemia (n = 157; 81%) had more baseline hypoglycemia, a lower proportion of detectable C-peptide, higher glycemic variability, longer disease duration, and higher proportion of insulin pump use., Conclusions: The decision rule underscores the benefits of CGM for older adults to reduce hypoglycemia. Diagnostic CGM and laboratory markers may inform decision-making surrounding therapeutic CGM and identify older adults for whom CGM may be a critical intervention to reduce hypoglycemia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RSW participated in multicenter clinical trials through her institution, sponsored by Insulet, Medtronic, Eli Lilly, Novo Nordisk, and Boehringer Ingelheim, and has used donated DexCom CGMs in projects sponsored by NIH and the Leona M. and Harry B. Helmsley Charitable Trust. KMM has used donated DexCom CGMs in projects sponsored by NIH and the Leona M. and Harry B. Helmsley Charitable Trust. REP reports consulting fees from Bayer AG, Corcept Therapeutics Incorporated, DexCom, Hanmi Pharmaceutical Co., Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma Inc., and Sun Pharmaceutical Industries, and grants/research support from Hanmi Pharmaceutical Co., Janssen, Metavention, Novo Nordisk, Poxel SA, and Sanofi. All funds are paid directly to Dr Pratley’s employer, AdventHealth, a nonprofit organization that supports education and research.

Background/objectives: Type 1 diabetes (T1D) is associated with an increase in resting metabolic rate (RMR), but the impact of T1D on other components of 24-h energy expenditure (24-h EE) is not known. Also, there is a lack of equations to estimate 24-h EE in patients with T1D. The aims of this analysis were to compare 24-h EE and its components in young adults with T1D and healthy controls across the spectrum of body mass index (BMI) and derive T1D-specific equations from clinical variables., Subjects/methods: Thirty-three young adults with T1D diagnosed ≥1 year prior and 33 healthy controls matched for sex, age and BMI were included in this analysis. We measured 24-h EE inside a whole room indirect calorimeter (WRIC) and body composition with dual x-ray absorptiometry., Results: Participants with T1D had significantly higher 24-h EE than healthy controls (T1D = 2047 ± 23 kcal/day vs control= 1908 ± 23 kcal/day; P < 0.01). We derived equations to estimate 24-h EE with both body composition (fat free mass + fat mass) and anthropometric (weight + height) models, which provided high coefficients of determination (R 2  = 0.912 for both). A clinical model that did not incorporate spontaneous physical activity yielded high coefficients of determination as well (R 2  = 0.897 and R 2  = 0.880 for body composition and anthropometric models, respectively)., Conclusion: These results confirm that young adults with established T1D have increased 24-h EE relative to controls without T1D. The derived equations from clinically available variables can assist clinicians with energy prescriptions for weight management in patients with T1D., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups., Methods: PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years)., Results: For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups., Conclusion: The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals., Competing Interests: Declaration of competing interest REP reports speaker fees from Merck and Novo Nordisk; consulting fees from Bayer AG, Endogenex, Inc., Gasherbrum Bio, Inc., Hengrui (USA) Ltd., Intas Pharmaceuticals, Inc., Lilly, Novo Nordisk, Pfizer, Rivus Pharmaceuticals Inc., and Sun Pharmaceutical Industries; and grants from Dompe and Novo Nordisk. All funds are paid directly to Dr. Pratley's employer, AdventHealth, a nonprofit organization that supports education and research. TKT reports consulting fees from Novo Nordisk and Lilly, research support from Novo Nordisk and Bayer. She is on the speaker bureau for Bayer and Lilly. CTR received research grant through institution from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis; Honoraria for scientific advisory boards and consulting fees from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer. CTR and KI are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Zora Biosciences. All other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m ® (Mifepri st one) (CATALYST) trial., Methods and Analysis: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym ® ). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life., Ethics and Dissemination: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals., Trial Registration Number: NCT05772169., Competing Interests: Competing interests: RAF reports: advisory board with AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Renalytix, Corcept Therapeutics; research support from Boehringer Ingelheim, AstraZeneca; speaker's bureau with AstraZeneca. RJA reports: research support from Neurocrine Biosciences and Diurnal, Spruce Biosciences, Corcept Therapeutics, Sparrow Pharmaceuticals; consulting fees from Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Adrenas Therapeutics, PhaseBio Pharmaceuticals, Novo Nordisk, Recordati Rare Diseases, H Lundbeck A/S, OMass Therapeutics, Sparrow Pharmaceuticals. IB reports: consulting and/or advisory board with Corcept, HRA Pharma, Recordati, Sparrow, Neurocrine, Diurnal, Spruce; data safety monitoring board with Adrenas; funding for investigator initiated award from Recordati. LB reports: contracted fees paid to the Ochsner Clinic Foundation by Novo Nordisk for consulting work, and to Corcept Therapeutics for both speaking and consulting services. RSB reports: grant funding from Corcept pharmaceuticals; research funding from Novo, Lilly and Novartis; and speaker bureaus for Novo, Lilly, AstraZeneca, Amgen,and Bayer. JBB reports: contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support from Dexcom, Insulet, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, CeQur, Cirius Therapeutics, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Medtronic, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, Valo and Zealand Pharma; stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. JWF reports: consultant and investigator for Corcept, Recordati. VAF reports: research support (to Tulane): grants from Fractyl, Jaguar Gene Therapy, Corcept; honoraria for consulting and lectures from Asahi, Bayer, Abbott, Boehringer Ingelheim, Corcept; stock options in Mellitus Health, BRAVO4Health; stock in Amgen, Abbott; patents pending for 1) BRAVO risk engine for predicting diabetes complications, 2) PAX4 gene therapy for type 1 diabetes. JPF reports: research support from Akero, Altimmune, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi, Shionogi, Corcept Therapeutics; advisory boards and consulting with Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, Sanofi, Sun Pharma; speaker’s bureau with Eli Lilly; employment and stock ownership in Biomea Fusion. OH reports: scientific advisory board participation with Corcept Therapeutics, Strongbridge Pharma, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Lantheus, Xeris. YH reports: research grant from Amgen, Applied Therapeutic, Corcept, Ionis, Lilly, Merck, Regor; advisory/consultant role with Amgen, Applied Therapeutic, AZ, Bayer, BI, Corcept, Esperion, Mankind Pharma, Merck, Merck-Pfizer, Novartis, Novo Nordisk, Sanofi; speaker’s bureau with Bayer, Esperion, Novo Nordisk. REP reports: consulting fees from Bayer AG, Corcept Therapeutics Incorporated, Dexcom, Hanmi Pharmaceutical Co., Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma, Sun Pharmaceutical Industries; grants/research support from Hanmi Pharmaceutical Co., Janssen, Metavention, Novo Nordisk, Poxel SA, Sanofi. All funds are paid directly to REP’s employer, AdventHealth, a non-profit organisation that supports education and research. JR reports: advisory panels with Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma and Zealand; research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, Sanofi. ICT, AGM and DE report: employed by and own stock in Corcept Therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)