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Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.
Aronne, LJ, Sattar, N, Horn, DB, Bays, HE, Wharton, S, Lin, WY, Ahmad, NN, Zhang, S, Liao, R, Bunck, MC, et al
JAMA. 2024;(1):38-48
Abstract
IMPORTANCE The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04660643.
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Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.
Januzzi, JL, Liu, Y, Sattar, N, Yavin, Y, Pollock, CA, Butler, J, Jardine, M, Heerspink, HJL, Masson, S, Breyer, M, et al
American heart journal. 2024;:38-47
Abstract
BACKGROUND Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. METHOD The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. RESULTS At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30). CONCLUSIONS People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. CLINICAL TRIAL CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791.
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Cardiovascular and Kidney Risks in Individuals With Type 2 Diabetes: Contemporary Understanding With Greater Emphasis on Excess Adiposity.
Sattar, N, Presslie, C, Rutter, MK, McGuire, DK
Diabetes care. 2024;(4):531-543
Abstract
In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways-e.g., hemodynamic, cellular overnutrition, and inflammatory-could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium-glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes.
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Incidence and Determinants of Spontaneous Normalization of Subclinical Hypothyroidism in Older Adults.
van der Spoel, E, van Vliet, NA, Poortvliet, RKE, Du Puy, RS, den Elzen, WPJ, Quinn, TJ, Stott, DJ, Sattar, N, Kearney, PM, Blum, MR, et al
The Journal of clinical endocrinology and metabolism. 2024;109(3):e1167-e1174
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With increasing age, circulating levels of thyroid stimulating hormone (TSH) generally rise, accompanied by a higher prevalence of subclinical hypothyroidism. Subclinical hypothyroidism is defined as an elevated TSH level while the serum free T4 (fT4) concentration is within the normal range. The aim of this study was to investigate the incidence of spontaneous normalisation of TSH levels and identify determinants of normalisation in a large group of adults aged 65 years and older with (persistent) subclinical hypothyroidism. This study was a longitudinal study that pooled data from 2 randomised, double-blind, placebo-controlled parallel-group clinical trials. Results showed that 60.8% of the older adults with biochemical subclinical hypothyroidism based on at least 1 elevated TSH measurement, TSH levels had returned to the normal range without intervention after a median follow-up of 1 year. Subsequently, TSH levels had still normalised after 1 year in 39.9% of older adults with persistent subclinical hypothyroidism. Younger age, female sex, lower initial TSH level, higher normal initial fT4 level, the absence of thyroid peroxidase antibodies, and a second measurement in summer were independent determinants for TSH normalisation. Authors concluded that since TSH levels spontaneously normalised in a large proportion of older adults with subclinical hypothyroidism, a third measurement is recommended before considering treatment.
Abstract
CONTEXT With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown. OBJECTIVE To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism. DESIGN Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial). SETTING Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom. PARTICIPANTS The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included. MAIN OUTCOME MEASURES Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization. RESULTS In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization. CONCLUSION Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. TRIAL REGISTRATION ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851.
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Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics.
Nicholls, SJ, Bhatt, DL, Buse, JB, Prato, SD, Kahn, SE, Lincoff, AM, McGuire, DK, Nauck, MA, Nissen, SE, Sattar, N, et al
American heart journal. 2024;:1-11
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BACKGROUND Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial. METHODS Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis). RESULTS Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m2. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing. CONCLUSION SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.
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Growth differentiation factor-15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program.
Ferreira, JP, Packer, M, Butler, J, Filippatos, G, Pocock, SJ, Januzzi, JL, Sattar, N, Maldonado, SG, Panova-Noeva, M, Sumin, M, et al
European journal of heart failure. 2024;(1):155-164
Abstract
AIMS: Growth differentiation factor-15 (GDF-15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin-like growth factor (IGF) and enhance signalling through adenosine monophosphate-activated protein kinase (AMPK). Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF-15 with baseline characteristics, the prognostic significance of GDF-15, and the effect of empagliflozin on GDF-15 in patients with heart failure with a reduced and preserved ejection fraction. METHODS AND RESULTS Growth differentiation factor-15 was determined in serum samples from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF-15, respectively. We studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF-15 levels at baseline of 2442 (interquartile range 1603-3780) pg/ml. Patients with higher GDF-15 levels were typically older men with more severe symptoms, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF-15 were well correlated with levels of IGF-binding protein 7 (rho = 0.64). Higher levels of GDF-15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF-15, the adjusted hazard ratio for cardiovascular death or heart failure hospitalization was 1.40 (95% confidence interval 1.15-1.71; p < 0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF-15 (interaction p-trend = 0.031). At week 52, when compared with placebo, empagliflozin increased GDF-15 by an additional 8% (p = 0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator. CONCLUSIONS Growth differentiation factor-15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF-15 is increased among metformin users, and empagliflozin was associated with an increase in GDF-15 levels, primarily in patients not receiving metformin.
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Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.
Harrington, J, Felker, GM, Januzzi, JL, Lam, CSP, Lingvay, I, Pagidipati, NJ, Sattar, N, Van Spall, HGC, Verma, S, McGuire, DK
Current cardiology reports. 2024;(3):61-71
Abstract
PURPOSE OF REVIEW Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. RECENT FINDINGS High-dose once weekly injectable semaglutide (2.4 mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.
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Appetite and its Regulation: Are there Palatable Interventions for Heart Failure?
Lee, MMY, Lean, MEJ, Sattar, N, Petrie, MC
Current heart failure reports. 2024;(1):1-4
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PURPOSE OF REVIEW Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of appetite regulation and/or dietary energy restriction in individuals with HF. RECENT FINDINGS Weight loss can be achieved by structured supervised diet programs with behavioural change, medications, or surgery. The new glucagon-like peptide-1 receptor agonists alone or in combination with other agents (e.g., glucose-dependent insulinotropic polypeptide and glucagon receptor agonists or amylin analogues) potently and sustainably reduce appetite, and, taken together with dietary advice, can produce substantial, life-changing, weight loss approaching that achieved by surgery. To date, data from the STEP-HFpEF trial show meaningful improvements in health status (Kansas City Cardiomyopathy Questionnaire). Effective weight management could relieve several drivers of HF, to complement the existing treatments for HF with both reduced and preserved ejection fraction. Further trials of weight loss interventions will provide more definitive evidence to understand their effects on clinical events in patients with HF.
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Effectiveness of lifestyle interventions/culturally bespoke programmes in South Asian ethnic groups targeting weight loss for prevention and/or remission of type 2 diabetes: a systematic review and meta-analysis of intervention trials.
Farhat, G, Mellor, DD, Sattar, N, Harvie, M, Issa, B, Rutter, MK
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2024;(2):550-563
Abstract
BACKGROUND People from South Asian heritage are at high risk of type 2 diabetes, but there are limited specific strategies to prevent and manage this condition. The aim was to assess the effectiveness of culturally bespoke lifestyle programmes in South Asians that target weight loss for the prevention or remission of type 2 diabetes mellitus (T2DM). METHODS We performed a systematic review and meta-analysis of intervention trials. PubMed, Scopus, MEDLINE (EBSCOhost), CINAHL, PsycINFO and CENTRAL were searched. Human intervention trials (randomised controlled trials and quasi-experimental) investigating the effect of lifestyle interventions on the prevention and remission of T2DM in South Asians were included. Studies including participants at risk of T2DM (prevention trials) and having the disease (remission trials) with duration ≥12 weeks were eligible. For prevention trials, the primary outcome was change in weight (kg) from baseline; for remission trials, it was decrease in HbA1c to non-diabetic levels (HbA1c ≤ 6.5%) without diabetes medications. Prevention trials were separated into (i) lifestyle modification advice and (ii) lifestyle modification advice including a supervised physical activity programme. RESULTS Twenty-four trials were eligible (21 prevention trials and 3 remission trials). In T2DM prevention trials involving only lifestyle modification advice, the mean postintervention difference in weight between intervention and control groups was -0.65 kg (95% confidence interval [CI]: -1.04, -0.26; p = 0.01). Lifestyle modification advice including a physical activity programme was associated with greater decreases in weight: -1.13 kg (95% CI: -2.04, -0.21; p = 0.02). Fasting blood glucose levels were slightly lower in intervention groups for both intervention subtypes, although there was no significant change in HbA1c levels or 2-h plasma glucose levels. Diabetes remission trials showed potential acceptability but were limited in number and involved a small sample size, and some did not include a control group. CONCLUSIONS In South Asians, lifestyle interventions for prevention of T2DM offer only modest impacts on weight and glucose control and will unlikely reduce diabetes incidence. Alternative lifestyle interventions co-designed with members of the communities and aimed at both prevention and remission of T2DM must be urgently considered. Systematic review registration number: PROSPERO CRD42022385174 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=385174.
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Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.
Bull, CJ, Hazelwood, E, Legge, DN, Corbin, LJ, Richardson, TG, Lee, M, Yarmolinsky, J, Smith-Byrne, K, Hughes, DA, Johansson, M, et al
EBioMedicine. 2024;:104977
Abstract
BACKGROUND Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.