Helena W. Rodbard

Aims: Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once‐weekly semaglutide 2.0 mg as add‐on to dose‐reduced insulin glargine (Sema+IGlar _reduced ) versus dose‐titrated IGlar (IGlar _titrated ) on glycated haemoglobin (HbA _1c ), body weight (BW), daily insulin dose, and participant satisfaction. Materials and Methods: SUSTAIN OPTIMIZE was a 40‐week, phase 3b, open‐label, randomised study. Adults with T2D, overweight (body mass index ≥ 25 kg/m ² ), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlar _reduced or IGlar _titrated . The primary endpoint was change in HbA _1c using a non‐inferiority approach. Secondary endpoints assessed superiority of Sema+IGlar _reduced versus IGlar _titrated in reducing HbA _1c , BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores. Results: Overall, 573 participants were randomised. Sema+IGlar _reduced achieved both non‐inferiority and superiority versus IGlar _titrated in HbA _1c reduction (estimated treatment difference [ETD]: −0.74%; 95% confidence interval [CI ₉₅ ]: −0.90, −0.59) and superiority in BW change (ETD: −8.5 kg; CI ₉₅ : −9.5, −7.4), relative daily insulin dose change (ETD: −121.9%; CI ₉₅ : −143.1, −100.6), and DTSQc scores (ETD: 2.6; CI ₉₅ : 1.6, 3.5) ( p < 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI ₉₅ : 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlar _reduced (310 vs. 32 events). Conclusions: Once‐weekly subcutaneous semaglutide 2.0 mg as add‐on to dose‐reduced IGlar achieved superior reductions in HbA _1c , BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose‐titrated IGlar alone.

The rising phenomenon of obesity, a major risk factor for the development and progression of type 2 diabetes, is a complex and multifaceted issue that requires a comprehensive and coordinated approach to be prevented and managed. Although novel pharmacological measures to combat obesity have achieved unprecedented efficacy, a healthy lifestyle remains essential for the long‐term success of any therapeutic intervention. However, this requires a high level of intrinsic motivation and continued behavioural changes in the face of multiple metabolic, psychological and environmental factors promoting weight gain, particularly in the context of type 2 diabetes. This review is intended to provide practical recommendations in the context of a holistic, person‐centred approach to weight management, including evidence‐based and expert recommendations addressing supportive communication, shared decision‐making, as well as nutritional and pharmacological therapeutic approaches to achieve sustained weight loss.

Aims: To evaluate gastrointestinal adverse events (AEs) and the impact of nausea, vomiting or diarrhoea (N/V/D) and any gastrointestinal (GI) AEs overall on weight change with tirzepatide across the SURPASS‐1 to ‐5 clinical trials. Materials and Methods: Participants with type 2 diabetes were randomized to receive once‐weekly tirzepatide (5, 10 or 15 mg) or comparator (placebo, semaglutide 1 mg once weekly, or titrated daily basal insulins) as monotherapy or added on to background antihyperglycaemic medication(s). This post hoc analysis subdivided participants within each trial into subgroups that self‐reported (yes/no) any N/V/D or GI AEs. Change from baseline in body weight at the primary timepoint was assessed within each trial and subgroup. Mediation analyses were conducted to evaluate the contribution of direct and indirect (mediated by N/V/D or GI AEs) effects of tirzepatide on weight change versus comparators. Results: Across the SURPASS‐1 to ‐5 trials (N = 6263), nausea (12%‐24%), diarrhoea (12%‐22%), and vomiting (2%‐13%) were the most common GI AEs reported with tirzepatide; these were transient and of mild‐to‐moderate severity. Mean weight reduction at the primary timepoint with tirzepatide was consistent between participants who reported N/V/D (−6.2 to −14.9 kg) and those who did not report N/V/D (−6.2 to −13.3 kg). Mean weight reduction was significantly ( P < 0.01) greater with tirzepatide compared with placebo, semaglutide 1 mg, and basal insulins within the N/V/D and GI AEs subgroups. Mediation analyses suggested minimal contribution (<6%) of N/V/D and GI AEs to the overall difference in weight change between tirzepatide and comparators. Conclusions: Superior weight reduction with tirzepatide versus comparators appears to be independent of reported N/V/D or GI AEs.

Aim: To compare the proportion of participants with type 2 diabetes (T2D) treated with once‐weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. Materials and Methods: SUSTAIN 1‐5, 7‐10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient‐level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). Conclusions: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Introduction Diabetes is associated with significant economic burden. Moreover, cardiovascular disease (CVD), including heart failure, and chronic kidney disease (CKD) are common comorbidities, leading to premature mortality. We conducted a systematic review to assess the humanistic and economic burden of cardio-renal-metabolic (CRM) conditions in individuals ≥ 18 years with CVD, CKD, and type 2 diabetes mellitus. Methods We searched Embase^® and Medline^® databases from 2011 to January 10, 2022 for English publications reporting humanistic and economic burden outcomes from observational studies, real-world evidence, and economic model studies. Intervention and validation studies were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Abstracts/posters were identified from four conferences (2020–2022). Results Of 1804 studies identified, 22 (including four conference publications) were selected involving 351,296,930 participants (one modeled the US population); eight reported healthcare resource utilization (HCRU), seven only cost data, six HCRU and cost data, one reported quality-of-life data (11/18 and 7/18 had estimated low and medium risk of bias, respectively). Participants were predominantly ≥ 65 years and identified as having White ethnicity. Higher costs and HCRU were observed in patients with all three conditions compared to those with two or none. Urban/metropolitan and insured patients had higher healthcare expenditure and service utilization compared to uninsured and racial/ethnic minority populations. Comorbidities were associated with increased hospitalizations, higher costs, and more emergency department visits. In general, patients identified as having Black ethnicity had low odds of using healthcare services, possibly due to disparities in healthcare access and distrust in the system. Limitations included no adjustment for inflation and a predominance of retrospective studies. Conclusions This review showed a greater economic burden for patients with CRM conditions, with a clear trend between increasing numbers of comorbidities and increasing healthcare costs/resource use. Comparisons between countries are complicated and the scarcity of evidence from minority racial and ethnic groups and lack of data from non-US geographies warrant further investigation.

The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.Trial registrationThe 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10–11, 2022 (http://www.cvot.org)

Introduction: As the vast majority of people with type 2 diabetes (T2D) are also overweight or obese, healthcare professionals (HCP) are faced with the task of addressing both weight management and glucose control. In this narrative review, we aim to identify the challenges of reaching and maintaining body weight targets in people with T2D and highlight current and future treatment interventions.Methods: A search of the PubMed database was conducted using the search terms “diabetes” and “weight loss.”Results: According to emerging evidence, treating obesity may be antecedent to the development and progression of T2D. While clinical benefits typically set in upon achieving a weight loss of 3–5%, these benefits are progressive leading to further health improvements, and weight loss of >15% can have a disease‐modifying effect in people with T2D, an outcome that up to recently could not be achieved with any blood glucose‐lowering pharmacotherapy. However, advanced treatment options with weight‐loss effects currently in development including the dual GIP/GLP‐1 receptor agonists may enable simultaneous achievement of individual glycemic and weight goals.Conclusion: Despite considerable therapeutic progress, there is still a large unmet medical need in patients with T2D who miss their individualized glycemic and weight‐loss targets. Nonetheless, it is to be expected that development of future therapies and their use will favourably change the scenario of weight and glucose control in T2D.