Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20–30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging.

Previous guidelines for the treatment of people with type 2 diabetes mellitus (T2D) have relied heavily upon rigid algorithms for the sequential addition of pharmacotherapies to achieve target glycemic control. More recent guidelines advocate a personalized approach for diabetes treatment, to improve patient satisfaction, quality of life, medication adherence and overall health outcomes. Clinicians should work with patients to develop personalized goals for their treatment, including targeted glycemic control, weight management, prevention and treatment of associated comorbidities and avoidance of complications such as hypoglycemia. Factors that affect the intensity of treatment and choice of pharmacotherapy should include medical and patient influences. Medical considerations include the diabetes phenotype, biomarkers including genetic tests, and the presence of comorbidities such as cardiovascular, renal, or hepatic disease. Patient factors include their treatment preference, age and life expectancy, diabetes duration, hypoglycemia fear and unawareness, psychological and social circumstances. The use of a personalized approach in the management of people with T2D can reduce the cost and failure associated with the algorithmic “one-size-fits-all” approach, to anticipate disease progression, improve the response to diabetes pharmacotherapy and reduce the incidence of diabetes-associated complications. Ultimately, the use of personalized medicine in people with T2D should improve medication adherence, patient satisfaction and quality of life to reduce diabetes distress and improve physical health outcomes.

The development of chronic kidney disease (CKD) in people with diabetes is commonplace, and is frequently associated with a significant and unfavourable impact on patient outcomes along with a substantial economic burden. With the development of novel classes of drug therapies in diabetes, there has been a recent focus on cardiovascular safety measures, with dedicated cardiovascular outcome trials (CVOTs) carried out for all new diabetes medications. More recently, there has been a growing regulatory view that such trials should report more specific renal outcomes to ensure simpler comparability between drugs and drug classes. This article explores some of the possible mechanisms by which these drugs may improve renal function in people with diabetes, and it reviews important CVOTs that have reported renal outcomes to date. These include CVOTS of sodium-glucose cotransporter-2 inhibitors (EMPA-REG OUTCOME study, CANVAS study, CREDENCE trial, DECLARE-TIMI trial and DAPA-HF study), dipeptidyl peptidase-4 inhibitors (EXAMINE trial, SAVOR-TIMI 53, TECOS trial and CARMELINA trial) and glucagon-like peptide-1 analogues (ELIXA trial, LEADER trial, SUSTAIN-6 trial, PIONEER-6 trial, EXSCEL trial, HARMONY Outcomes study and the REWIND study). Ongoing cardiovascular and renal outcome studies such as Dapa-CKD, EMPA-KIDNEY, EMPEROR-Preserved and EMPEROR-Reduced are also discussed. The heterogeneity of patient characteristics and reported renal outcomes, which hinders comparisons between trials and drug classes, is highlighted. Novel classes of diabetes therapies present an important opportunity for nephroprotection beyond the blockade of the renin–angiotensin–aldosterone system in this high-risk group. Clinicians should be aware of such benefits when prescribing these medications for people with, and possibly those without, type 2 diabetes.

Drug therapies for people with heart failure and preserved ejection fraction (HFpEF) are often limited to diuretics to improve symptoms as no therapies demonstrate a mortality benefit in this cohort. People with diabetes have a high risk of developing HFpEF and vice versa, suggesting shared pathophysiological mechanisms exist, which in turn engenders the potential for shared treatments. Dapagliflozin is a sodium–glucose co-transporter 2 (SGLT2) inhibitor which has demonstrated significantly improved cardiovascular and hospitalisation for heart failure (HHF) outcomes in previous cardiovascular outcome trials (CVOTs). These CVOTs include the DECLARE-TIMI and DAPA-HF studies which observed significant benefits for people with heart failure and specifically those with heart failure and reduced ejection fraction (HFrEF), respectively. The ongoing DELIVER study is evaluating the use of dapagliflozin specifically in people with HFpEF, which may have enormous implications for treatment and considerable economic consequences. This will complement previous and other ongoing CVOTs evaluating dapagliflozin use. In this review we discuss the use of SGLT2 inhibitors in HFrEF and HFpEF with a focus on the DELIVER study and its potential health and economic implications.

Clinically important improvements in cardiovascular risk factors and adverse cardiovascular, heart failure and renal outcomes have been observed in numerous cardiovascular outcome trials (CVOTs) investigating the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors over the last 5 years. However, differences in study outcomes between the various SGLT2 inhibitor CVOTs are often challenging to interpret because of differences in the study design, participant characteristics and primary outcomes of the various trials. In clinical practice, this frequently challenges the clinician when choosing between the different SGLT2 inhibitors for a patient with type 2 diabetes and various cardiovascular or renal comorbidities. Discussion around the choice of SGLT2 inhibitor has been again revived by the recent publication of results from the VERTIS-CV, EMPEROR-reduced and DAPA-CKD trials investigating cardiovascular, heart failure and renal outcomes associated with various SGLT2 inhibitors. This narrative review gives an overview of the mechanism of action and differences in the underlying pharmacology of the various SGLT2 inhibitors and discusses the key cardiovascular, heart failure and renal outcomes from completed CVOTs for SGLT2 inhibitors. Discussion highlights important differences in the study design and participant characteristics which limit the comparison of trials and medications within this drug class.

Introduction The glucagon-like peptide-1 receptor analogue (GLP-1RA) semaglutide is associated with improvements in glycaemia and cardiovascular risk factors in clinical trials. The aim of this study was to examine the real-world impact of semaglutide administered by injection in people with type 2 diabetes (T2D) across three secondary care sites in Wales. Methods A retrospective evaluation of 189 patients with T2D initiated on semaglutide between January 2019 and June 2020 with at least one follow-up visit was undertaken. Results At baseline, participants had a mean age of 61.1 years, mean glycated haemoglobin (HbA1c) of 77.8 mmol/mol (9.3%) and mean body weight of 101.8 kg. At 6 and 12 months of follow-up, mean HbA1c reductions of 13.3 mmol/mol (1.2%) and 16.4 mmol/mol (1.5%), respectively, were observed, and mean weight loss at 6 months was 3.0 kg (all p < 0.001). At 12 months, there were significant reductions in total cholesterol (0.5 mmol/L) and alanine transaminase (4.8 IU/L). Patients naïve to GLP-1RAs or with higher baseline HbA1c at baseline had greater glycaemic reductions, although clinically significant HbA1c reductions were also observed in those who switched from other GLP-1RAs, whose body mass index was < 35.0 and > 35.0 kg/m² or who had lower baseline HbA1c. Semaglutide was generally well tolerated, although adverse-effects limited use in 18 patients (9.5%). Conclusion Semaglutide provided clinically and statistically significant reductions in HbA1c, body weight, lipids and liver enzymes.