Clifford J. Bailey

Despite the availability of at least nine differently acting classes of glucose-lowering agents, many people with type 2 diabetes do not achieve or maintain sufficiently tight glycaemic control to avoid the complications of chronic hyperglycaemia. This narrative review examines the prospects for future non-insulin agents and therapeutic approaches in early development that aim to improve glycaemic control in type 2 diabetes. Such therapies will ideally enhance glucose lowering through existing mechanisms or by targeting different aspects of disease pathophysiology. They will avoid overt hypoglycaemia and facilitate weight control and be convenient to use, have minimal adverse effects, provide benefits against common comorbidities and have a commendable overall safety profile. Particularly promising therapies in development are the co-agonist and multi-agonist incretin-based and amylin-based synthetic peptides that improve glycaemic control and body weight regulation. Initial studies suggest that such therapies can improve insulin secretion, assist pancreatic beta cell preservation and enhance insulin-mediated glucose metabolism while reducing glucagon secretion and risk of fatty liver disease. Antibodies and small molecules that interact with incretin targets are also being developed, as well as agents to modulate mitochondrial function, fatty acid receptors and receptors for selected gastrointestinal and adipocyte peptides that affect appetite or pathways of nutrient metabolism. Multiomics, miRNAs, gene-editing technologies and epigenetic targets have received considerable attention but have yet to deliver usable therapies. Directing therapeutic agents to specific organs or tissues and avoiding unwanted off-target effects continue to challenge the application of laboratory innovations into viable clinical agents. However, recent successes with weight-lowering incretin-based medicines have raised expectations for pharmaceutical pipelines to transform the management of type 2 diabetes. Graphical Abstract

Metformin (dimethyl‐biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose‐lowering agent in 1957, this medicine has emerged as a first‐line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long‐term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost‐effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended‐release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D.

Introduction Recent updates to guidelines for the management of type 2 diabetes (T2DM) have emphasised the importance of addressing cardiorenal risk and weight control, in conjunction with blood glucose regulation.1–4 All guidelines remain committed to lifestyle interventions (diet, physical activity and behaviou ...

Randomized controlled trials, which are considered the highest level of scientific evidence, have shown significant glycemic benefits associated with use of continuous glucose monitoring (CGM) in individuals with diabetes who are treated with intensive insulin regimens. However, numerous prospective, retrospective, and observational studies have investigated the impact of CGM in various diabetes populations treated with nonintensive therapies. Results from these studies have contributed to changes in payer coverage, prescriber behaviors, and expanding use of CGM. This article reviews findings from recent real-world studies, highlights the key lessons learned from these studies, and discusses how we need to move forward in increasing utilization of and access to CGM among all diabetes patients who would benefit from this technology.

Tirzepatide is a novel glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide 1 (GLP‐1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non‐cirrhotic non‐alcoholic steatohepatitis. The Phase 3 SURPASS 1‐5 clinical trial programme was designed to assess efficacy and safety of once‐weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (−1.87 to −2.59%, −20 to −28 mmol/mol) and body weight (−6.2 to −12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS‐2, these reductions were greater than with the GLP‐1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP‐1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

Objectives: Pre-existing or new diabetes confers an adverse prognosis in people with Covid-19. We reviewed the clinical literature on clinical outcomes in metformin-treated subjects presenting with Covid-19.Methods: Structured PubMed search: metformin AND [covid (ti) OR covid-19 (ti) OR covid19 (ti) OR coronavirus (ti) OR SARS-Cov2 (ti)], supplemented with another PubMed search: “diabetes AND [covid OR covid-19 OR covid19 OR coronavirus (i) OR SARS-Cov2 (ti)]” (limited to “Clinical Study”, “Clinical Trial”, “Controlled Clinical Trial”, “Meta-Analysis”, “Observational Study”, “Randomized Controlled Trial”, “Systematic Review”).Results: The effects of metformin on the clinical course of Covid-19 were evaluated in retrospective analyses: most noted improved clinical outcomes amongst type 2 diabetes patients treated with metformin at the time of hospitalisation with Covid-19 infection. These outcomes include reduced admission into intensive care and reduced mortality in subgroups with versus without metformin treatment.Conclusion: The pleiotropic actions of metformin associated with lower background cardiovascular risk may mediate some of these effects, for example reductions of insulin resistance, systemic inflammation and hypercoagulability. Modulation by metformin of the cell-surface ACE2 protein (a key binding target for SARS-CoV 2 spike protein) via the AMP kinase pathway may be involved. While pre-existing metformin treatment offers potentially beneficial effects and can be continued when Covid-19 infection is not severe, reports of increased acidosis and lactic acidosis in patients with more severe Covid-19 disease remind that metformin should be withdrawn in patients with hypoxaemia or acute renal disease. Prospective study of the clinical and metabolic effects of metformin in Covid-19 is warranted.