Underuse of GLP-1 receptor agonists in the management of type 2 diabetes despite a favorable benefit-safety profile.

INTRODUCTION: Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM. AREAS COVERED: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD. EXPERT OPINION: The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.

Patients with type 2 diabetes are at high risk of atherosclerotic cardiovascular disease, especially myocardial infarction and ischemic stroke. Cardiovascular protection should be considered as a key objective when treating those patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), an injectable therapy for the treatment of hyperglycemia, have proven their efficacy in reducing major cardiovascular events (cardiovascular mortality, myocardial infarction, ischemic stroke) both in controlled trials compared to placebo and in real-life studies compared with other glucose-lowering agents. These consistent findings profoundly influence international guidelines which recommend GLP-1RAs as preferred glucose-lowering agents in patients with atherosclerotic cardiovascular disease or at high risk of developing this complication. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA. An even more surprising finding was that GLP-1RAs are less prescribed in patients with established atherosclerotic cardiovascular disease, including antecedents of coronary heart disease and cerebrovascular disease, than in patients without such cardiovascular complications. The reasons for GLP-1RA underuse in clinical practice are multiple and concern physicians, patients, and health-care system. Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and their underuse in daily clinical practice in patients with type 2 diabetes at high risk is crucial from a public health viewpoint.

Cardiovascular protection significantly depends on HbA1c improvement with GLP-1RAs but not with SGLT2 is in type 2 diabetes: A narrative review.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), while developed as antihyperglycaemic medications for the treatment of type 2 diabetes, have proven to reduce major cardiovascular adverse events (MACEs) and hospitalization for heart failure (especially for SGLT2is) in dedicated cardiovascular outcome trials. The contribution of the glucose-lowering effect in the cardiovascular protection is uncertain and may differ between the two drug classes. METHODS: This narrative review compares the relative effects of glycated hemoglobin (HbA1c) reduction on the cardiovascular protection provided by GLP-1RAs and SGLT2is in placebo-controlled cardiovascular outcome trials by using the results of either post-hoc mediation analyses or meta-regression studies. RESULTS: Both mediation and meta-regression analyses suggest that the lower cardiovascular risk with GLP-1RAs partially but substantially tracks with their glucose-lowering effect, especially when considering the reduction in nonfatal strokes. In contrast, similar analyses fail to demonstrate any significant contribution of the glucose-lowering effect with SGLT2is, not only on MACEs but also on heart failure issues. CONCLUSION: The contribution of improved glucose control in cardiovascular protection is limited, but is much greater for GLP-1RAs than for SGLT2is. Of note, such mediation or meta-regression analyses are exploratory and can only be viewed as hypothesis generating.

Bridging the gap in cardiovascular care in diabetic patients: are cardioprotective antihyperglycemic agents underutilized?

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) are two major complications of type 2 diabetes (T2DM). Cardiovascular protection is a key objective, yet not fully reached in clinical practice. AREAS COVERED: Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM and SGLT2is in reducing hospitalization for HF in placebo-controlled randomized trials. However, real-life studies worldwide revealed that only a minority of patients with T2DM receive either a GLP-1RA or an SGLT2i and surprisingly even less patients with established ASCVD or HF are treated with these cardioprotective antihyperglycemic agents. EXPERT OPINION: Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. However, the task appears hazardous and the goal not attained considering the current failure. Education of specialists/primary care physicians and patients is critical. Multifaceted and coordinated interventions involving all actors (physicians, patients and broadly health-care system) must be implemented to stimulate the adoption of these cardioprotective antihyperglycemic medications as part of routine cardiovascular care among patients with T2DM.

Type 2 diabetes can lead to major cardiovascular complications including cardiovascular disease linked to narrowing of the arteries (atherosclerosis), and heart failure. These complications are associated with lower quality of life and life expectancy. Thus, cardiovascular protection in people with type 2 diabetes is an important objective. However, clinical practice often fails in fully achieving this goal.Two types of medications that lower blood sugar (so-called antidiabetic agents) have shown efficacy in reducing major cardiovascular events (such as strokes and heart attacks) in high-risk patients with type 2 diabetes. One of them has also shown effectiveness in decreasing hospitalizations due to heart failure. However, in clinical practice, most patients with type 2 diabetes do not receive these medications, even people with known cardiovascular disease or heart failure, despite the proven effectiveness of these drugs. Many studies worldwide have highlighted socioeconomic inequities regarding the use of these medications, which can be expensive.From a public health perspective, it is imperative to bridge the gap between the under-use of cardioprotective antidiabetic agents in routine daily practice among high-risk patients with type 2 diabetes and the clear-cut recommendations of international guidelines. Given the current limitations, this task appears challenging. Education of physicians (both primary care practitioners and specialists, including cardiologists) and patients is most important in addressing this issue. Finally, in every country, the global health-care system should facilitate the use of these agents among patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease and heart failure.

Do SGLT2 inhibitors and GLP-1 receptor agonists modulate differently the risk of stroke ? Discordance between randomised controlled trials and observational studies.

Stroke represents a major burden in patients with type 2 diabetes, yet this cerebrovascular complication has been less carefully investigated than the risk of cardiovascular mortality, heart failure and renal disease. Some data suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert a better protection against stroke than sodium-glucose cotransporter 2 inhibitors (SGLT2is). However, this conclusion was derived from indirect comparisons in absence of any head-to-head randomised controlled trial (RCT). The present comprehensive review compares the effects of SGLT2is versus GLP-1RAs on nonfatal and fatal/nonfatal strokes in network meta-analyses of RCTs (mostly cardiovascular outcome trials) versus placebo, on the one hand, and in real-life observational cohort studies, on the other hand. Whereas network meta-analyses of placebo-controlled RCTs confirm a slight but significant (in 11 out of 13 meta-analyses) higher incidence of stroke in patients treated with SGLT2is compared with those treated with GLP-1RAs, a large majority of retrospective observational cohort studies (19 out of 21) failed to find any significant difference in the risk of stroke between the two pharmacological classes. Available, yet limited, findings suggest that SGLT2is may be more efficacious against haemorrhagic than ischaemic strokes, in patients at risk for atrial fibrillation and in patients with chronic kidney disease.

[Use of antidiabetic medications in the course of bariatric/metabolic surgery]. / Gestion des médicaments antidiabétiques dans le décours d'une chirurgie bariatrique/métabolique.

The management of type 2 diabetes (T2D) after a gastric bypass or a sleeve gastrectomy requires some cautions depending on the timing after the surgical procedure and the patient evolution. Even before the intervention, gliflozins should be interrupted to avoid euglycemic diabetic ketoacidosis while sulphonylureas should be stopped and insulin doses should be reduced (with caution) to limit the risk of hypoglycemia. If a remission of T2D occurs, the maintenance of metformin or of a glucagon-like peptide-1 receptor agonist should be considered with the main objective to prolong the remission. Finally, if T2D remains or if a relapse occurs, the management of hyperglycemia should a priori follow the same rules as those used for patients with T2D who are not treated with bariatric/metabolic surgery.

Gérer le diabète de type 2 (DT2) dans les suites d'une dérivation gastrique (bypass) ou d'une gastrectomie en manchon (sleeve) demande une attention particulière en fonction du moment considéré et de l'évolution du patient. Dès avant l'intervention, il faut arrêter les gliflozines pour éviter une acidose diabétique euglycémique, stopper les sulfamides et réduire (prudemment) les doses d'insuline pour limiter le risque d'hypoglycémie. Si une rémission du DT2 s'installe, le maintien de la metformine ou d'un analogue du glucagon-like peptide-1 doit être discuté pour prolonger cette phase de rémission. Enfin, si le DT2 persiste après la chirurgie ou en cas de rechute, l'hyperglycémie devra être traitée avec, a priori, les mêmes règles que celles dévolues aux patients avec DT2 qui n'ont pas subi de chirurgie bariatrique/métabolique.

[Effects of antidiabetic medications on metabolic-associated fatty liver disease]. / Effets des médicaments antidiabétiques sur la stéatopathie métabolique (MAFLD).

Metabolic-Associated Fatty Liver Disease (MAFLD) is a prevalent metabolic complication among patients with obesity and type 2 diabetes, associated with bad prognosis. Classical antidiabetics have little effects on this complication, except pioglitazone that exerts a positive impact but with uncertain safety. Gliptins are almost neutral, whereas glucagon-like peptide-1 receptor agonists showed benefits, the most potent ones being those associated with a greater weight loss such as liraglutide or semaglutide. Gliflozins also reduce hepatic fat content and liver enzymes used as biomarkers of steatosis. However, histological data remain scarce, especially those focusing on inflammation and fibrosis, and direct comparative data between available therapies are still lacking.

La stéatopathie ou MAFLD pour « Metabolic-Associated Fatty Liver Disease ¼ est une complication métabolique fréquente de l'obésité et du diabète de type 2, grevée d'un mauvais pronostic. Les antidiabétiques classiques n'ont que peu d'effets sur cette complication, hormis la pioglitazone qui exerce un impact positif. Les gliptines sont peu efficaces, à l'inverse des agonistes des récepteurs du glucagon-like peptide-1, les plus efficaces étant ceux associés à la plus forte perte de poids comme le liraglutide et le sémaglutide. Les gliflozines réduisent également le contenu graisseux hépatique et les biomarqueurs de la stéatose. Cependant, les données histologiques restent limitées, notamment concernant l'inflammation et la fibrose, et il manque de données comparatives directes entre les divers traitements existants.

Pharmacokinetic, toxicological, and clinical considerations for the treatment of type 2 diabetes in patients with liver disease: a comprehensive update.

INTRODUCTION: Type 2 diabetes and liver disease, mainly metabolic-associated fatty liver disease (MAFLD) and more rarely cirrhosis, coexist in many patients. This duality has direct implications for the physician when choosing glucose-lowering agents, with classical concerns but also recent new hopes. AREAS COVERED: This updated comprehensive review will consider the pharmacokinetics, the tolerance/safety profile, the benefit/risk balance in cirrhosis, the effects on MAFLD and the risk of hepatocellular carcinoma of old and new glucose-lowering compounds in patients with liver disease, with a special focus on glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. EXPERT OPINION: We are currently facing a new paradigm in the management of patients with diabetes and liver disease. From previous reluctance when using antidiabetic agents (except insulin) in diabetic patients with hepatic impairment because of safety concerns, the commercialization of novel glucose-lowering agents has changed the scene. These agents, which have a good safety profile, are associated with weight loss and pleiotropic effects. They have proven their efficacy in improving MAFLD. However, more specific studies are still needed to prove their efficacy in preventing the progression to fibrosis/cirrhosis and confirm this new opportunity for the management of patients with diabetes and liver disease.

The current role of SGLT2 inhibitors in type 2 diabetes and beyond: a narrative review.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2is, gliflozins), the most recent oral antihyperglycaemic agents, provide a cardiorenal protection, an effect independent of their glucose-lowering potency. AREAS COVERED: The antihyperglycaemic potency of SGLT2is was compared with that of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, especially when added to metformin monotherapy. Main results of cardiovascular/renal outcome trials with SGLT2is were summarized in different populations: patients with type 2 diabetes mellitus (T2DM) with or without established cardiovascular disease, patients (with or without T2DM) with heart failure (with reduced or preserved left ventricular ejection fraction) and in patients (with or without T2DM) with chronic kidney disease (CKD, including stage 4). Original papers and meta-analyses of these different trials have consistently reported a reduction in hospitalization for heart failure (alone or combined with cardiovascular mortality) and a reduced progression of CKD, with an overall good safety profile. EXPERT OPINION: Global use of SGLT2is has increased over time but remains suboptimal despite clinically relevant cardiovascular and renal protection, particularly in patients most likely to benefit. SGLT2is has proven both positive benefit-risk balance and cost-effectiveness in at risk patients. New prospects are expected in other complications, i.e. metabolic-associated fatty liver disease and neurodegenerative disorders.

Use of SGLT2 inhibitors after bariatric/metabolic surgery: Risk/benefit balance.

Bariatric/metabolic surgery and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are becoming increasingly popular for the management of overweight/obese patients with type 2 diabetes mellitus (T2DM). Consequently, the chance that a patient undergoing bariatric/metabolic surgery is also treated with an SGLT2i would be rather common in clinical practice. Both risks and benefits have been reported. On the one hand, several cases of euglycemic diabetic ketoacidosis have been reported within the few days/weeks after bariatric/metabolic surgery. The causes are diverse but a drastic reduction in caloric (carbohydrate) intake most probably plays a crucial role. Thus, SGLT2is should be stopped a few days (and even more if a pre-operative restricted diet is prescribed to reduce liver volume) before the intervention and reintroduced only when the caloric (carbohydrate) intake is sufficient. On the other hand, SGLT2is may exert a favorable effect to reduce the risk of postprandial hypoglycemia, a complication reported among patients who have been treated with bariatric/metabolic surgery. An increased hepatic glucose production and a reduced production of interleukin-1ß have been proposed as possible underlying mechanisms for this protective effect. Finally, whether SGLT2is could prolong diabetes remission following surgery and improve the prognosis of patients with T2DM who benefit from bariatric/metabolic surgery remains to be investigated.

Metabolic disorders induced by psychotropic drugs.

Psychotropic drugs may be associated with metabolic disorders, often but not only triggered by weight gain. Disorders include dysglycemia and diabetes, atherogenic dyslipidemia and metabolic syndrome. Overall, metabolic risk is lower with antidepressants than with antipsychotics. Among antidepressants, metabolic disorders may occur with both selective serotonin reuptake inhibitors and tricyclics, but with some between-molecule differences in each pharmacological family. Among antipsychotics, the risk is higher with second-generation (atypical) than first-generation agents. Higher risk was reported with clozapine and olanzapine, and lower risk with risperidone and aripiprazole. Weight gain is associated with increased insulin resistance, but impaired insulin secretion was also reported with clozapine and olanzapine. Metabolic disorders may be attenuated by the medication withdrawal and replacement by another safer drug. Besides deleterious effects of medications, the psychiatric population is also exposed to bad lifestyle habits (unhealthy diet and sedentary life), which also increase the risk of metabolic disorders. Management should first reinforce lifestyle measures. If this proves insufficient, specific drugs may be considered to tackle the metabolic disorder on a strategy similar to that applied in the general population.

Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists currently occupy a privileged place in the management of type-2 diabetes (T2D). Dual glucose-dependent insulinotropic polypeptides (GIP/GLP-1) have been recently developed. Tirzepatide is the most advanced unimolecular dual GIP/GLP-1 receptor agonist to be used as once weekly subcutaneous injection in T2D and recently received approval by the European Medicines Agency. Because of the complementarity of action of the two incretins, tirzepatide showed better dose-dependent (5, 10 and 15mg) efficacy (greater reduction in HbA1c and body weight) than placebo, basal insulin or two GLP-1 analogues (dulaglutide and semaglutide) in the SURPASS program. Its cardiovascular protective effect is currently being assessed versus dulaglutide in the SURPASS-CVOT study. Finally, studies for the treatment of obesity (SURMOUNT program) and metabolic-associated fatty liver disease (MAFLD) are also ongoing. Gastrointestinal tolerance of tirzepatide appears comparable to that of GLP-1 analogues, except for higher incidence of diarrhea. Other original molecules have been built, including triple GIP/GLP-1/glucagon receptor agonists. The risk/benefit ratio will decide whether dual (or triple) receptor agonists should replace pure GLP-1 receptor agonists for the management of T2D in the near future, with a significant role in the pharmacotherapy of obesity.

Efficacy and safety profile of SGLT2 inhibitors in the elderly: How is the benefit/risk balance?

Type 2 diabetes mellitus (T2DM) is a highly prevalent health condition in the aging population. Older adults with T2DM have higher risks of cardiovascular disease, heart failure (long underestimated) and premature death than those without diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their ability to improve cardiovascular prognosis and reduce the risk of hospitalization for heart failure (hHF). However, several adverse events have been reported, whose incidence and severity might be increased in the elderly population. The aims of this comprehensive review were to analyze the benefit-risk ratio of SGLT2i therapy in older patients with T2DM by collecting data from (i) large prospective placebo-controlled cardiovascular outcome trials (including those dedicated to heart failure), using both original publications and dedicated post-hoc analyses across different age groups and (ii) observational cohort studies, describing the effects of SGLT2is versus other glucose-lowering agents on cardiovascular outcomes and hHF in elderly patients or these effects in different age groups. Overall, consistent results showed a similar relative risk reduction in cardiovascular mortality and hHF with SGLT2is independently of age. The absolute risk reduction may be greater in elderly because of a higher background risk in older versus younger patients. Similarly, the safety profile of SGLT2is appeared comparable in older versus younger patients. In conclusion, the benefit/risk balance favors the use of SGLT2is in older patients at risk of cardiovascular disease and/or heart failure. Caution may be required in very old frail patients, especially those exposed to an increased risk of volume depletion.

Clinical pharmacology of antidiabetic drugs: What can be expected of their use?

The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.

Glucagon, from past to present: a century of intensive research and controversies.

2022 corresponds to the 100th anniversary of the discovery of glucagon. This TimeCapsule aims to recall the main steps leading to the discovery, characterisation, and clinical importance of the so-called second pancreatic hormone. We describe the early historical findings in basic research (ie, discovery, purification, structure, α-cell origin, radioimmunoassay, glucagon gene [GCG], and glucagon receptor [GLR]), in which three future Nobel Prize laureates were actively involved. Considered as an anti-insulin hormone, glucagon was rapidly used to treat insulin-induced hypoglycaemic coma episodes in people with type 1 diabetes. A key step in the story of glucagon was the discovery of its role and the role of α cells in the physiology and pathophysiology (ie, paracrinopathy) of type 2 diabetes. This concept led to the design of different strategies targeting glucagon, among which GLP-1 receptor (GLP1R) agonists were a major breakthrough, and combination of inhibition of glucagon secretion with stimulation of insulin secretion (both in a glucose-dependent manner). Taking advantage of the glucagon-induced increase in energy metabolism, biased coagonists were developed. Besides the GLP-1 receptor, these coagonists also target the glucagon receptor to further promote weight loss. Thus, the 100-year story of glucagon has most probably not come to an end.

Glucose-lowering agents and risk of ventricular arrhythmias and sudden cardiac death: A comprehensive review ranging from sulphonylureas to SGLT2 inhibitors.

Type 2 diabetes is associated with a higher risk of cardiac arrhythmias, especially in presence of cardiovascular disease and/or heart failure. Even if atrial fibrillation/flutter episodes are the most frequent and well-studied, ventricular arrhythmias (VA: tachycardia/fibrillation) are more severe and can lead to sudden cardiac arrest/death (SCA/SCD). The effects of glucose-lowering agents on the risk of VA/SCD remain poorly understood. Findings may be derived from experimental animal studies, randomised controlled trials/cardiovascular outcome trials and observational retrospective studies. A higher risk was attributed to hypoglycaemia when induced by insulin or even more critically by sulphonylureas. Insulin-secreting agents seem to be associated with a higher risk of cardiac arrhythmias compared with insulin sensitizers (metformin, thiazolidinediones), yet the risk linked to sulphonylureas remains controverted. Incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) overall appear to be neutral regarding the risk of cardiac arrhythmias, despite some heterogeneous results. SGLT2 inhibitors appear to reduce the risk of SCA/SCD and possibly VA, yet only a non-significant trend was noticed in most reports. Overall, hazard ratios with SGLT2 inhibitors versus other therapies were lower for SCD (presumably of diverse causes) than for well demonstrated VA episodes. Underlying mechanisms remain uncertain and numerous pleiotropic effects may be involved. Prospective controlled trials and experimental studies specifically devoted to the effects of SGLT2 inhibitors on cardiac arrhythmias are needed to confirm their positive effects in diabetic patients and in individuals with heart failure irrespective of diabetes and, if possible, to carefully dissect the underlying protective mechanisms.

Antidiabetic agents and risk of atrial fibrillation/flutter: A comparative critical analysis with a focus on differences between SGLT2 inhibitors and GLP-1 receptor agonists.

Atrial fibrillation/flutter (AF/AFL) is a common cardiac arrhythmia in patients with diabetes and is associated with an increased risk of morbidity, including ischaemic stroke and heart failure, and mortality. Different classes of glucose-lowering agents have shown distinct effects on the risk of stroke and heart failure. Their effects on cardiac arrhythmias such as AF/AFL have not been carefully investigated yet and even less their possible relationship with classical complications such as stroke and heart failure. The present comprehensive review aims at analysing the effects of each pharmacological class on the risk of new-onset AF/AFL episodes in patients with type 2 diabetes mellitus (T2DM) and in patients with heart failure (with or without diabetes). Relevant findings were collected both in post-hoc analyses of placebo-controlled trials and in real-life retrospective observational studies, which both led to the publication of several meta-analyses. Of note, no randomised controlled trials evaluated the effects on AF/AFL as a pre-specified endpoint and none included head-to-head active drug comparisons, so that caution is required in the conclusion. Overall, sodium-glucose cotransporter 2 inhibitors, besides their remarkable effects on heart failure issues, were associated with the most pronounced and consistent reduction in incident AF/AFL, an effect surprisingly not accompanied by a significant reduction in stroke. In contrast, glucagon-like peptide-1 receptor agonists, which have proven their ability to reduce stroke, apparently failed to demonstrate a significant reduction in new-onset AF/AFL in most reports. A better understanding of both reasons for these discrepancies and underlying mechanisms supporting the drug antiarrhythmic effect requires further careful dedicated studies.