SGLT2 Research Articles

Cardiovascular effectiveness of newer glucose-lowering agents, with and without baseline lipid-lowering therapy in type 2 diabetes: A systematic meta-analysis of cardiovascular outcome trials and real-world evidence

BackgroundWhether the cardiovascular treatment benefits of sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) differ by baseline use of statins/lipid lowering therapy is unclear. This systematic review and meta-analysis investigated whether baseline statin use (users vs non-users) influences the cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs in patients with type 2 diabetes (T2D). MethodsWe identified relevant cardiovascular outcome trials (CVOTs) and observational cohort studies from MEDLINE, Embase, the Cochrane Library, and bibliographic searches up to March 2024. The analysis pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for outcomes, categorized by baseline statin use status. We also assessed the interactions between these medications and baseline statin use by calculating and pooling the ratio of HRs (RHRs) within each trial. ResultsTwenty-five articles (13 articles comprising 6 unique CVOTs and 12 articles comprising 9 unique cohort studies) were eligible. In CVOTs of SGLT-2is, the HRs (95% CIs) of MACE; composite of CVD death or hospitalisation for heart failure; stroke; and kidney events in statin users were 0.90 (0.82-1.00), 0.78 (0.60-1.02), 1.00 (0.77-1.31), and 0.60 (0.53-0.69), respectively. The corresponding estimates were similar in non-statin users. In CVOTs of GLP-1RAs, the HRs (95% CIs) for MACE in statin and non-statin users were 0.81 (0.73-0.90) and 0.92 (0.77-1.11), respectively. In observational cohort studies, SGLT-2is similarly reduced the risk of several cardiovascular and kidney outcomes in both statin and non-statin users. The estimated RHRs and p-values for interaction indicated that baseline statin use status did not significantly modify the cardio-kidney benefits of SGLT-2is and GLP-1RAs. ConclusionsAggregate analyses of intervention and real-world evidence show that SGLT-2is and GLP-1RAs provide comparable cardio-kidney benefits in patients with T2D, regardless of baseline statin use status.PROSPERO Registration: CRD42024498939

S1689 Use of Sodium-Glucose Transport Protein 2 Inhibitors and Dipeptidyl Peptidase 4 Inhibitors in Patients with MASLD in a Real-World Setting is Associated with Lower All-Cause Mortality

S1689 Use of Sodium-Glucose Transport Protein 2 Inhibitors and Dipeptidyl Peptidase 4 Inhibitors in Patients with MASLD in a Real-World Setting is Associated with Lower All-Cause Mortality

Sodium-glucose Cotransporter-2 Inhibition And Exercise Affect Pathways Related To Nonalcoholic Fatty Liver Disease

Sodium-glucose Cotransporter-2 Inhibition And Exercise Affect Pathways Related To Nonalcoholic Fatty Liver Disease

Protocolo terapéutico de la diabetes mellitus tipo 2 con obesidad y riesgo cardiovascular

The management of type 2 diabetes mellitus (DM2) with obesity and cardiovascular risk is a growing challenge due to the high prevalence of both conditions. This protocol describes therapeutic recommendations based on glycemic control and the cardiovascular benefits of certain drugs. Two classes of drugs with weight and cardiometabolic efficacy stand out: glucagon-like peptide-1 agonists (GLP-1a) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). This document suggests the joint use of both to reduce cardiovascular risk and promote weight loss. It also describes the role of metabolic surgery as an effective option for the management of DM2 and obesity, as it significantly improves glycemic outcomes and reduces cardiovascular risk. Continuous follow-up is recommended to adjust treatment according to the patient's clinical response and to avoid therapeutic inertia.

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

Euglycemic Ketoacidosis Associated with SGLT-2 Inhibitors in Non-diabetic Patients-A Narrative Review.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Efficacy and safety of henagliflozin combined with continuous subcutaneous insulin infusion in the treatment of Chinese inpatients with type 2 diabetes mellitus based on a continuous glucose monitoring system: protocol of a multicentre, open-label, inpatient, randomised, controlled trial

IntroductionThe role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in diabetes treatment is expanding; however, few studies have investigated the efficacy and safety of combining SGLT2is with insulin pump therapy. Notably,...

Perirenal fat and chronic kidney disease in type 2 diabetes: The mediation role of afferent arteriolar resistance

AimPerirenal fat (PRF) is an independent predictor for chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients. Previous studies speculated that PRF may promote renal dysfunction through affecting renal hemodynamics. To verify this hypothesis, we studied the relationship between PRF and renal hemodynamics in T2DM. Methods91 T2DM patients were included. PRF thickness (PRFT) was measured by magnetic resonance imaging. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by renal dynamic imaging. Renal vascular resistance (RVR), glomerular hydrostatic pressure (PGLO), afferent (RA) and efferent (RE) arteriolar resistance were calculated by Gomez equations. Multiple linear regression was used to determine the relationship between PRFT and renal hemodynamics. Mediation analysis was conducted to estimate the mediation effects of renal hemodynamics on the relationship between PRF and CKD. ResultsAll patients were divided into three groups according to the tertiles of PRFT. Compared with patients in tertile 1, GFR and ERPF were significantly decreased in patients in tertile 3, while RVR and RA were significantly increased. PRFT was negatively correlated with GFR, ERPF and PGLO, and positively correlated with RVR and RA after adjustment for sex, age, visceral adipose tissue and treatments with ACE inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter protein-2 inhibitors. Moreover, RVR and RA mediated the effect of PRF on GFR, with a mediated proportion of 29.1 % and 41.4 % respectively. ConclusionIn T2DM patients, PRF was negatively correlated with GFR, and positively correlated with RA. RA mediated the relationship between PRF and CKD.

TCT-819 Impact of Sodium-Glucose Co-Transporter Inhibitors on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction: A Systematic Review and Meta-Analysis

TCT-819 Impact of Sodium-Glucose Co-Transporter Inhibitors on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction: A Systematic Review and Meta-Analysis

Benefit and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors in Older Patients with Type 2 Diabetes Mellitus.

People with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular disease, heart failure, chronic kidney disease, and premature death than people without diabetes. Therefore, treatment of diabetes aims to reduce these complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown beneficial effects on cardiorenal and metabolic health beyond glucose control, making them a promising class of drugs for achieving the ultimate goals of diabetes treatment. However, despite their proven benefits, the use of SGLT2 inhibitors in eligible patients with T2DM remains suboptimal due to reports of adverse events. The use of SGLT2 inhibitors is particularly limited in older patients with T2DM because of the lack of treatment experience and insufficient long-term safety data. This article comprehensively reviews the risk-benefit profile of SGLT2 inhibitors in older patients with T2DM, drawing on data from prospective randomized controlled trials of cardiorenal outcomes, original studies, subgroup analyses across different age groups, and observational cohort studies.

Management Strategies for Children and Adolescents with Diabetes Mellitus

The principles of treatment for diabetes in children and adolescents cannot simply be derived from care routinely provided to adults with diabetes. The major consideration is that the epidemiology, pathophysiology, developmental considerations, and response to treatment of pediatric diabetes are often different from those of adult diabetes. Second, recommended treatments for children and adolescents with type 1 diabetes (T1DM), type 2 diabetes (T2DM), and other pediatric conditions such as monogenic diabetes (neonatal diabetes and MODY [maturity-onset diabetes of the young]) also differ. HbA1c goals in T1DM and T2DM must be individualized and reassessed over time. A HbA1c < 7% is appropriate for many children and adolescents with T1DM. In a case with hypoglycemia, hypoglycemic unawareness, lack of access to analog insulins, advanced insulin delivery technology and/or continuous glucose monitoring, a less stringent HbA1c < 7.5% will be required. A reasonable HbA1c goal for T2DM is < 7%. If possible, a strict HbA1c target of < 6.5% can be implemented. Metformin is the first-line treatment of choice in T2DM. In a case with ketosis or HbA1c > 8.5%, insulin will be required with once daily basal insulin (0.25~0.5 IU/kg). If the glycemic goal is not attained, the addition of a second agent is considered in adult patients but might not be applicable or safe in pediatric cases. Therefore, the efficacy and safety of these drugs used in adult patients, including glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors, should be evaluated in pediatric patients worldwide.

Cost-effectiveness of sodium-glucose cotransporter-2 inhibitors in the treatment of diabetic nephropathy in Japan.

To assess the cost-effectiveness of diabetic nephropathy treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors in Japanese clinical practice, considering diabetes-related complications. A population-based Monte Carlo simulation was used to estimate the cost-effectiveness for people with diabetic nephropathy who initiated pharmacotherapy with an SGLT2 inhibitor plus conventional treatment or conventional treatment alone, based on quality-adjusted life-years (QALYs) and healthcare costs. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) and the Japanese Society for Dialysis Research statistical survey were the primary sources of probability and mortality, while Japanese Health Insurance Claims Data were the cost source. The state transition model included diabetic nephropathy, hospitalization due to cardiovascular disease, dialysis, and death. One-way and probabilistic sensitivity analyses were used to explore model uncertainty. Using the threshold of JPY 5 000 000 per QALY, SGLT2 inhibitor plus conventional treatment was more cost-effective than conventional treatment alone, with an incremental cost-effectiveness ratio of JPY 654 309 per QALY. Treating 100 000 people, SGLT2 inhibitor plus conventional treatment prevented 2234 deaths and reduced 5793 fewer heart failure cases, 3967 fewer myocardial infarctions and stroke events. Sensitivity analysis affirmed the robustness of these results for patients aged under 70 years. The SGLT2 inhibitor treatment appeared to be cost-effective for the overall population of our study and particularly for younger patients (<70 years old). For older patients (≥70 years old), the cost-effectiveness was less clear and may require further evaluation. Decision-makers should consider this age-based heterogeneity when making recommendations about SGLT2 inhibitor treatment.

Analysing the influence of dapagliflozin on urinary tract infection vulnerability and kidney injury in mice infected with uropathogenic Escherichia coli.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have revolutionized clinical medicine, but their association with urinary tract infection (UTI) risk remains debated. This study investigates the influence of dapagliflozin on UTI outcomes, focusing on kidney injury. Female non-diabetic C57BL/6J and C3H/HeOuJ mice, along with diabetic db/db mice, were orally administered dapagliflozin (1 mg/kg or 10 mg/kg) for 7 days before transurethral uropathogenic Escherichia coli (UPEC) infection. Mice were killed either 24 h after UTI or after six additional days of dapagliflozin treatment. UPEC titers were enumerated, and kidney histopathology, injury, fibrosis and function were assessed. Vehicle- and dapagliflozin-treated C57BL/6J mice exhibited similar urine and bladder UPEC titers, with minimal kidney burden 24 h after UTI. In C3H/HeOuJ mice, UPEC burden was comparable in vehicle- and 1 mg/kg dapagliflozin-treated groups both 24 h and 7 days after UTI. However, C3H/HeOuJ mice receiving 10 mg/kg dapagliflozin had increased UPEC titers in the urine, bladder and kidneys at both endpoints. Kidney injury and fibrosis markers, as well as kidney function, were similar in vehicle and dapagliflozin groups. In diabetic db/db mice receiving dapagliflozin, UPEC strain UTI89 titers were reduced 7 days after UTI compared to vehicle-treated mice, but no difference in UPEC titers was observed when mice were infected with UPEC strain CFT073. Kidney injury and fibrosis markers and kidney function remained similar across treatment groups. Dapagliflozin does not consistently influence UTI susceptibility and shows limited impact on kidney injury or fibrosis, suggesting SGLT2 inhibitors have minimal effects on UTI-related kidney complications.

Comparison of the Risk of Diabetic Retinopathy Between Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus in Japan: A Retrospective Analysis of Real-World Data.

Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes mellitus (T2DM), is a leading cause of blindness and has detrimental effects on patients' quality of life. We compared the risk of DR diagnosis with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM in Japan. This Japanese retrospective cohort study used the JMDC Claims Database (data collected from January 2015 to September 2022). Patients with T2DM and no record of microvascular or macrovascular diseases who were newly treated with an SGLT2i (23,061 patients) or a DPP-4i (53,986 patients) were matched 1:1 using propensity score (10,166 per matched group). Incidence rates (IRs) and cumulative IRs of DR diagnosis were calculated for each treatment group; hazard ratio (HR) and its 95% confidence interval (CI) were calculated using Cox proportional hazard models to compare the risk between the groups. The IR of DR diagnosis was 46.23 and 57.12 per 1000 person-years in the SGLT2i and DPP-4i groups, respectively, with a significantly lower risk in the SGLT2i group than in the DPP-4i group (HR 0.83, 95% CI 0.75-0.92, P = 0.0003). In this study, the risk of DR diagnosis was lower with SGLT2i compared with DPP-4i in patients with T2DM without microvascular and macrovascular diseases in Japan. Findings suggest that early SGLT2i treatment may be beneficial in preventing DR development in early-stage T2DM. Graphical abstract available for this article.

Interpretation of cardiovascular outcome trials results of new antidiabetic agents

The incidence of diabetes is continuously increasing worldwide, resulting in a considerable socioeconomic burden. Glycemic control using traditional diabetes medications prevents microvascular complications; however, there is no objective evidence that it prevents macrovascular complications. In the 21st century, concerns have arisen that strict glycemic control and the diabetes drug rosiglitazone might increase mortality. This led the United States Food and Drug Administration to establish guidelines that require that cardiovascular outcome trials (CVOTs) with 3-point major adverse cardiovascular events (3-P MACE) as the primary endpoints be performed for new diabetes drugs. Since then, 20 CVOTs have been reported. Dipeptidyl peptidase 4 inhibitors do not increase the incidence of cardiovascular disease; however, saxagliptin increases the risk of heart failure. Sodium-glucose cotransporter inhibitors (SGLT2is) and glucagonlike peptide 1 receptor agonists (GLP-1RAs) not only have proven cardiovascular safety but also have shown results beyond expectations by reducing the incidence of cardiovascular diseases. Additionally, SGLT2is have been reported to markedly prevent heart failure and kidney disease. The reduction in 3-P MACE by GLP-1RAs was observed only with long-acting agents; long-acting GLP-1RAs also markedly reduced renal endpoints. However, no preventive effect against heart failure was observed with GLP-1RAs. The preventive effects of both drug types against cardiovascular and kidney diseases appear to be independent of glycemic control. In conclusion, based on CVOT results, it is necessary to actively prescribe SGLT2is and GLP-1RAs to prevent cardiovascular disease in patients with diabetes, regardless of glycemic control.

Efficacy of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in Heart Failure Management: A Narrative Review

Background: Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, requiring effective management strategies. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes, have emerged as promising therapeutic agents for HF.Objective: This narrative review aimed to evaluate the efficacy of SGLT2 inhibitors in reducing HF hospitalizations, cardiovascular mortality, and secondary outcomes, such as renal function and quality of life in patients with HF.Methods: A comprehensive literature search was conducted across PubMed, Embase, and Cochrane databases. Randomized controlled trials (RCTs) involving SGLT2 inhibitors in HF patients were included. Primary outcomes were HF hospitalizations and cardiovascular mortality. Secondary outcomes included all-cause mortality, ejection fraction, renal function, and quality of life.Results: Thirty-eight RCTs with 35,746 patients were analyzed. SGLT2 inhibitors significantly reduced HF hospitalizations (RR: 0.74, 95% CI: 0.68–0.80, p &lt; 0.001) and cardiovascular mortality (RR: 0.86, 95% CI: 0.78–0.95, p = 0.004). Renal function and quality of life improved significantly.Conclusion: SGLT2 inhibitors are effective in reducing HF hospitalizations and cardiovascular mortality, particularly in HFrEF patients, and improve renal function and quality of life.

Glucose-Lowering Drugs and Primary Prevention of Chronic Kidney Disease in Type 2 Diabetes Patients: A Real-World Primary Care Study

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1–326.5) per 10,000 person-years. In the nested case–control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73–0.99 and AOR = 0.89; 95%CI: 0.74–1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56–0.94 and AOR = 0.64; 95%CI: 0.46–0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD.

Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium–glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7–31.2) vs. 55.9 (51.0–64.5), STZ: 83.4 (53.7–91.7) vs. 121.2 (57.0–136.0) μL·min−1·kg−1, median (1st–3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8–18.4) vs. 10.5 (2.9–19.0), STZ: 36.9 (25.7–54.9) vs. 32.8 (15.1–37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA–AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Sodium-glucose Cotransporter-2 Inhibitors versus Dipeptidyl Peptidase IV Inhibitors and Risk of Dementia Among Patients with Type 2 Diabetes and Comorbid Mental Disorders: A Population-based Cohort Study

AimTo evaluate whether the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors which have shown potential neuroprotective effects, is associated with lower risk of dementia in patients with type 2 diabetes (T2D) and comorbid mental disorders, who are considerably more susceptible to dementia. MethodsUsing the nationwide healthcare data of South Korea between 2010 and 2022, we conducted a retrospective cohort study among patients with T2D and comorbid mental disorders initiating SGLT2 inhibitors versus active comparator (Dipeptidyl Peptidase IV (DPP4) inhibitors). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years of incident dementia were estimated after weighting by propensity score fine stratification method. ResultsOver a 4.8-year median follow-up, SGLT2 inhibitors were associated with a 12% lower risk of dementia compared with DPP4 inhibitors (11.31 vs. 12.86 events per 1000 person years; HR 0.88, 95% CI 0.84 to 0.92; RD -1.55, -2.13 to -0.97). The results were consistent when stratified by age, sex, individual component, severe mental disorders, presence of insulin, history of cardiovascular disease, or history of hypertension. ConclusionsSGLT2 inhibitors versus DPP4 inhibitors were associated with a lower risk of incident dementia in patients with T2D and comorbid mental disorders. Further randomized controlled trials are required to confirm our findings.

Antidiabetic Treatment and Prevention of Ischemic Stroke: A Systematic Review

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke.