BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia. RESULTS We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I 2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I 2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I 2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I 2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I 2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I 2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I 2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I 2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, th...

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Objective: Patients with type 2 diabetes mellitus (T2DM) experience a significantly increased risk for atrial fibrillation (AF) compared to unaffected subjects. The latter confers to increased risk for heart failure, all-cause and cardiovascular mortality. Notably, even patients with sufficient glycemic control feature an increased risk for AF. Thus, it seems to be of interest whether antidiabetic treatment can affect the risk for AF among patients with T2DM. Design and method: We searched PubMed from its inception to 2 October 2020. We sought to determine the risk of AF with the use of newer antidiabetics, namely dipeptidyl-peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, extracting corresponding data from the published cardiovascular and renal outcome trials. We assessed the risk for AF with each drug class separately. Results: We pooled data from 4 trials with DPP-4 inhibitors versus placebo or active comparator in a total of 34,884 patients, from 7 trials with GLP-1RAs versus placebo in a total of 55,943 patients and from 7 trials with SGLT-2 inhibitors versus placebo in a total of 55,966 patients. Risk of bias is considered as low across all selected studies. DPP-4 inhibitor treatment resulted in a non-significant decrease in the risk for AF, equal to 7% (RR = 0.93, 95% CI; 0.75 to 1.16, I2 = 1%). Similarly, GLP-1RA treatment produced a non-significant decrease in the risk for AF, equal to 12% (RR = 0.88, 95% CI; 0.76 to 1.03, I2 = 29%). Notably, SGLT-2 inhibitor treatment significantly decreased the risk for AF 19% (RR = 0.81, 95% CI; 0.69 to 0.95, I2 = 0%). Conclusions: Collectively, newer antidiabetics do not confer an increased risk for AF among patients with T2DM, while, SGLT-2 inhibitors seem to be protective, providing an additional cardiovascular benefit, besides the well-established ones.

Objective Hypertension augments overall cardiovascular risk in patients with type 2 diabetes mellitus (T2DM); however, control rates remain suboptimal. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the field of T2DM therapeutic management due to their multiple pleiotropic effects. Therefore, we sought to determine the effect of this class on ambulatory blood pressure monitoring (ABPM), pooling data from relevant randomized controlled trials (RCTs). Methods We searched major electronic databases, namely PubMed and Cochrane Library, along with gray literature sources, for RCTs assessing the effect of various GLP-1RAs on ambulatory BP in patients with T2DM. Results We pooled data from seven RCTs in total. GLP-1RA treatment compared to placebo or active control resulted in a nonsignificant decrease in 24-h SBP (mean difference = −1.57 mm Hg; 95% CI,−4.12 to 0.98; I 2 = 63%) and in 24-h DBP (mean difference = 1.28 mmHg; 95% CI,−0.31 to 2.87; I 2 = 49%). No subgroup differences between the various GLP-1RAs were detected. Conclusion GLP-1RAs treatment does not influence either systolic or diastolic ambulatory BP in patients with T2DM.

Objective:SGLT-2 inhibitors confer cardiovascular protection for patients with heart failure (HF) regardless of diabetes mellitus (DM) or chronic kidney disease (CKD) status at baseline. However, it has not been extensively studied whether SGLT-2 inhibitors exert reno-protective effects in patients with heart failure (HF), either with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). Declining of renal function is of utmost importance for patients with HF; thus, development of optimal treatment strategies to prevent or delay this progression to renal failure is required.Design and method:We sought to evaluate whether SGLT-2 inhibitors confer reno-protection in patients with HF, pooling data from relevant trials. We evaluated the following surrogate outcomes: the composite renal outcome, as defined across the 3 included trials, and the > 40% decrease in estimated glomerular filtration rate (eGFR) from baseline. Definition of composite renal endpoint is as follows: time to first occurrence of: (1) chronic dialysis; (2) renal transplantation; (3) sustained reduction of > 40% in estimated GFR; or (4) sustained estimated GFR of less than 15 ml per minute per 1.73 m2.Results:We pooled data from 3 randomized, controlled trials for a total of 14,462 enrolled subjects with HFrEF or HFpEF, assigned either to SGLT-2 inhibitor treatment or placebo. Overall risk of bias was evaluated as low across all trials. SGLT-2 inhibitor treatment resulted in a non-significant decrease in the risk for the primary composite outcome by 27% (RR = 0.73, 95% CI; 0.50–1.08 I2 = 66%, p = 0.11). In addition, SGLT-2 inhibitor treatment led to a non-significant decrease in the risk for > 40% decrease in eGFR from baseline, compared to placebo (RR = 0.70, 95% CI; 0.48–1.03, I2 = 54%, p = 0.07). No difference was identified between HFpEF and HFrEF enrolled subjects.Conclusions:SGLT-2 inhibitors provide significant cardiovascular benefits in patients with HFrEF or HFpEF; however, they do not exert significant reno-protection among patients with HF.

Background Hypertension augments overall cardiovascular risk in patients with type 2 diabetes mellitus (T2DM), constituting a major additional burden for diabetic subjects; however, control rates of hypertension remain suboptimal. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), second-line treatment option for diabetics, have revolutionized the field of T2DM therapeutic management due to their pleiotropic effects, while they seem to hold multiple cardiovascular benefits. A few randomized controlled trials (RCTs) evaluated the effect of GLP-1RAs on ambulatory blood pressure (ABP). Ambulatory blood pressure monitoring (ABPM) provides a better method to predict long-term cardiovascular outcomes than office blood pressure. Purpose We sought to determine the effect of GLP-1RAs on ABPM, pooling data from relevant randomized controlled trials (RCTs). Methods We searched 2 major electronic databases, namely PubMed and Cochrane/CENTRAL, along with grey literature sources, for RCTs assessing the effect of various GLP-1RAs on ABP in patients with T2DM. Results After screening of the potentially eligible records, 7 RCTs were finally included in our meta-analysis (4 parallel-group and 3 cross-over). GLP-1RA treatment compared to placebo or active control resulted in a nonsignificant decrease in 24-h systolic blood pressure (MD=−1.57 mm Hg, 95% CI: −4.12 to 0.98, I2=63%) (Figure 1) and in 24-h diastolic blood pressure (MD=1.28 mmHg, 95% CI: −0.31 to 2.87, I2=49%) (Figure 2). No subgroup differences between the various GLP-1RAs were identified. More specifically, it was demonstrated that liraglutide once daily produced a non-significant decrease in 24-h systolic blood pressure (MD=−1.43 mm Hg, 95% CI: −5.24 to 2.38, I2=72%) and a non-significant increase in 24-h diastolic blood pressure (MD=1.47 mm Hg, 95% CI: −1.12 to 4.05, I2=61%), while data concerning the effect of once weekly dulaglutide and twice daily exenatide on ABPM were pooled from one RCT respectively (Figures 1, 2). Conclusions Antidiabetic treatment with GLP-1RAs does not influence either systolic or diastolic ABP in patients with T2DM. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Objective:Endothelial dysfunction seems to play a pivotal role in the pathogenesis of cardiovascular disease and related complications among high-risk patients, such as those suffering from type 2 diabetes mellitus (T2DM). Non-invasive peripheral endothelial function assessment with measurement of brachial artery flow-mediated dilation (FMD) has been demonstrated to predict adverse cardiovascular events. Herein, we sought to determine whether SGLT-2 inhibitors provide a significant effect on endothelial function, as assessed through FMD.Design and method:We searched PubMed, Cochrane Library and grey literature from inception to 10th October 2021 for parallel group randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on FMD. We set as primary efficacy outcome the change in FMD with SGLT-2 inhibitor versus control.Results:We pooled data from 4 trials in a total of 270 subjects with T2DM. We demonstrated that treatment with SGLT-2 inhibitor versus placebo or active comparator produced a significant increase in FMD by 1.66% (95% CI; 0.56 – 2.76, I2 = 28%, p = 0.003). Notably, all eligible RCTs utilized dapagliflozin. Overall risk of bias was evaluated as low across the selected studies.Conclusions:The present meta-analysis demonstrated a clear benefit on endothelial function with SGLT-2 inhibitors compared to placebo or active comparator. Although the sample size is small, it seems that amelioration of endothelial dysfunction with SGLT-2 inhibitors constitutes another significant mechanism that confers to cardio-protection with this drug class. Larger RCTs will shed further light on this important pathophysiologic link.

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