Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials

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(T2 DM). 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 T2 DM 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, I2 = 0%], hospitalization for heart failure(RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death(RR = 1.02, 95%CI: 0.93-1.11, I2 = 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, I2 = 0%) and coronary revascularization(RR = 0.99, 95%CI: 0.90-1.09, I2 = 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, I2 = 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, I2 = 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, I2 = 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 T2 DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics(glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.     

基础胰岛素联合DPP-4抑制剂对2型糖尿病患者的临床研究

摘要:目的：探讨基础胰岛素联合二肽基肽酶Ⅳ (DPP-4)抑制剂在治疗2型糖尿病方面的临床疗效。方法：选择我院2012年7月至2014年7月收治的80例2型糖尿病（FBS＞11.1mmol/L）患者，随机进行分组，治疗组与对照组，各40例，全部患者均给予生活方式干预，治疗组给予地特胰岛素联合西格列汀100mg，每日服用一次，餐前口服；对照组给予地特胰岛素联合瑞格那奈1mg，每日服用三次，三餐前口服治疗。结果：经治疗16周后，治疗组患者在空腹及餐后两小时血糖（PBG、2hPBG），HBA1C，血脂谱，体重指数（BMI）较前明显下降，具有统计学意义（P＜0.05）；与对照组比较，结果具有显著性差异（P＜0.05）；两组患者比较，胰岛β功能均较治疗前明显下降，但治疗组改善情况更为明显（P＜0.05）；治疗期间，两组患者均未出现低血糖反应，未见其它临床不良反应，两组比较，无显著性差异（P>0.05）。治疗组患者血糖达标率显著高于对照组，血糖达标中位时间显著短于对照组，两组数据具有显著性差异（P<0.05）。结论：基础胰岛素联合DPP-4抑制剂在治疗2型糖尿病方面具有较好的临床疗效，且治疗安全性高。 关键词:2型糖尿病；DPP-4抑制剂；胰岛素     

二肽基肽酶-4抑制剂对2型糖尿病心血管系统的影响

2型糖尿病(T2DM)与包括冠心病、慢性心力衰竭在内的心血管疾病危险增加有关.某些传统降糖药物可引起心血管疾病的不良后果.新型降糖药物二肽基肽酶-4(DPP-4)抑制剂对T2DM总体心血管事件、心肌梗死面积、心功能的影响仍存在争议.但近期大量临床及动物实验发现,DPP-4抑制剂具有降糖作用以外的抗炎、抗氧化应激、保护内皮等多重心血管益处.同时对高血脂、高血压等心血管危险因素表现出有益作用.短期临床观察未显示出DPP-4抑制剂对心血管系统的不良影响.     

Comparison of glucagons like peptide-1 receptor agonists and dipeptidyl peptide-4 inhibitors regarding cardiovascular safety and mortality in type 2 diabetes mellitus: A network meta-analysis

AimThe effects of dipeptidyl peptide-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on type 2 diabetes mellitus (T2DM) on cardiovascular events and all-cause mortality were compared.MethodsThe literature on DPP-4is and SGLT-2is treatment of T2DM was searched through Pubmed, Embase, and the web of science databases with the search deadline May 15, 2020. Network meta-analysis (NMA) was used to compare the effects of two types of inhibitors on cardiovascular events (major adverse cardiovascular events (MACE), nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death) and all-cause mortality in T2DM patients.ResultsA total of 15 articles were screened, including 125,796 patients. Compared with DPP-4is, SGLT-2is can significantly reduce MACE [OR: 0.86 95% CI (0.78, 0.92)], CV death [OR: 0.85 95% CI (0.71, 1.01)], nonfatal MI [OR: 0.84 95%CI (0.74, 0.95)] and all-cause mortality [OR: 0.78 95% CI (0.69, 0.89)]. For nonfatal stroke, DPP-4is and SGLT-2is have no statistically significant difference [OR: 0.99 95% CI (0.91, 1.07)].ConclusionThese data indicate that SGLT-2is is more beneficial to MACE and all-cause mortality in T2DM patients than DPP-4is.     

Surrogate cardiovascular outcomes with sodium-glucose co-transporter-2 inhibitors in women: An updated meta-analysis

The burden of cardiovascular disease morbidity and mortality among women with type 2 diabetes mellitus remains high, despite the improvement in therapeutic management over the recent years. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have revolutionized treatment of cardiovascular disease in subjects with diabetes. However, previous meta-analyses of cardiovascular outcome trials failed to prove a significant effect on surrogate cardiovascular outcomes among female participants. Therefore, we sought to update these results, by incorporating data from the most recently published trials. We pooled available data from all available trials (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS CV, DAPA-HF, EMPEROR-Reduced), except for the CANVAS trial. In the present updated meta-analysis we document that SGLT-2 inhibitors do not confer a significant decrease in the risk for major adverse cardiovascular events among women; however, they provide significant results in terms of reduction in the risk for cardiovascular death or hospitalization for heart failure, primarily driven by the results observed in the heart failure with reduced ejection fraction population. Better representation of women in future trials will provide further insights into the question whether there are true gender differences in the cardiovascular efficacy with this drug class.     

Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: A population-based study

Aims

This study examined whether dipeptidyl peptidase (DPP)-4 inhibitor use is beneficial or harmful to diabetic retinopathy (DR) compared with other glucose-lowering agents in patients with type 2 diabetes (T2D).

Effect of SGLT2 inhibitors versus DPP4 inhibitors or GLP-1 agonists on diabetic foot-related extremity amputation in patients with T2DM: A meta-analysis

AimTo compare the contribution of sodium-glucose cotransporter-2 inhibitors (SGLT2is) with that of DPP4i or GLP-1ra toward lower extremity amputation rate.MethodsElectronic databases were searched for articles published on the differences between the rates of lower extremity amputation among patients with type 2 diabetes mellitus (T2DM) undergoing SGLT2i treatment and those undergoing other anti-hyperglycemic agent (dipeptidyl peptidase-4 inhibitors [DPP4is], glucagon-like peptide-1 receptor agonist [GLP-1as], or sulfonylurea [SUs]) treatments. Random-effect models were used to generate data if heterogeneity was detected.ResultsEight studies based on retrospective case-control designs with propensity matching were included. The propensity score-matching method increased credibility. Compared with SGLT2i treatment, DPP4i or GLP-1a treatment tended to result in a higher amputation rate (pooled hazard ratio [HR] = 1.1, 95% confidence interval [CI]: 0.98–1.23), whereas SU treatment resulted in similar amputation rates (pooled HR = 0.92, 95% CI: 0.74–1.13). After excluding the heterogeneous study, the meta-analysis of the remaining studies attained a statistical value (pooled HR = 0.81, 95% CI: 0.65–1.01).ConclusionThe study findings suggest that, with respect to diabetic foot-related limb amputations, SGLT2is are not superior to novel anti-hyperglycemic agents (DPP4is and GLP-1as) or other types of oral hypoglycemic agents (SUs). Therefore, SGLT2is may not have significantly positive effects on the prognosis for T2DM patients with complicated diabetic foot.     

Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease

Chronic low-grade inflammation is a recognized key feature associated with type 2 diabetes mellitus (T2DM) and its complications. In prospective randomized trials, sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated benefits related to several cardiovascular and renal risk factors, including HbA_1c, blood pressure, body weight, renal hyperfiltration, and improvement of cardiorenal outcomes. SGLT2 inhibitors may improve adipose tissue function and induce decreases in serum leptin, TNF-α and IL-6 while increasing adiponectin. While data on high-sensitivity C-reactive protein and other inflammatory markers are relatively scarce in humans, in animals, a number of reports have shown reductions in cytokine and chemokine concentrations in parallel with protective effects against progression of atherosclerotic lesions. Experimental findings also suggest that part of the renoprotective effects of SGLT2 inhibition may be related to anti-inflammatory actions at the kidney level. Underlying mechanisms to explain this anti-inflammatory effect are multiple, but may involve weight loss, and reduction in adipose tissue inflammation, slight increase in ketone bodies and diminution of uric acid levels or attenuation of oxidative stress. However, further studies in diabetes patients with specific assessment of inflammatory markers are still necessary to determine the specific contribution of the anti-inflammatory action of SGLT2 inhibitors to the reduction of cardiovascular and renal complications and mortality observed with this class of antidiabetic drugs.     

Clinical use of GLP-1 agonists and DPP4 inhibitors

Type 2 diabetes is a growing problem, with 387 million people currently affected, and 592 million by 2035. Whilst diet and exercise are the corner stones of treatment, oral hypoglycaemic agents are often needed to achieve glycaemic control, thereby reducing the chance of long term diabetic complications. Biguanides and sulfonylureas have been the standard tablets used for this disorder, until 2005–7 when glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors became available. Their major advantage over sulfonylureas is that they are weight lowering or weight neutral, and have a very low incidence of hypoglycaemia. GLP-1 agonists are injectables, whereas the DPP4 inhibitors are administered orally. Both agents are best used in combination with other hypoglycaemic medication, especially metformin and sodium glucose co-transporter 2 (SGLT2) inhibtors. Usage is increasing, being roughly equal to that of sulfonylureas, but less than that of metformin. Side effects appear to be minimal.     

Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis

Aims

Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin.

The cardiovascular safety trials of DPP-4 inhibitors,GLP-1 agonists,and SGLT2 inhibitors

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.     

Renal outcomes with dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are increasingly being used in the management of type 2 diabetes (T2D). The present review summarizes the current knowledge of the effects of DPP-4is on renal outcomes by analyzing the experimental preclinical data, the effects of DPP-4is on urinary albumin–creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) from observational studies and clinical trials, and renal events (including kidney failure requiring renal replacement therapy) in recent large prospective cardiovascular outcome trials. Renal protection has been demonstrated in various animal models that have implicated different underlying mechanisms independent of glucose control, whereas prevention of new onset microalbuminuria and/or progression of albuminuria has been reported in some clinical studies, but with no significant effects on eGFR in most of them. The long-term clinical effects of DPP-4is on renal outcomes and the development of end-stage renal disease remain largely unknown and, thus, demand further investigations in prospective trials and long-term observational studies. In conclusion, despite promising results in animal models, data on surrogate biological markers of renal function and clinical renal outcomes remain rather scanty in patients with T2D, and mostly demonstrate the safety rather than true efficacy of DPP-4is.     

Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT‐2 inhibitors and GLP‐1 receptor agonists

Patients with type 2 diabetes mellitus (T2D) present an increased risk for cardiovascular (CV) complications. In addition to improvement in glycaemic control, glucose‐lowering therapies, such as glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐dependent glucose cotransporter (SGLT)‐2 inhibitors, have been shown to significantly reduce CV events. In 2008, the US Food and Drug Administration mandated that all new glucose‐lowering drugs undergo CV outcomes trials (CVOTs) to determine their CV safety. These trials have largely demonstrated no major CV safety concerns. Most notably, the GLP‐1RAs and SGLT‐2 inhibitors have been found to be not only safe, but also cardioprotective compared to placebo. The SGLT‐2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their ‘pleiotropic’ effects, specifically on heart failure, while GLP‐1RAs seem to present more favourable effects on atherosclerotic events. In this review, we discuss the role of GLP‐1RAs and SGLT‐2 inhibitors to reduce CV risk in T2D patients and suggest an individualized therapeutic approach in this population based on the presence of metabolic and CV comorbidities.     

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials

AimAlpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE).Data synthesisA Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH–OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH–OR 0.76 [0.28; 2.05]).ConclusionsThe evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.     

Dipeptidyl Peptidase-4 Inhibitors,Peripheral Arterial Disease,and Lower Extremity Amputation Risk in Diabetic Patients

Background

Recent studies have elucidated the vascular protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, to date, no large-scale studies have been carried out to determine the impact of DPP-4 inhibitors on the occurrence of peripheral arterial disease, and lower extremity amputation risk in patients with type 2 diabetes mellitus.