SGLT2 inhibitor plus DPP‐4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta‐analysis

To assess the efficacy and safety of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors plus a dipeptidyl peptidase‐4 (DPP‐4) inhibitor in patients with type 2 diabetes mellitus (T2DM), we performed a systematic review and meta‐analysis of 14 randomized controlled trials (RCTs) involving 4828 patients. Compared with a DPP‐4 inhibitor, SGLT2 inhibitor/DPP‐4 inhibitor combination therapy was significantly associated with a decrease in glycaemic control (HbA1c, ?0.71%; fasting plasma glucose [FPG], ?25.62 mg/dL; postprandial plasma glucose, ?44.00 mg/dL), body weight (?2.05 kg) and systolic blood pressure (?5.90 mm Hg), but an increase in total cholesterol (TC) of 3.24%, high‐density lipoprotein of 6.15% and low‐density lipoprotein of 2.55%. Adding a DPP‐4 inhibitor to an SGLT2 inhibitor could reduce HbA1c by ?0.31%, FPG by ?8.94 mg/dL, TC by ?1.48% and triglycerides by ?3.25%. Interestingly, low doses of an SGLT2 inhibitor in the combination has similar or even better efficacy in some aspects than high doses. Similar adverse events were observed for the combination therapy, with the exception of genital infection vs DPP‐4 inhibitor (risk ratio [RR], 5.31) and consistent genital infection vs an SGLT2 inhibitor (RR, 0.61). Further studies are warranted to confirm these results.     

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes

Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run‐in period, eligible patients inadequately controlled on long‐acting, intermediate‐acting or premixed insulin (HbA1c ≥ 7.5% and ≤ 11%), were randomised 1:1 to the addition of once‐daily sitagliptin 100 mg or matching placebo over a 24‐week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m²), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long‐acting and intermediate‐acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2‐h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol‐specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24‐week study, the addition of sitagliptin to ongoing, stable‐dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.     

SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis

Background

Sodium–glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and <60 ml/min/1.73 m² and/or UACR > 300 and ≤5000 mg/g] by conducting a systematic review and meta-analysis of available studies.

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase‐4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of “euglycaemic” diabetic ketoacidosis. It is important to balance the benefits over the older‐oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost‐effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP‐4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP‐4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use.     

Saxagliptin and sitagliptin in adult patients with type 2 diabetes: a systematic review and meta-analysis

The objective of this study is to compare the efficacy and safety of sitagliptin and saxagliptin with placebo and other hypoglycaemic medications in adults with type 2 diabetes. We searched MEDLINE®, Embase, the Cochrane Library and the International Pharmaceuticals from their inception through 3 February 2011. Studies were included of adults with type 2 diabetes that were 12 weeks or more in duration. Meta‐analyses were conducted when included studies were homogenous enough to justify combining their results. A total of 32 articles met inclusion criteria. Sitagliptin 100 mg monotherapy and saxagliptin 5 mg resulted in greater HbA1c reduction compared to placebo [weighted mean difference (WMD) ?0.82%, 95% CI ?0.95 to ?0.70 and WMD ?0.70, 95% CI ?0.84 to ?0.56, respectively]. Sitagliptin was similar to sulfonylureas for HbA1c reduction (WMD 0.08%, 95% CI 0–0.16, 3 trials) and to saxagliptin in one head‐to‐head trial. There was no statistically significant difference in hypoglycaemia between sitagliptin (pooled RR 1.55, 95% CI 0.55–4.36) or saxagliptin (pooled RR 1.04, 95% CI 0.28–3.81) and placebo. Sitagliptin and saxagliptin result in similar modest HbA1c reductions and do not increase the risk of hypoglycaemia unless combined with other therapies. Their role in the long‐term treatment of type 2 diabetes remains unclear given the lack of long‐term data on efficacy, harms and health outcomes.     

Impact of demographic characteristics and antihyperglycemic and cardiovascular drugs on the cardiorenal benefits of SGLT2 inhibitors in patients with type 2 diabetes mellitus: A protocol for systematic review and meta-analysis

Background:It is unclear whether demographic characteristics and baseline use of hypoglycemic and cardiovascular drugs significantly affect the efficacy of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM).Methods:Randomized trials assessing the efficacy of SGLT2 inhibitors on cardiorenal outcomes in adult patients with T2DM were included in analysis. Three endpoints of interest were major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular death (HHF or CV death), and kidney composite outcome (KCO). We performed random-effects meta-analysis using the aggregate data of hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses were done according to 17 factors of interest, including 7 factors related to demographic characteristics and 10 related to baseline use of antihyperglycemic and cardiovascular drugs such as renin–angiotensin system (RAS) inhibitor. We conducted meta-regression analyses to calculate P values for subgroup differences.Results:Seven trials were included in this meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of MACE (HR 0.90, 95% CI 0.84–0.97) regardless of demographic characteristics and baseline use of insulin, statin or ezetimibe, RAS inhibitor, beta-blocker, and diuretic (P_subgroup from 0.088–0.981); that of HHF or CV death (HR 0.78, 95% CI 0.71–0.85) regardless of demographic characteristics and baseline use of 10 antihyperglycemic and cardiovascular drugs (P_subgroup from 0.147–0.999); and that of KCO (HR 0.63, 95% CI 0.57–0.69) regardless of demographic characteristics and baseline use of statin or ezetimibe, RAS inhibitor, and diuretic (P_subgroup from 0.073–0.918).Conclusions:The cardiorenal benefits of SGLT2 inhibitors were consistent in a broad population of T2DM patients. The findings of this meta-analysis suggest that SGLT2 inhibitors should be recommended in T2DM patients for the prevention of cardiorenal events, regardless of various demographic characteristics and baseline use of various hypoglycemic and cardiovascular drugs.     

Longer term safety of dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta‐analysis

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are oral antidiabetic agents that hold the potential of slowing the progress of type 2 diabetes mellitus. Their long‐term safety is still a subject of debate. A systematic review of randomized, controlled trials was undertaken to comprehensively profile the safety of chronic treatment of type 2 diabetes mellitus with DPP‐4 inhibitors. We searched data sources including MEDLINE, CENTRAL, publishers' and manufacturers' databases. Eligible trials were double‐blind, randomized, placebo or active‐controlled trials with ≥18 weeks duration in patients with type 2 diabetes reporting safety outcomes. Meta‐analysis was performed separately for trials in which the control group received placebo (44 studies), another gliptin (3 studies) and any other antidiabetic drug (20 studies). Risk ratios with 95% confidence intervals were computed using a Mantel‐Haenszel fixed‐effect model for general safety outcomes, hypoglycaemia and adverse events by system organ class. Of 307 publications retrieved, 67 randomized, controlled trials met the eligibility criteria and were included in this review (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin trials). Adverse events with gliptin treatment were at placebo level (relative risk (RR) 1.02 [0.99, 1.04]). No increased risk of infections was detectable (RR 0.98 [0.93, 1.05] compared to placebo and 1.02 [0.97, 1.07] compared to other antidiabetic drugs). Asthenia (RR 1.57 [1.09, 2.27]) as well as cardiac (RR 1.37 [1.00, 1.89]) and vascular disorders (RR 1.74 [1.05, 2.86] for linagliptin) emerged as adverse events associated with DPP‐4 inhibitor treatment. The risk of hypoglycaemia was low with DPP‐4 inhibitor treatment (RR 0.92 [0.74, 1.15] compared to placebo, RR 0.20 [0.17, 0.24] compared to sulphonylureas) in the absence of sulphonylurea or insulin co‐therapy, but significantly elevated for combination therapy of sulphonylurea or insulin with sitagliptin or linagliptin (RR 1.86 [1.46, 2.37] compared to placebo). A large body of data supports the long‐term safety of gliptin treatment and refutes an increased risk of infections. Further research is needed to clarify a possible link to asthenia, cardiac and vascular events. For combination therapy with insulin or insulin secretagogues, a careful choice of the agent used may limit the risk of hypoglycaemia.     

Impact of SGLT2 inhibitors in comparison with DPP4 inhibitors on ascites and death in veterans with cirrhosis on metformin

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have favourable neurohumoral and metabolic effects in patients with chronic liver disease. However, studies examining SGLT2i in this population have been limited to patients with non-alcoholic fatty liver disease and have focused on surrogate biomarkers. Our aim was to evaluate whether SGLT2i can reduce the incidence of ascites and death over a period of 36 months in patients with cirrhosis and diabetes mellitus. Using electronic health data from Veterans Affairs hospitals in the United States, we conducted a propensity score matched intention-to-treat analysis among veterans on metformin who subsequently received either SGLT2i or dipeptidyl peptidase-4 inhibitors. Among 423 matched pairs (in total, 846 patients), we found no significant difference in the risk for ascites (hazard ratio 0.68 for SGLT2i, 95% confidence interval 0.37-1.25; p = .22) but did find that SGLT2i users had a reduced risk for death (adjusted hazard ratio 0.33, 95% confidence interval 0.11-0.99; p < .05). In comparison with dipeptidyl peptidase-4 inhibitors, SGLT2i may improve survival for patients with cirrhosis who require additional pharmacotherapy for diabetes mellitus beyond metformin, but confirmatory studies are necessary.     

维格列汀和二甲双胍联合治疗2型糖尿病的疗效与安全性

维格列汀是一种二肽基肽酶4( DPP-4)抑制剂,常与二甲双胍合用治疗2型糖尿病.多个临床试验表明,维格列汀和二甲双胍合用可以有效降低2型糖尿病患者HbA1c、、空腹血精和餐后血糖,不增加体重,胃肠道耐受性好,而且低血糖发生率低.维格列汀通过增加血浆胰升糖素样肽1( GLP-1)促进胰岛素分泌,而二甲双胍除增加肝脏胰岛素敏感性,抑制肝糖输出外,尚有增强维格列汀增加GLP-1的作用.     

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta‐analysis

The effects of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta‐analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75 540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta‐analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.