Miaoran Wang1,2, Xuexue Zhang1,2, Zhengchuan Zhu3, Qiuyan Li4, Tian Ni1,2, Yi Wang5, Xujie Wang1,2, Yufei Wu1,5. 1. Department of General Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, No. 1, Xiyuan Playground, Zhong Zhi Road, Hai Dian District, Beijing, 100091, China. 2. Department of Endocrinology, China Academy of Chinese Medical Sciences, Beijing, 100700, China. 3. Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), No. 1, Xiyuan Playground, Zhong Zhi Road, Hai Dian District, Beijing, 100091, China. zhuzhengchuan999@pku.edu.cn. 4. Department of General Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, No. 1, Xiyuan Playground, Zhong Zhi Road, Hai Dian District, Beijing, 100091, China. liqiuyan0928@163.com. 5. Department of Endocrinology, Beijing University of Chinese Medicine, Beijing, 100029, China.
Abstract
INTRODUCTION: Dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors have often been used for patients with T2DM because of the reduced risk of hypoglycemia. However, DPP4 inhibitors and SGLT2 inhibitors may increase the risk of infectious diseases. This network meta-analysis (NMA) was performed to investigate the risk of urinary tract and genital infections associated with the use of two new glucose-lowering drug classes in patients with type 2 diabetes. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were comprehensively searched for articles from the date of database inception until September 8, 2020. Placebo-controlled or head-to-head trials of the two new drug classes used for treatment of adults with type 2 diabetes were included. The primary outcome was the incidence of any confirmed urinary tract infection; genital infection was also used as an important outcome indicator. RESULTS: Fifty-five studies were identified, covering 29,574 participants. Regarding urinary tract infections, SGLT2 inhibitors were not associated with increased risk, and among all drugs, sitagliptin, ipragliflozin, and linagliptin were the safest according to probability ranking. Regarding genital infections, saxagliptin was associated with significantly reduced risk in pairwise comparisons with placebo (RR 0.12, 95% CI 0.00-0.78), linagliptin (RR 0.09, 95% CI 0.00-0.78), canagliflozin (RR 0.04, 95% CI 0.00-0.31), dapagliflozin (RR 0.04, 95% CI 0.00-0.26), empagliflozin (RR 0.03, 95% CI 0.00-0.25), and ertugliflozin (RR 0.03, 95% CI 0.00-0.24). Among all drugs, saxagliptin, sitagliptin, and ipragliflozin were the safest according to probability ranking. Considering both urinary tract and genital infection risks, DPP4 inhibitors showed greater reductions than SGLT2 inhibitors and placebo. Saxagliptin was the safest drug according to probability ranking for both infection risks. CONCLUSIONS: This NMA showed that, to reduce genital infection risk, current evidence favors DPP4 inhibitors over SGLT2 inhibitors. Most SGLT2 inhibitors may not be associated with the risk of urinary tract infections. Considering both infection risks, saxagliptin may be the safest drug. Finally, mechanistic studies are needed to better understand the physiological basis for these effects.
INTRODUCTION: Dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors have often been used for patients with T2DM because of the reduced risk of hypoglycemia. However, DPP4 inhibitors and SGLT2 inhibitors may increase the risk of infectious diseases. This network meta-analysis (NMA) was performed to investigate the risk of urinary tract and genital infections associated with the use of two new glucose-lowering drug classes in patients with type 2 diabetes. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were comprehensively searched for articles from the date of database inception until September 8, 2020. Placebo-controlled or head-to-head trials of the two new drug classes used for treatment of adults with type 2 diabetes were included. The primary outcome was the incidence of any confirmed urinary tract infection; genital infection was also used as an important outcome indicator. RESULTS: Fifty-five studies were identified, covering 29,574 participants. Regarding urinary tract infections, SGLT2 inhibitors were not associated with increased risk, and among all drugs, sitagliptin, ipragliflozin, and linagliptin were the safest according to probability ranking. Regarding genital infections, saxagliptin was associated with significantly reduced risk in pairwise comparisons with placebo (RR 0.12, 95% CI 0.00-0.78), linagliptin (RR 0.09, 95% CI 0.00-0.78), canagliflozin (RR 0.04, 95% CI 0.00-0.31), dapagliflozin (RR 0.04, 95% CI 0.00-0.26), empagliflozin (RR 0.03, 95% CI 0.00-0.25), and ertugliflozin (RR 0.03, 95% CI 0.00-0.24). Among all drugs, saxagliptin, sitagliptin, and ipragliflozin were the safest according to probability ranking. Considering both urinary tract and genital infection risks, DPP4 inhibitors showed greater reductions than SGLT2 inhibitors and placebo. Saxagliptin was the safest drug according to probability ranking for both infection risks. CONCLUSIONS: This NMA showed that, to reduce genital infection risk, current evidence favors DPP4 inhibitors over SGLT2 inhibitors. Most SGLT2 inhibitors may not be associated with the risk of urinary tract infections. Considering both infection risks, saxagliptin may be the safest drug. Finally, mechanistic studies are needed to better understand the physiological basis for these effects.