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Adverse Effects and Safety of SGLT2 Inhibitor Use Among Patients with Type 2 Diabetes: Findings from RCT Evidence

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Adverse Effects and Safety of SGLT2 Inhibitor Use Among Patients with Type 2 Diabetes: Findings from RCT Evidence 78 Apr 2017 Vol 10 No.2 North American Journal of Medicine and Science Review Adverse Effects and Safety of SGLT2 Inhibitor Use among Patients with Type 2 Diabetes: Findings from RCT Evidence Huilin Tang, MSc;1,2,3 Jingjing Zhang, MD;4 Yiqing Song, MD, ScD2,3* 1 Department of Pharmacy, Peking University Third Hospital, Beijing, China 2 Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 3 Center for Pharmacoepidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 4 Division of Nephrology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Sodium-glucose cotransporter 2 (SGTL2) inhibitors, a novel class of glucose-lowering agents, act in an insulin-independent manner by increasing urinary glucose excretion. In addition to reduce hyperglycemia, SGTL2 inhibitor exerts beneficial effects on cardiovascular risk factors (e.g., lower blood pressure and enhance weigh loss), which may confer additional health benefits for type 2 diabetes patients. The EMPA- REG OUTCOME trial showed that empagliflozin not only reduced the risk of major adverse cardiovascular events but also slowed down the progression of kidney disease compared with placebo. However, some evidence indicated an increased risk of composite renal events among patients using dapagliflozin. The beneficial cardiovascular and renal effects of EMPA-REG OUTCOME trial representing a class effect or a specific drug effect warrants to be further investigated. SGLT2 inhibitors were associated with increased risks of genital mycotic infections and urinary tract infections. Some mechanisms indicated that SGLT2 inhibitor might lead to diabetic ketoacidosis and bone fracture. These risks remain uncertain, though some evidence from the meta-analyses did not find any significantly increased risks of diabetic ketoacidosis and bone fracture. The findings of ongoing trials will provide more definitive evidence on safety of SGLT2 inhibitors. [N A J Med Sci. 2017;10(2):78-82. DOI: 10.7156/najms.2017.1002078] Key Words: SGLT2 inhibitor, type 2 diabetes, safety outcomes INTRODUCTION Type 2 diabetes mellitus (T2DM) is a chronic metabolism marketed in Japan, and further SGLT2 inhibitors are still under disease, which is characterized by relative insulin deficiency development (e.g., ertugliflozin, sotagliflozin, and caused by pancreatic β-cell dysfunction and insulin remogliflozin etabonate).9 In contrast to other glucose resistance.1 It is estimated that about 6% of the world’s adult lowering agents, SGLT2 inhibitors offer a novel insulin- population are diagnosed T2DM around the world, which independent hypoglycemia mechanism by selectively accounts for approximately 90% of all diabetes cases.2 T2DM inhibiting renal glucose reabsorption to increase urinary is associated with increased risk of microvascular and glucose excretion.10,11 Because of the advantage of this novel macrovascular complications (e.g., cardiovascular disease, mechanism,SGLT2 inhibitors, in addition to reduce stroke, and nephropathy), leading to huge economic burden on hyperglycemia,12 have also been demonstrated to improve both patients and health-care systems.3 Estimated evidences cardiovascular risk factors (e.g., lower blood pressure and have been showed that intensive glucose management may enhance weight loss).13 Moreover, SGLT2 inhibitors were reduce the diabetes related complications.4-7 shown to reduce major cardiovascular end points,14 and were associated with slower progression of kidney disease and Sodium glucose cotransporter 2 (SGLT2) inhibitors are a lower risk of clinically relevant renal events in patients with novel class of glucose-lowering agents.8 Currently, three T2DM at high cardiovascular risk as compared to placebo.15 SGLT2 inhibitors (canagliflozin, dapagliflozin, and However, other potential safety issues of SGLT2 inhibitors empagliflozin) have been approved for treating T2DM in the raise our concern. U.S. Food and Drug Administration (FDA) United States, European Union and in other parts of the world. successively issued drug safety warnings about potential risks Three additional SGLT2 inhibitors (ipragliflozin, of diabetic ketoacidosis (DKA),16,17 bone fracture,18 urinary luseogliflozin, and tofogliflozin) have been approved and tract infections (UTIs),17 and acute kidney injury 19 associated __________________________________________________________________________________________________ with SGLT2 inhibitors. In this article, we reviewed current Received: 03/16/2017; Revised: 04/14/2017; Accepted: 04/20/2017 evidence from randomized controlled trials (RCTs) and meta- *Corresponding Author: Department of Epidemiology, Richard M. analyses or systematic reviews of RCTs to summarize the Fairbanks School of Public Health, Indiana University, 1050 Wishard Blvd, adverse effects and safety issues of SGLT2 inhibitor use in Indianapolis, Indiana, 46202. Tel: 317-274-3833, Fax: 317-274-3443. (Email: [email protected]) patients with T2DM. North American Journal of Medicine and Science Apr 2017 Vol 10 No.2 79 METHODS NCT01032629), dapagliflozin (DECLARE-TIMI58; We searched PubMed, Embase and Cochrane Central Register NCT01730534), and ertugliflozin (VERTIS CV; of Controlled Trials (CENTRAL) from inception to 15 NCT01986881) will in further clarify whether SGLT2 February 2017 to identify eligible articles using the following inhibitors have a cardiovascular protective effect. search terms: sodium-glucose co-transporter; SGLT2; SGLT- 2; and the names of individual SGLT2 inhibitors Renal Safety (empagliflozin, dapagliflozin, canagliflozin, sotagliflozin, SGLT2 raises our concern about their renal safety, because luseogliflozin, ipragliflozin, remogliflozin etabonate, their hypoglycemic mechanisms of action are depending on tofogliflozin and ertugliflozin). References lists of included kidney. The osmotic diuresis associated with SGLT2 articles were also screened for additional studies. We included inhibitors may lead to intravascular volume depletion.26 RCTs and systematic reviews/meta-analyses of RCTs that Subsequently, transient hypotensive episodes secondary to evaluated the safety outcomes and adverse effects of SGLT2 volume reduction are likely to result in acute kidney injury.27 inhibitors (e.g., cardiovascular outcomes, renal outcomes, On June 14th, 2016, the U.S. FDA strengthened an existing bone fracture, ketoacidosis, genital mycotic infections and warning about the risk of acute kidney injury for canagliflozin UTIs). and dapagliflozin based on the fact that 101 confirmable cases of acute kidney injury were reported associated with these two RESULTS drugs.19 Some evidence also indicated that the risk of adverse Beneficial Effects on Cardiovascular Outcomes renal events was increased with the use of dapagliflozin or Cardiovascular disease is one of the leading causes of death in canagliflozin as compared to placebo.12,28 Some trials found an patients with T2DM, accounting for more than 60% of early dose-dependent increase in serum creatinine or blood deaths.20 Although SGLT2 inhibitors have demonstrated their urea nitrogen levels and a decrease in estimated glomerular ability to improve cardiovascular risk factors, their effect on filtration rate during the initial weeks of therapy, especially in preventing and/or reducing cardiovascular outcomes is unclear patients with chronic kidney disease.29,30 However, the early until the publication of the EMPA-REG OUTCOME trial in observed abnormal renal parameters returned toward baseline September 2015.14 In the EMPA-REG OUTCOME trial, a in patients receiving SGLT2 inhibitors over time.31 Inversely, total of 7,020 patients with T2DM at high risk of SGLT2 inhibitors are associated with an renal benefit.32 cardiovascular disease were randomized to receive Recently, the EMPA-REG OUTCOME trial with a median empagliflozin 10 mg or 25 mg or placebo per day in addition follow-up of 3.1 years showed that patients taking to standard care and followed up for a median of 3.1 years. empagliflozin were less likely to experience incident or Empagliflozin could significantly decreased major adverse worsening nephropathy than those taking placebo (HR, 0.61; cardiovascular events, including death from cardiovascular 95%CI, 0.53-0.70; P<0.01). In addition, use of empagliflozin causes, nonfatal myocardial infarction, and nonfatal stroke, by was associated with decreased risk of doubling of the serum 14%, the hazard ratio [HR] was 0.86 (95% confidence interval creatinine level (HR, 0.56; P < 0.001) and initiation of renal- [CI], 0.74 - 0.99). In addition, we noted a 38% reduction in therapy therapy (HR, 0.45; P = 0.04) as compared to placebo. risk of cardiovascular deaths (P = 0.001) and a 35% reduction No significant difference in rate of incident albuminuria was in hospitalization for heart failure (P = 0.002).14 However, the observed (HR, 0.95; P = 0.25).15 In agree with the findings underlying mechanisms for these findings remain unclear, from EMPA-REG OUTCOME trial, one network meta- especially since the non-fatal myocardial infarction (HR, 0.87; analysis included 1,334 composite renal events among 39,741 P = 0.22) and non-fatal stroke (HR, 1.24; P = 0.23) were not patients from 58 RCTs and 511 acute renal impairment/failure significantly reduced. All these evidence suggested that the events among 36,716 patients from 53 RCTs. The meta- beneficial effect of empagliflozin on cardiovascular outcomes analysis found that empagliflozin seemed to
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