Meta-Analysis on Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus

Objective: To evaluate the safety of dapagliflozin for Type 2 Diabetes Mellitus (T2DM). Methods: A systematic search of Pubmed, Embase, Cochrance Library, Web of Science, CNKI, Wanfang Data and VIP database for randomized controlled trials (RCTs) comparing dapagliflozin with placebo was performed up to February 2018. The index words included dapagliflozin, type 2 diabetes mellitus and randomized controlled trial. Results: A total of 19 RCTs involving 7704 participants were incorporated into the study. Compared with placebo, dapagliflozin did not increase the risk of hypoglycemia [OR = 1.14, 95%CI (0.95, 1.36), P = 0.17] and hypotension [OR = 1.43, 95%CI (0.94, 2.17), P = 0.10], but significantly increased the incidences of renal adverse events [OR = 1.57, 95%CI (1.17, 2.09), P = 0.002], genital tract infection [OR = 3.65, 95%CI (2.93, 4.56), P < 0.00001] and urinary tract infection [OR = 1.36, 95%CI (1.15, 1.61), P = 0.0004] and related doses. Conclusions: Generally, dapagliflozin had no risk of hypoglycemia and hypotension in patients with T2DM, but there were risks of renal adverse events and urogenital tract infection. Due to the limitations of this study, larger samples and RCTs with long-term follow-up are needed for further verification.


Introduction
As a common disease in China, the incidence of T2DM has been increasing year by year, and drug therapy is the main method of treatment.Sodium glucose co-transporter 2 (SGLT-2), as the most important glucose transporter in the kidney, is responsible for the reabsorption of 90% glucose in the kidney [1].The SGLT-2 inhibitor, dapagliflozin is a novel oral hypoglycemic drug for the treatment of T2DM, which is independent from islet β-cell function and insulin sensitivity.It functions by increasing renal clearance of glucose, attenuating renal reabsorption of glucose and excreting excess glucose from the urine, thereby reducing blood glucose [2].Studies have shown that dapagliflozin has multiple benefits such as reduction in blood glucose, weight and blood pressure.However, there is also risk for urogenital tract infections [3].In this study, the safety is further analyzed by retrieving RCTs of dapagliflozin versus placebo through meta-analysis.

Exclusion criteria:
Treatment observation time < 12 weeks, type 1 and special types of diabetes, review, non-RCT and so on.

Evaluation Index
Safety related indicators: hypoglycemia events, hypotension events, adverse renal reactions, genital tract infections, urinary tract infections.

Search Strategy
The search strategy follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [4].Relevant studies for the analysis were selected by searching PubMed, Embase, Cochrance Library, Web of Science, CNKI, Wanfang Data and VIP database up to the end of February 2018.Taking Pubmed database as an example, subject words and free words are combined to search, and the retrieval scheme is as follows: #1 AND #2 AND #3.

Data Extraction
Data were independently abstracted by the two principal reviewers and any discrepancies were resolved by consensus.The data extracted included title, author, and year of publication, country, intervention measures, sample size, patient age, treatment time, main outcome indicators and intentionality analysis.

Quality Assessment
Jadad scoring criteria were used [5], including 4 items: random method, assignment concealment, blind method and withdrawal.The RCT score was 1 -7, 1 -3 as low quality and 4 -7 as high quality.

Data Analysis
Outcomes were pooled using Review Manager 5.3 software.Dichotomous data were presented as odds ratio (OR) or risk ratio (RR).All results were estimated from each study with 95% confidence intervals (CIs).Heterogeneity was assessed using the I 2 statistic.If P > 0.1, I 2 < 50%, a fixed-effect model with the Mantel-Haenszel method was used; otherwise, the random-effect model was adopted.
Subgroup analysis was performed according to the different doses of dapagliflozin (1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg).Funnel plot was adopted to evaluate the publication bias.The bilaterally symmetric graph indicates a low risk of publication bias.Otherwise, the risk of publication bias may exist.

The Basic Characteristics and Process of Inclusion Study
A total of 19 RCTs involving 7704 participants was incorporated into the study, including 5304 cases of dapagliflozin group and 2400 cases of the placebo group.
All 19 RCTs were performed from 2009 to 2016, and the follow-up duration was ≥12 weeks.Baseline data for both groups were described in all trials, and there was no statistical difference in general between the dapagliflozin and placebo groups before treatment (P > 0.05).The screening process is displayed in Figure 1.The basic information contained in the study is shown in Table 1.

Hypotension Event
A total of 13 studies were implemented to compare hypotension events.Heterogeneity was detected in the study subgroups (2.5 mg, 5 mg, 10 mg), indicating that there was no statistically significant heterogeneity (I 2 = 0%, P = 0.60), (I 2 = 0%, P = 0.85), (I 2 = 0%, P = 0.79) between studies included in the analysis (Figure 5).Therefore, the M-H fixation   effect model was used for meta-analysis.Funnel plot of publication bias evaluation is presented in Figure 6.There was no risk of publication bias among subgroups in the study.No significant differences were observed in the comparison results of dapagliflozin with placebo in the incidence of hypotension event [OR = 1.43, 95%CI (0.94, 2.17), P = 0.10], as shown in Figure 5.

Discussion
The meta-analysis suggests that dapagliflozin had no difference in the risk of hypoglycemia and hypotension events compared with placebo, and was safer than sulfonylurea, insulin and other hypoglycemic agents with a higher risk of hypoglycemia.Studies have illustrated that Chinese adults with type 2 diabetes were more complicated due to hypertension and other cardiovascular risk factors [24].Dapagliflozin can reduce blood glucose while reducing blood pressure and weight [25] [26], improve oxidative stress and endothelial function and reduce arteriosclerosis [27] [28], with potential cardiovascular benefits [29].Multiple studies on the effects of renal function proved that the eGFR and urinary albumin-creatinine ratio were not significantly changed in the dapagliflozin

Inclusion criteria: 1 ) 2 )
Research type: Included in the study were clinical RCTs of different doses of dapaglilfozin versus placebo in the treatment of T2DM officially published before February 2018; full text is available; languages are limited to Chinese and English.Research object: Age > 18 years, in accordance with the diagnostic criteria for T2DM (WHO Committee of Experts on Diabetes 1999 diagnosis and classification criteria), in accordance with the dapagliflozin guidelines.3) Interventions: The experimental group was treated with dapagliflozan alone, regardless of dose size; placebo in the control group; or on the basis of other similar interventions.

Figure 1 .
Figure 1.Screening flow chart for inclusion studies.

Figure 4 .
Figure 4. Funnel plot for publication bias evalution of dapagliflozin versus placebo for hypoglycemia events in patients with T2DM in different dose subgroups.

Figure 5 .
Figure 5.Comparison of dapagliflozin versus placebo for hypotention events in patients with T2DM in different dose subgroups.

Figure 6 .Figure 7 .
Figure 6.Funnel plot for publication bias evalution of dapagliflozin versus placebo for hypotention events in patients with T2DM in different dose subgroups.

Figure 8 .
Figure 8. Funnel plot for publication bias evalution of dapagliflozin versus placebo for renal adverse events in patients with T2DM in different dose subgroups.

Figure 9 .Figure 10 .
Figure 9.Comparison of dapagliflozin versus placebo for genital tract infections in patients with T2DM in different dose subgroups.

Figure 11 .Figure 12 .
Figure 11.Comparison of dapagliflozin versus placebo for urinary tract infections in patients with T2DM in different dose subgroups.