Sodium Glucose Co-transport 2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

A Meta-analysis of Randomized Double-Blind Controlled Trials

Asres Berhan; Alex Barker


BMC Endocr Disord. 2013;13(58) 

In This Article


In agreement with prior meta-analyses[13,14] this meta-analysis demonstrated the significant improvement of glycemic control in patients with type 2 diabetes treated with SGLT2 inhibitors. Patients treated with SGLT2 inhibitors either as monotherapy or in combination with other antidiabetic agents significantly decreased HbA1c and FPG from baseline at all doses studied as compared to patients treated with placebo or placebo with other antidiabetic agents. A significantly large number of patients treated with SGLT2 inhibitors achieved HbA1c < 7% at the end of the study period of the included studies. The reduction of HbA1c from baseline with SGLT2 inhibitors may reflect the long term mean glycemic control for the previous 2 to 3 months; while, FPG indicates the glycemic control on the day of the visit.[33,34]

On top of this, the meta-regression and subgroup analysis did not demonstrate a significant change in the efficacy of SGLT2 inhibitors depending on the duration of therapy and the doses SGLT2 inhibitors studied. Accordingly, the glycemic control with SGLT2 inhibitors does not seem to decline when the duration of therapy gets longer. On the other hand, the increase in doses of SGLT2 inhibitors was not accompanied by an increase in the efficacy of SGLT2 inhibitors. A phase 3 long-term extension dapagliflozin study (102 weeks), reported the sustained reductions in HbA1c and FPG level.[35] However, the finding of the meta-regression should not be taken as a confirmation of the long term efficacy and safety of SGLT2 inhibitors at all doses. The included studies in the meta-regression reported the change in HbA1c and FPG level after a duration of therapy not more than 26-weeks (Table 1).

Treatment with SGLT2 inhibitors was associated with a significant reduction in body weight, systolic and diastolic blood pressure. Therapy with SGLT2 inhibitors was associated with a rise in HDL cholesterol level without a significant change in LDL cholesterol level. Provided that most of the antidiabetic agents are associated with weight gain[9,10] and the vast majority of patients with type 2 diabetes are overweight or obese,[36] the introduction of SGLT2 inhibitors with an insulin independent mechanism could have a pivotal role in the management of type 2 diabetes. The drop in blood pressure and the rise in HDL cholesterol level with SGLT2 inhibitor therapy could even make SGLT2 inhibitors more promising. This is because; in patients with type 2 diabetes the major cause of morbidity and mortality is attributed to cardiovascular diseases.[4,37] But SGLT2 inhibitors long term effects on cardiovascular outcomes is uncertain. Moreover, in this study, the meta-analyses of change in blood pressure and cholesterol levels were not controlled to change in body weight. Since body weight reduction was strongly associated with a drop in blood pressure and a change in cholesterol levels,[38,39] the changes in blood pressure and cholesterol levels in SGLT2 inhibitors treated groups could be mediated by the weight changes.

This meta-analysis has shown a statistically significant association of SGLT2 inhibitors based therapy with adverse events. The number of patients experiencing genital or urinary tract infections was significantly higher in SGLT2 inhibitors treated groups than placebo treated groups. Both genital and urinary tract infections were more common among females than males.[40] However, the proportions of patients with severe adverse events, hypoglycemic events and discontinuation of medication because of adverse events in SGLT2 inhibitors treated groups were not different from placebo treated groups. Similarly, previous meta-analyses reported an increased risk of urinary and genital tract infections with dapagliflozin without a significant increase in hypoglycemic events.[13,14] Moreover, a study of women with type 2 diabetes has established the significant association of canagliflozin therapy with vulvovaginal candidiasis.[41]

As limitations, firstly heterogeneity testing has revealed the presence of significant inconsistency among the included studies. But, the uncertainty of the results from this meta-analysis did not appear increased. This is because; sensitivity analysis by removing any of the study with a specific dose from the analysis confirmed the stability of the overall values. The possible explanation for the significant heterogeneity could be: the variation in the patients' antidiabetic agents experience, the variation in the SGLT2 inhibitors regimens, and the difference in baseline demographic and clinical characteristics of the patients recruited.

Secondly, a pooled data from phase 2b and 3 clinical trials has shown an increased incidence of cancer and hepatotoxicity with dapagliflozin.[42] This meta-analysis did not have any evidence to rule out or to share these concerns. That is, further analyses were not conducted to determine the association of SGLT2 inhibitors with rare adverse events like cancer development and hepatotoxicity. Meta-analysis of rare adverse events, using studies that were not primarily designed to test adverse events, can yield misleading information.[43] Thirdly, since all the included studies were sponsored by pharmaceutical companies, the findings of studies could be biased by business interests. Lastly, the number of studies on canagliflozin, ipragliflozin and empagliflozin that were included in this meta-analysis is very small. Thus, the pooled values of this meta-analysis may not reveal the clinical effect.