Differences in Effectiveness of Flozins

An independent systematic review and metanalysis of the comparative effectiveness of SGLT2 inhibitors has suggested that monotherapy with canagliflozin 300 mg may be slightly better at lowering HbA1c than the other members of this drug class. However, this advantage does not hold up in dual therapy, and suggesting few clinically meaningful differences between SGLT2 inhibitors.

The study was published online in BMJ Open.

“Our NMA [network meta-analysis] showed few differences among the flozins,” wrote first author Deepson S. Shyangdan, MSc, formerly of Warwick Medical School (Coventry, UK), and colleagues.

The lack of head-to-head comparisons of the different SGLT2 inhibitors (also called flozins) makes it difficult to know whether any drug is in this class is better than the others. 

Flozins mainly work on the SGLT2 transport system in the kidney without significantly affecting the SGLT1 transport system in the gut. The exception seems to be canagliflozin, which may have a larger effect on the gut’s SGLT1 system than other flozins. This raises the possibility that canagliflozin may lower blood glucose by acting on both the kidney and the gut. Whether or not that translates into clinically meaningful difference in HbA1c reduction compared to other flozins has been an open question.

In the study, researchers searched MEDLINE and EMBASE for articles published from January 2005 to January 2015. The analysis included randomized controlled trials (RCTs) that looked at the efficacy of SGLT2 inhibitors taken for a minimum of 24 weeks and a maximum of 26 weeks. Study participants had inadequately controlled type 2 diabetes, and were being treated with diet and exercise or metformin monotherapy.

The analysis included thirteen trials: six of dapagliflozin, three of canagliflozin, two of empagliflozin, and luseogliflozin, ipragliflozin and tofogliflozin (these last three are newer drugs, not yet FDA-approved). Eight trials looked at monotherapy, and six looked at dual therapy. All were funded by pharmaceutical companies. The analysis did not look at safety data.

Key results for monotherapy:

• HbA1c <7%: More patients achieved this goal with canagliflozin 300 mg than with other flozins

♦ Canaglifozin 100 mg: 28% less likely to reach goal than those on canagliflozin 300 mg (risk ratio (RR) 0.72%, 95% credible intervals [CrI] 0.59% to 0.87%)

♦ Dapagliflozin 10 mg: 37% less likely to reach goal than those on canagliflozin 300 mg (RR 0.63, 95% CrI 0.48 to 0.85)

♦ No significant differences between canagliflozin 300 mg and empagliflozin 10 mg or 25 mg

• Weight loss: No significant differences between agents

• Systolic blood pressure (SBP): All flozins more effective than placebo

♦ Greatest reduction with canagliflozin 300mg (-6 mm Hg)

Key results for dual therapy with metformin:

• HbA1c <7%:  Similar proportions of participants reached this goal for each agent

♦ Canagliflozin 300 mg decreased HbA1c more than the other drugs but only reached statistical significance compared to canagliflozin 100 mg (MD 0.15, CrI 0.04 to 0.26)

• Weight loss: All drugs had greater weight loss than placebo

♦ Greatest reduction with canagliflozin 300 mg (-2.5 kg)

• SBP: Significant reductions in SBP with all flozins, with no significant differences between them

The authors noted that reductions in HbA1c and weight with dual therapy using canagliflozin 300 mg were probably not clinically meaningful compared to the other agents. They also pointed out that participants in clinical trials were randomized to canagliflozin 300 mg, which may not approximate clinical practice because patients are started on canagliflozin 100 mg before increasing the dose.

“There are few clinically significant differences among the drugs. In monotherapy, reductions in HbA1c were largest with canagliflozin and smallest with dapagliflozin. Differences in HbA1c were insignificant in dual therapy,” the authors concluded.

Take-home Points

• Independent network meta-analysis shows few clinically meaningful differences in the effectiveness on HbA1c, weight, and systolic blood pressure of different SGLT2 inhibitors.

• Monotherapy with canagliflozin 300 mg may be slightly better at lowering HbA1c than the other members of this drug class, but this advantage does not hold up in dual therapy.

The study was not industry-funded.

Dr. Shyangdan has joined Eli Lilly since doing the research for this paper. Drs. Shyangdan, Waugh, and Uthman have been involved in NICE trials investigating flozins.

Reference: Shyangdan DS, et al. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open. 2016 Feb 24;6(2):e009417. doi: 10.1136/bmjopen-2015-009417.