Combination Therapy with SGLT2s and Metformin Does Not Increase Fracture Risk

A new meta-analysis including data from more than 19,000 patients with type 2 diabetes from clinical trials is shedding light on the potential risk of fracture associated with combination therapy with SGLT2 inhibitors and metformin reported in previous studies.

The analysis, which was conducted by members of the Department of Endocrinology at the Northern Jiangsu People’s Hospital in China, assessed data from more than 2 dozen randomized clinical trials and concluded combination therapy with SGLT2 inhibitors and metformin was not associated with increased risk of fracture in diabetics.

“The results of our meta-analysis manifested no detrimental effect of SGLT2is combined with metformin therapy on fracture risk in T2DM patients. When stratified by control regimen, drug type, follow-up duration, and type of fracture, we still did not see a significant difference in the two sets of results,” wrote study investigators.

With the antidiabetic drugs having varying effects on bone health and density in patients, investigators sought to determine whether combination therapy with SGLT2 inhibitors and metformin impacted the risk of fracture. Investigators aimed to do so through an analysis of data from the PubMed, Embase, and Cochrane Library databases. Investigators also searched ClinicalTrials.gov for completed but unpublished studies.

The investigators’ search included all studies published in their aforementioned databases from inception through December 27, 2019 that were designed as randomized controlled trials assessing the effects of SGLT2 inhibitors combined with metformin treatment in type 2 diabetics. Search terms used by investigators included SGLT2 inhibitors, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin, bexagliflozin, metformin, and randomized controlled trial.

For inclusion in the meta-analysis, studies needed to include adult patients with type 2 diabetes, have SGLT2 inhibitors in combination with metformin therapy as the exposure variable in the experimental group, include no insulin use in both study groups, have a duration of at least 24 weeks, and report data related to fracture events.

After their initial search yield 657 records, investigators were left with a group of 25 studies for inclusion in their meta-analysis. These 25 trials included 19,500 patients, including 9662 who received combination therapy with SGLT2 inhibitors and metformin. The mean age of participants ranged from 51.6-60.7 years and trial duration ranged from 24-208 weeks.

Of note, patients included in the SGLT2 inhibitor groups received either dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin, or bexagliflozin. Control therapies used in the control groups included metformin, sulfonylurea, DPP-4 inhibitors, SGLT2 inhibitors, and GLP1 receptor agonists.

Overall, 167 fractures occurred in the study population. Of these 167, 88 (0.91%) occurred in patients receiving SGLT2 inhibitors and in 79 (0.80%) of patients in the control group.

Results of the investigators' analysis indicated combination therapy with SGLT2 inhibitors and metformin did not increase the risk of bone fracture compared with metformin monotherapy or other comparators (OR, 0.97; 95% CI, 0.71-1.32) and investigators did not observe heterogeneity (I²=0%; P=.86). Investigators noted results remained stable after stratification by drug type, follow-up time, control regimen, and type of fracture.

Investigators also performed analyses evaluating impact on bone mineral density and bone turnover markers using data from 2 and 4 trials, respectively, that reported data related to these outcomes. These results indicated no clinically meaningful changes in bone turnover markers and no significant changes in bone mineral density were seen over 102 weeks with dapagliflozin plus metformin or over 104 weeks with ertugliflozin plus metformin.

This study, “Association between combined treatment with SGLT2 inhibitors and metformin for type 2 diabetes mellitus on fracture risk: a meta-analysis of randomized controlled trials,” was published in Osteoporosis International.