Risk of limb amputation and bone fractures with sodium glucose cotransporter-2 inhibitors: a network meta-analysis and meta-regression

ABSTRACT

Background

Sodium glucose cotransporter-2 inhibitors (SGLT2is) have gained immense attention for a variety of indications. Limb amputations (LA) and fractures were reported in clinical trials. This network meta-analysis and meta-regression were carried out to quantify the risks of these events.

Research design and methods

Randomized clinical trials evaluating SGLT2is and reporting patients developing LA/fracture were included. Odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Sub-group analyses and meta-regression analysis were carried out.

Results

Ninety articles were included (LA: 36 studies; 96522 participants and fracture: 66 studies; 102,862 participants). An increased risk of LA (OR: 1.2; 95% CI: 1.1, 1.3) was observed. Amongst SGLT2is, canagliflozin was associated with increased risk of LA (OR: 1.6, 95% CI: 1.1, 2.4) while dapagliflozin with fracture (OR: 1.1, 95% CI: 1, 1.2). Sub-group analysis revealed increased risk of LA with an OR of 1.3 among those in the age group of > 40 to < 65, body-mass index of > 30 kg/m², HbA1c category of > 7%, duration of diabetes of > 10 years, type 2 diabetes, and an OR of 1.2 for SGLT2is administration of > 6 months.

Conclusions

SGLT2is were observed with an increased risk of LA. High- risk categories were identified for which precautions should be recommended in the standard treatment guidelines.

Protocol registration

Open Science Framework (https://osf.io/5fwyk)

KEYWORDS:

• SGLT2i
• sodium glucose cotransporter inhibitors
• NMA
• network meta-analysis
• amputation
• fractures

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

This meta-analysis was carried out with the data available in the public domain and the analysis remains with the corresponding author that can be shared upon a reasonable request.

Authors contribution statement

Kannan Sridharan-conceived the study idea; Kannan Sridharan, Gowri Sivaramakrishnan-data collection; Kannan Sridharan-data analysis and interpretation; Kannan Sridharan-wrote the first draft of the manuscript; and Kannan Sridharan, Gowri Sivaramakrishnan-involved in revision and final approval of manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2024.2377755.

Additional information

Funding

This paper was not funded.