Study Finds No Increase in Below-Knee Amputations with SGLT2 Inhibitor Use

August 13, 2020

An analysis of data from the UK and Canada has found no significant increase in below-knee amputations with SGLT2 inhibitor use versus DPP-4 inhibitor use.

New research from an observational study of patients in the UK and Canada is providing an overview of the risk of amputations seen with SGLT2 inhibitor use among patients with type 2 diabetes.

While there have been reports of increased incidence of below-knee amputations among type 2 diabetics receiving SGLT2 inhibitors, results of the study indicate there was no association between SGLT2 inhibitor use and increase of below-knee amputations compared to patients receiving dipeptidyl peptidase 4 (DPP-4) inhibitors.

“We found no evidence of an association between SGLT2 inhibitor use and incident below-knee amputation compared with DPP-4 inhibitor use among patients with type 2 diabetes. Similarly, there was no increased risk of below-knee amputation associated with specific SGLT2 inhibitor molecule use compared with DPP-4 inhibitor use,” wrote study investigators.

With information from the CANVAS program and other observational studies indicating a potential increased risk of below-knee amputations associated with SGLT2 inhibitor use, a team of investigators from Canada sought to investigate whether this apparent increase was evident in a real-world population. To do so, they designed their study as a multicenter observational study using the UK Clinical Practice Research Datalink and administrative databases from 7 Canadian provinces.

For the current study, investigators assessed data related to all patients 18 years of age and older with a prescription for an antidiabetic medication from January 2006 through June 30, 2018. For the purpose of analysis, investigators matched incident SGLT2 inhibitor users to DPP-4 inhibitor users using a new-user design and time-conditional propensity scores.

The primary outcome of the study was incident below-knee amputation, which investigators defined as having transtibial amputations or amputations involving the ankle and foot. Investigators noted a multitude of covariates were included in their adjusted analyses such as demographic information, history of multiple diseases, history of medication uses, number of inpatient hospitalizations in the past, and diabetes duration, among others.

In total, investigators identified a source population of nearly 3 million diabetics. From this group, 270,902 met the criteria of a new user of SGLT2 inhibitors. After application of exclusion criteria, investigators were left with 207,817 SGLT2 inhibitors patients matched with a 207,817-patient cohort of DPP-4 inhibitor users. The mean follow-up time for the matched cohort was 11±9 months, contributing 369,458 person-years of data for analysis.

Upon analysis, the amputation rate among SGLT2 inhibitor users was 1.3 per 1000 person-years compared to 1.5 per 1000 person-years among those using DPP-4 inhibitors. Based on these results, investigators determined the corresponding hazard ratio for below-knee amputations with SGLT2 inhibitor use compare with DPP-4 inhibitor use was 0.88 (95% CI, 0.71-1.09).

In secondary analyses, investigators found results did not differ according to subgroup analyses when stratified by age, sex, or history of prior insulin use or SGLT2 inhibitor molecule. assessing impact of SGLT2 inhibitor use versus DPP-4 inhibitor use. Investigators did note an increased trend toward increased risk of below-knee amputation among patients meeting the criteria for prevalent new users of SGLT2 inhibitors compared with DPP-4 inhibitor users (HR, 1.29; 95 CI, 0.97-1.70).

Investigators pointed out multiple limitations within their study for clinicians to consider when interpreting the results of their study. Specific limitations included the possibility for residual confounding, potential trial for confounding by contraindication, a modest follow-up duration, and not specifying the site below-knee amputations.

This study, “Sodium–Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study,” was published in Diabetes Care.