Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor

Nov 15, 2017Circulation

Heart health risks and outcomes after starting sodium glucose cotransporter 2 inhibitor treatment in a real-world population

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Abstract

Initiation of SGLT2 inhibitors was associated with a lower rate of all-cause mortality and hospitalization for heart failure compared to other antihyperglycemic agents.

SGLT2i initiation resulted in 1.73 events per 100 person-years for all-cause mortality and hospitalization for heart failure, compared to 3.01 events per 100 person-years for non-SGLT2i.
The hazard ratio for all-cause mortality and hospitalization for heart failure was 0.57, suggesting a significant reduction in risk.
SGLT2i users experienced 2.31 major adverse cardiovascular events per 100 person-years, compared to 3.45 events per 100 person-years in non-SGLT2i users.
The hazard ratio for major adverse cardiovascular events associated with SGLT2i use was 0.67, indicating a lower risk.
SGLT2i initiation was linked to an approximately 2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years).
Most amputations were associated with canagliflozin, suggesting variability in risk among different SGLT2i medications.

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BACKGROUND: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns.

METHODS: We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed.

RESULTS: After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.

CONCLUSIONS: In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.

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Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor

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