Risk of major adverse limb events in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based retrospective cohort study

Abstract

Background: Both sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular protective effects in patients with type 2 diabetes mellitus. However, the comparative risk of GLP-1RA versus SGLT-2i for major adverse limb events remains unknown.Materials and methods: We studied a nationwide cohort involving 123,048 diabetes patients 20–100 years of age who initiated a SGLT-2i or GLP-1RA during 2012 and 2017. The patients in the two groups were matched by propensity score (PS), and incidence rates for hospitalization for major adverse limb events, critical limb ischemia (CLI) and lower extremity amputation (LEA), were assessed. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) between patients receiving SGLT-2i as compared with GLP-1RA. The modification effects of age, a history of established cardiovascular disease, and chronic kidney disease were examined. In addition, use of dipeptidyl peptidase-4 inhibitor (DPP-4i) was chosen as a second active comparator.Results: After PS-matching, a total of 13,378 SGLT-2i and 13,378 GLP-1RA initiators were identified. Use of SGLT-2i was not associated with an increased risk for hospitalization for CLI and LEA, either compared with GLP-1RA (HR, 1.13; 95% CI, 0.77–1.65 and 1.27; 95% CI, 0.63–2.55, respectively) or compared with DPP-4i use (HR, 1.06; 95% CI, 0.75–1.50 and HR, 0.80; 95% CI, 0.42–1.53, respectively). Although the study was underpowered to explore potential effect modification, a trend of higher risks for LEA was noted among SGLT-2i users with cardiovascular disease as compared with either GLP-1RA or DPP-4i.Conclusion: Use of SGLT-2i was not associated with higher risks for hospitalization for CLI and LEA as compared with reference drugs. Further large-scale studies are needed for a precise risk estimation.

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nation-wide cohort study

“…Moreover, in contrast to our study, the comparison of SGLT2-I with GLP1-RA did not allow for distinction between the effects exerted by the drug classes separately. Finally, our results are in line with several cohort studies which reported no higher risk of LLA with SGLT2-Is [17,33,34] and a lower risk of LLA with GLP1-RAs [30,35]. Overall, the available evidence for the association between SGLT2-I use and GLP1-RA use and the risk of LLA is limited, has high uncertainty [31], and the studies are highly heterogeneous [36].…”

“…Some studies investigating the risk of LLA with SGLT2-I have chosen GLP1-RAs as the reference group. Several of these studies report no difference [33,34,37], whereas LLA lower limb amputation, IR incidence rate, PY person years, HR hazard ratio, CI confidence interval, NIGLD non-insulin glucose lowering drug, SU sulfonylurea, DPP4-I dipeptidyl peptidase-4 inhibitor, GLP1-RA glucagon-like peptide-1 receptor agonist a Adjusted for age; sex; diabetes duration; income category; immigrant status; education; history of diabetic foot ulcer, neuropathy, atherosclerosis, peripheral arterial disease, hypertension, retinopathy, heart failure, hyperlipidaemia, ischaemic heart disease, osteomyelitis, renal disease, pulmonary heart disease, or bacterial foot infection; and the use of loop diuretics, antithrombotic agents, potassium sparing diuretics, beta blockers, lipid lowering drugs, angiotensin receptor blockers, digoxin, angiotensin converting enzyme blockers, or calcium channel blockers in the 6 months before the start of the exposure interval b Adjusted for age; sex; diabetes duration; income category; immigrant status; education; history of diabetic foot ulcer, neuropathy, atherosclerosis, peripheral arterial disease, hypertension, retinopathy, heart failure, hyperlipidaemia, ischaemic heart disease, osteomyelitis, renal disease, pulmonary heart disease, or bacterial foot infection; and the use of antithrombotic agents, beta blockers, lipid lowering drugs, angiotensin receptor blockers, digoxin, angiotensin converting enzyme blockers, or calcium channel blockers in the 6 months before the start of the exposure interval c Adjusted for age; sex; diabetes duration; income category; immigrant status; education; history of diabetic foot ulcer, neuropathy, atherosclerosis, peripheral arterial disease, hypertension, retinopathy, heart failure, hyperlipidaemia, ischaemic heart disease, osteomyelitis, renal disease, pulmonary heart disease, or bacterial foot infection; and the use of loop diuretics, antithrombotic agents, potassium sparing diuretics, beta blockers, lipid lowering drugs, digoxin, or calcium channel blockers in the 6 months before the start of the exposure interval d Adjusted for age; sex; diabetes duration; income category; immigrant status; education; history of diabetic foot ulcer, neuropathy, atherosclerosis, hypertension, retinopathy, heart failure, hyperlipidaemia, ischaemic heart disease, osteomyelitis, renal disease, pulmonary heart disease, or bacterial foot infection; and the use of loop diuretics, antithrombotic agents, potassium sparing diuretics, beta blockers, lipid lowering drugs, angiotensin receptor blockers, digoxin, angiotensin converting enzyme blockers, or calcium channel blockers in the 6 months before the start of the exposure interval others report a higher risk with SGLT2-I [12,13,38,39].…”

Risk of lower limb amputation in diabetic patients using SGLT2 inhibitors versus DPP4 inhibitors or GLP-1 agonists: a meta-analysis of 2 million patients

“…On deduplication, 258 were screened by titles and abstracts and 34 were selected for full-text analysis. Of these, 13 studies fulfilled the inclusion criteria [8][9][10][11][12][18][19][20][21][22][23][24][25] (Figure 1).…”

“…It is important that the adjusted HR generated by the study is pooled to avoid the influence of confounders. Given these shortcomings from the prior reviews and with the inclusion of newer studies 23,24 in our updated analysis, the current review provides the most updated and reliable evidence on the risk of LLA between users of SGLT2i and DPP4i or GLP1a.…”