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Major Adverse Cardiovascular and Limb Events in People With Diabetes Treated With GLP-1 Receptor Agonists vs SGLT2 Inhibitors
TAKE-HOME MESSAGE
- This retrospective cohort study assessed the real-world outcomes of people with diabetes treated with GLP-1 receptor agonists (GLP1RA) compared with those treated with SGLT2 inhibitors (SGLT2i) in terms of major adverse cardiovascular and limb events. A total of 287,091 patients were included in the analysis. The incidence rate of major adverse limb events (MALE) was significantly lower among the GLP1RA group than among the SGLT2i group (HR, 0.80) owing to a lower incidence of critical limb ischemia. The reduced risks of MALE were particularly noticeable in people with diabetic peripheral neuropathy.
- GLP1RA use is associated with a significantly reduced risk of MALE compared with SGLT2i in people with diabetes, especially people with diabetic neuropathy.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAIMS/HYPOTHESIS
This study aimed to assess the real-world outcomes of people with diabetes mellitus treated with glucagon-like peptide-1 receptor agonists (GLP1RAs) compared with those treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in terms of major adverse cardiovascular and limb events. Peripheral artery disease is a common cause of morbidity in people with diabetes. Previous cardiovascular outcome trials have demonstrated the benefits of GLP1RAs and SGLT2is for reducing various cardiovascular events, but the safety and efficacy of these drugs on limb outcomes remain subject to debate and ambiguity.
METHODS
A retrospective cohort study was conducted in which data were collected from the Taiwan National Health Insurance Research Database. In total, 379,256 individuals with diabetes receiving either GLP1RA or SGLT2i with treatment initiated between 1 May 2016 and 31 December 2019 were identified. The primary outcome was major adverse limb events (MALE), defined as the composite of newly diagnosed critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for peripheral artery disease, and non-traumatic amputation. The secondary outcome was major adverse cardiac events, which was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Other examined outcomes included death from any cause and hospitalisation for heart failure. Propensity score matching was performed at a 1:4 ratio between the GLP1RA and SGLT2i groups to mitigate possible selection bias.
RESULTS
A total of 287,091 patients were eligible for analysis, with 81,152 patients treated with SGLT2i and 20,288 patients treated with GLP1RA after matching. The incidence of MALE was significantly lower in the GLP1RA group than in the SGLT2i group (3.6 vs 4.5 events per 1000 person-years; subdistribution HR 0.80; 95% CI 0.67, 0.96), primarily due to a lower incidence of critical limb ischaemia. The reduced risks of MALE associated with GLP1RA use were particularly noticeable in people with diabetic peripheral neuropathy (subdistribution HR 0.66 vs 1.11; p for interaction 0.006).
CONCLUSIONS/INTERPRETATION
In people with diabetes, GLP1RA use was associated with significantly reduced risks of MALE compared with SGLT2i within the first 2 years after initiation, especially among people with diabetic neuropathy.
Additional Info
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Major adverse cardiovascular and limb events in people with diabetes treated with GLP-1 receptor agonists vs SGLT2 inhibitors
Diabetologia 2022 Dec 01;65(12)2032-2043, DS Lin, AL Yu, HY Lo, CW Lien, JK Lee, WJ ChenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In this article, Lin et al report the findings of a large retrospective cohort study using claims data from the Taiwan National Health Insurance Research Database, which included patients with type 2 diabetes initiating a GLP-1 receptor agonist or a SGLT2 inhibitor without a history of prior amputation.
While the CANVAS trial showed an increase in the risk of lower limb amputations among people randomized to canagliflozin compared with placebo,1 more recent meta-analyses of placebo-controlled clinical trials found neutral effects of the class of SGLT2 inhibitors on the risk of lower limb amputations.2,3 However, these trials included highly selected patient populations and were not powered to assess major adverse limb events (MALE). Accumulating evidence from observational studies, including broader and sicker patient populations, indicated a small but significant increase in MALE risk among SGLT2 inhibitor users.4,5
Similarly, the study by Lin et al found that the initiation of GLP-1 receptor agonists was associated with a 20% relative rate reduction of MALE compared with initiators of SGLT2 inhibitors. This association was stronger in patients with known diabetic peripheral neuropathy compared with patients without history of this condition, with a relative rate reduction of 34% and evidence for effect modification (P = .006). When looking at the absolute rate difference of MALE, there were 0.9 fewer events per 1000 person-years among initiators of a GLP-1 receptor agonist.
While consistent with evidence from previous observational investigations, the results from this study may need to be interpreted with some caution in light of the challenges associated with its study design, which excluded study participants on the basis of information collected during the study follow-up (eg, study participants who experienced MALE within 3 months after cohort entry were excluded). Nevertheless, this cohort study adds to the existing evidence indicating a small but statistically significant increase in the risk of adverse limb events associated with the use of SGLT2 inhibitors. Such evidence helps better contextualize the risk of adverse limb events with SGLT2 inhibitors in routine care, thus improving clinical decision-making.
References
GLP-1 receptor agonists vs SGLT2 inhibitors for major adverse limb events (MALE)
Limb amputation risk was highlighted in the CANVAS study wherein patients on canagliflozin had double the number of limb amputations. This sparked a review of the other SGLT2 inhibitors, and the results showed that, for dapagliflozin and empagliflozin there was no imbalance of amputations between the treated and the placebo groups.
On the other hand, GLP-1 receptor agonists (RA) were shown to have a beneficial effect on limb amputations in the LEADER trial. Hence, this group in Taiwan decided to look at the National Health Insurance Research Database and compare patients on GLP-1RA with patients on SGLT2 inhibitors. After propensity matching of 287,091 patients, they ended up matching 81,152 patients on SGLT2 inhibitors to 20,288 patients on GLP-1 RA. The authors then looked at the MALE outcomes, which included critical limb ischemia, angioplasty or peripheral bypass for peripheral artery disease (PAD), and amputation.
They found a 20% reduction in the MALE outcomes in favor of GLP-1 RA (HR, 0.80; 95% CI, 0.67–0.96). The number of absolute events were small, with SGLT2 inhibitors associated with 4.5 events per 1000 person-years and GLP-1RA associated with 3.5 events per 1000 person-years. The absolute difference was 0.9 per 1000 person-years.
Subgroup analysis showed a pattern emerging in which patients would do better on a GLP-1 RA. Patients who had more vascular disease and complications seemed to do better with GLP-1 RA. Therefore, patients with cardiovascular disease, retinopathy, peripheral neuropathy, and nephropathy seemed to do better with GLP-1 RA compared with SGLT2 inhibitors in terms of the MALE outcomes.
Interestingly, all-cause death was reduced by 10% in favor of the GLP-1 RA group (HR, 0.90; 95% Cl, 0.80–1.00). However, the 95% confidence interval did touch one so we cannot put too much emphasis on these results.
There are two concerns that I would like to point out about this study. The first is that they excluded 1588 participants because they had a MALE outcome within 3 months of starting the medication. It would be important to observe the data for this group because, if it is a drug effect, then we would expect to see MALE outcomes early on. Perhaps a separate analysis of that group would be very helpful. The other issue is that they did not give details about which SGLT2 inhibitors or GLP-1 RA the patients were on. This is especially important for the SGLT2 Inhibitors because, in the randomized trials, there were differences among canagliflozin, dapagliflozin, and empagliflozin in terms of amputations. It would be useful if the patients were analyzed based on which SGLT2 inhibitor they were on.
For now, let’s continue to use both these agents since they do provide cardiorenal protection. However, we should look at the vascular burden of disease for our patients, and perhaps for those with a high vascular burden and/or diabetic complications, maybe GLP-1 RA might be the better choice. But, realistically, many of our patients will need both agents.