How SGLT2 inhibitors and GLP-1 receptor agonists relate to death rates in diabetic patients with heart disease

What is currently known about this topic?

Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to reduce cardiovascular risk and mortality in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease, yet remain underutilized in clinical practice.

What is the key research question?

What are the real-world treatment patterns and associated mortality outcomes among patients with T2D and established atherosclerotic cardiovascular disease (ASCVD)?

What is new?

How might this study influence clinical practice?

Patients with type 2 diabetes mellitus (T2D) and established atherosclerotic cardiovascular disease (ASCVD) face a substantially elevated risk of major adverse cardiovascular events and premature mortality [1–3]. In recent years, two classes of glucose-lowering medications,sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide-1 receptor agonists (GLP-1RA),have emerged as cornerstone therapies due to their robust cardiovascular and renal protective effects. Large randomized clinical trials have consistently demonstrated that these agents not only improve glycemic control but also significantly reduce rates of cardiovascular death, heart failure hospitalization, and progression of chronic kidney disease [4–6]. Reflecting this evidence, major international guidelines, now provide class I recommendations for the use of SGLT2-I and GLP-1RA in patients with T2D and high cardiovascular risk,regardless of baseline glycemic control or HbA1c levels [7, 8]. Despite these strong recommendations, real-world studies indicate that SGLT2-I and GLP-1RA remain markedly underutilized in routine practice [9–11]. This therapeutic gap is concerning, as observational data suggest that failure to initiate these agents is associated with increased morbidity and mortality [12]. The factors contributing to this underutilization are multifactorial and may include demographic disparities, clinical complexity, healthcare access, provider awareness, and socioeconomic barriers.

The present study aimed to evaluate treatment patterns of SGLT2-I and GLP-1RA in a large cohort of patients with T2D and concomitant ASCVD identify predictors of their underuse, and examine the association between these therapies and all-cause mortality in real-world clinical practice.

The CARDIAB cohort comprised 138,397 patients with T2D and concomitant ASCVD, with a median follow-up of 65 (30.1, 72.5) months. Overall, the use of guideline-recommended therapies was suboptimal: 78,611 patients (57%) were not treated with either a GLP-1RA or a SGLT2-I. In contrast, 23,897 patients (17%) received both medications, 8,507 (6%) were treated with GLP-1RA only, and 27,382 (20%) received SGLT2-I only. Baseline demographic and clinical characteristics stratified by treatment group are summarized in Table 1. Characteristics associated with lower rates of GLP-1RA or SGLT2-I use included older age, female sex, chronic kidney disease (CKD), and non-cardiac vascular diseases such as cerebrovascular accident/transient ischemic attack (CVA/TIA) and peripheral vascular disease (PVD). As anticipated, GLP-1RA use was more prevalent among patients with obesity. In contrast, follow-up in cardiology and diabetes specialty clinics was positively associated with the likelihood of receiving either or both medication classes (Table 2).

Treatment with SGLT2-I and GLP-1RA was significantly associated with improved survival (Fig. 1), with the highest survival rates observed in patients treated with both medication classes. The all-cause mortality rates per 10,000 patient-years were 172 for those treated with both medications, 346 for SGLT2-I only, 451 for GLP-1RA only, and 1506 for those not treated with either (p < 0.001) (Fig. 2). These associations remained significant following a multivariate analysis (Table 3). Using the group not treated with either medication as the reference, the hazard ratios (HR) for all-cause mortality were: HR = 0.28 (95% CI 0.26–0.28) for SGLT2-I only, HR = 0.38 (95% CI 0.36–0.4) for GLP-1RA only and HR = 0.17 (95% CI 0.16–0.17) for both medications. Combination therapy with both SGLT2-I and GLP-1RA was associated with significantly lower all-cause mortality compared to monotherapy with SGLT2-I (HR = 0.61, 95% CI 0.58–0.64) or GLP-1RA (HR = 0.44, 95% CI 0.35–0.47).

The CARDIAB study aimed to evaluate real-world treatment patterns and outcomes among patients with diabetes and concomitant cardiovascular disease. In this large, nationwide cohort of 138,397 patients, we found that despite strong clinical guideline recommendations, the use of SGLT2-I and GLP-1RA remains low. Factors independently associated with lower prescription rates included older age, female sex, CKD, and the presence of non-coronary cardiovascular disease. In contrast, referral to specialized cardiology or diabetes clinics was linked to higher treatment rates. Lack of treatment with SGLT2i or GLP-1RA was associated with the highest risk of all-cause mortality.

The cardiovascular benefits of treatment with either SGLT2-I or GLP-1RA in high-risk patients with type 2 diabetes (T2D) have been well established in multiple randomized controlled trials [13–16]. However, evidence supporting the combined use of both drug classes is primarily derived from retrospective studies [12, 17–19]. A large retrospective cohort analysis involving patients with T2D receiving insulin, across 85 healthcare organizations, evaluated the effect of SGLT2-I, GLP-1RA, and combination therapy on clinical outcomes [12]. Compared to a propensity-matched control group, each treatment approach was associated with reduced all-cause mortality and improved cardiovascular outcomes, with the greatest benefit observed in the combination therapy group. Another large retrospective study, analysing data from over 400,000 U.S. adults with T2D, found that combination therapy with SGLT2-I and GLP-1RA resulted in significantly better cardiometabolic outcomes, and reduced risk of stroke and myocardial infarction, compared with SGLT2-I alone [17]. In a smaller propensity score–matched study of patients with T2D and established coronary artery disease, 208 matched pairs were compared between those treated with SGLT2-I alone versus combination therapy with GLP-1RA [18]. The combined use of both agents was associated with a significantly reduced risk of cardiovascular mortality and stroke. Additionally, a prospective study of 443 patients post–acute myocardial infarction evaluated outcomes of treatment with either SGLT2-I, GLP-1RA, or both [19]. Patients in good glycemic control maintained the same glucose-lowering regimen while those with HbA1C > 7% were prescribed either SGLT-2I or GLP-1RA to obtain a combination therapy. The incidence of major adverse cardiovascular events (MACE) was significantly lower in the combination group compared to those receiving monotherapy. The current study adds to the growing body of evidence by providing a comprehensive, real-world assessment of treatment patterns and outcomes among high-risk patients with T2D and established cardiovascular disease. First, it includes a large, unselected cohort representative of routine clinical practice. Second, it evaluates treatment rates and predictors of underuse of SGLT2-I and GLP-1RA. Finally, it demonstrates a significant survival benefit associated with both drug classes.

Our findings carry several important clinical implications. First, the marked underutilization of both SGLT2 inhibitors and GLP-1 receptor agonists, despite their well-documented benefits, and the associated reduction in survival underscore the urgent need for healthcare systems and policymakers to implement strategies that promote broader use of these therapies. Targeted efforts should be directed toward populations with the lowest treatment rates, including women and older adults. Second, we observed significantly higher prescription rates of SGLT2-I and GLP-1RA among patients followed in cardiology or diabetes specialty clinics. This highlights the pivotal role of specialized care in optimizing the management of high-risk patients with T2D and suggests that expanding access to such clinics may improve adherence to evidence-based therapies. Finally, our results add to the growing body of evidence supporting the superiority of combination therapy with SGLT2-I and GLP-1RA over either monotherapy.

This study has several limitations that warrant consideration. First, as a retrospective observational analysis, the cohort is subject to healthy subject treatment bias. Patients who were prescribed SGLT2-I or GLP-1RA may represent a subgroup that is generally healthier, more health-conscious, or more engaged with the healthcare system. These individuals may possess other favorable characteristics, beyond the use of SGLT2-I or GLP-1RA, that could independently contribute to improved outcomes. Although we adjusted for a wide range of baseline clinical and demographic characteristics, the possibility of residual confounding by unmeasured factors, such as lifestyle, frailty, or socioeconomic status, remains. Second, the database lacked information on specific causes of death, limiting the analysis to all-cause mortality as the primary endpoint. Third, Treatment with GLP-1RA or SGLT2-I was defined as at least three dispensations of the medication. Unfortunately, our database did not include information regarding treatment duration, distribution of time from index date to treatment initiation, the percentage of covered time or whether both medications were taken concurrently in patients receiving combination therapy. Fourth, Although initial clinical evidence supporting the cardiovascular benefits of SGLT2-I and GLP-1 RA in high-risk diabetic patients emerged in 2015, several additional large-scale trials were published in the following years. These accumulating data led to progressive updates and strengthening of international clinical guideline recommendations for the use of SGLT2-I and GLP-1 RA therapies throughout the study period. Finally, while the CARDIAB cohort represents a large, national real-world population, the generalizability of these findings to other healthcare systems or countries should be approached with caution.

In conclusion, among patients with T2D and concomitant cardiovascular disease, treatment with SGLT2-I and GLP-1 RA is associated with a significant survival benefit, with the greatest effect observed in those receiving combination therapy. Despite this, real-world treatment rates with these medications remain suboptimal, highlighting a critical gap in the implementation of evidence-based care.

Not applicable.

Conceptualization, Z.A. and D.P.; methodology, D.P.; software, R.H. and T.H.-L.; validation, E.G.; formal analysis, Z.A.; investigation, D.P. and Z.A.; resources, Y.A.; data curation, H.V.-A. AND Y.A.; writing—original draft preparation, Z.A.; writing—review and editing, D.P. and A.A.; visualization, D.P. AND H.V.-A.; supervision, A.A. and D.P.; project administration, Z.A. and D.P. All authors read and approved the final manuscript.

This study did not receive any external funding.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.