Cardiovascular outcomes of sodium-glucose co-transporter-2 inhibitors in heart failure and coexisting chronic obstructive pulmonary disease: A meta-analysis

Abstract

BACKGROUND

Sodium-glucose co-transporter-2 inhibitors (SGLT-2Is), originally developed as anti-hyperglycemic medications, have emerged as cornerstone therapies for heart failure (HF) due to their cardioprotective effects. While their mortality benefits in HF are established, their role in patients with both HF and chronic obstructive pulmonary disease (COPD) remains unclear.

AIM

To evaluate the effects of SGLT-2Is in patients with HF with coexisting COPD, focusing on hospitalization, cardiovascular (CV) mortality, and drug-related complications.

METHODS

A systematic search of PubMed and Cochrane Library databases was conducted through February 17, 2025, for randomized controlled trials assessing the safety and efficacy of SGLT-2I in HF patients with coexistent COPD. Outcomes analyzed included composite first hospitalization for HF (HHF), CV death, all-cause mortality, and time-to-first HHF. Safety endpoints included drug discontinuation, serious adverse events (AE), volume depletion, major hypoglycemia, and renal AE, reported as relative risk (RR) with 95% confidence intervals.

RESULTS

Four trials (n = 3224) met inclusion criteria. Of these, 1727 patients (53.6%) received SGLT-2Is, while 46.4% received placebo. Compared with placebo, SGLT-2I significantly reduced the risk of composite HHF + CV death (RR = 0.80, 95%CI: 0.70-0.91, P = 0.0006, I² = 0%), HHF (RR = 0.77, 95%CI: 0.67-0.88, P < 0.0001, I² = 0%), and time-to-first HHF (RR = 0.75, 95%CI: 0.57-0.99, P = 0.04, I² = 47%). No significant differences were observed for CV death (RR = 1.01, P = 0.88) or all-cause mortality (RR = 0.94, P = 0.46). SGLT-2I did not increase risk of drug discontinuation, serious AE, renal AE, volume depletion, nor hypoglycemia.

CONCLUSION

In patients with HF and COPD, SGLT-2Is significantly reduce HF hospitalizations but do not lower all-cause mortality or CV mortality. Importantly, these drugs are well tolerated without excess AE, supporting their role as a safe therapeutic option in this population.

Key Words: Chronic obstructive pulmonary disease; Heart failure; Sodium-glucose co-transporter-2 inhibitors; Sodium-glucose co-transporter-2; Cardioprotective; Dapagliflozin; Empagliflozin

Core Tip: This meta-analysis evaluated the safety and efficacy of sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) in patients with congestive heart failure (HF) and coexisting chronic obstructive pulmonary disease, a population underrepresented in major HF trials. Across four randomized controlled trials, SGLT-2I significantly reduced HF hospitalizations and time-to-first hospitalization without increasing adverse events. However, no mortality benefit was observed. These findings support the safe use of SGLT-2Is to reduce hospitalization burden in this high-risk comorbid population.

INTRODUCTION

Sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) were originally developed to improve glycemic control in patients with type 2 diabetes mellitus. This is achieved through the drug’s ability to promote urinary excretion of glucose. Over the last several years, landmark clinical trials have consistently demonstrated that these agents have a much broader therapeutic role than initially anticipated. Having demonstrated cardiovascular (CV) and renal protective effects, SGLT-2Is are now an integral part of guideline-directed medical therapy for patients with heart failure (HF) with reduced ejection fraction. SGLT-2Is have been proposed to provide CV benefits through a few mechanisms, including increased natriuresis, improved myocardial metabolism, reduced cardiac remodeling, and attenuation of the sympathetic nervous system[1,2]. These agents have transformed the management of HF by significantly reducing the number of hospitalizations for HF (HHF) and improving overall CV outcomes independent of diabetes status.

Chronic obstructive pulmonary disease (COPD) often coexists with HF, especially in older populations with shared risk factors such as smoking and CV disease. This population presents unique diagnostic and therapeutic challenges. Patients with both diagnoses have more severe symptoms, an increased risk of hospitalization, and overall worse prognoses compared with those with HF alone. These patients are underrepresented in most HF trials, raising questions about the safety and efficacy of SGLT-2I sin the context of COPD. Our study aims to address the gap in knowledge for the use of SGLT-2Is in combined COPD-HF patients.

We performed this meta-analysis to examine the effects of SGLT-2Is in patients with both HF and COPD. Our objective is to generate greater understanding of this complex group, in which overlapping symptomatology and inflammatory pathways complicate disease management. Key clinical outcomes, including hospitalization rates, CV-related mortality, all-cause mortality, and drug-related complications, are explored in this study.

MATERIALS AND METHODS

Study design and objectives

This meta-analysis aims to systematically evaluate the impact of SGLT-2Is on clinical outcomes in patients with HF and COPD. The primary objective was to assess the efficacy and safety of SGLT-2Is in this population, focusing on key HF outcomes such as all-cause mortality, CV mortality, HF-related hospitalizations, and changes in cardiac function. Secondary objectives include evaluating adverse events (AE), including volume depletion, acute kidney injury, and major hypoglycemic events.

Search strategy and data sources

A comprehensive literature search was conducted using PubMed, Cochrane Library, and Google Scholar to identify relevant studies published up to February 2025. The search strategy included a combination of Medical Subject Headings terms and free-text keywords, such as “SGLT2 inhibitors”, “dapagliflozin”, “empagliflozin”, “canagliflozin”, “ertugliflozin”, “heart failure”, “congestive heart failure”, “COPD”, and “chronic obstructive pulmonary disease”. To ensure comprehensive data retrieval, the following additional sources were screened: (1) Clinical trial registries; (2) Grey literature; and (3) Conference abstracts from major cardiology and pulmonology societies.

Eligibility criteria and study selection

Studies were included if they evaluated the use of SGLT-2Is in patients with HF and COPD, reporting on clinical outcomes such as mortality, hospitalization, symptom improvement, or safety endpoints. Both randomized controlled trials (RCTs) and high-quality observational studies were considered. Studies that did not separately analyze outcomes for patients with HF and COPD were excluded. Other reasons for exclusion were lack of clinical-endpoint reporting or publication in a non-English language. Case reports, reviews, editorials, and non-human studies were also excluded. This is depicted in Figure 1. Two independent reviewers (Khan ZA and Sohail R) performed the study selection process, screening titles and abstracts followed by a full-text review. Any disagreements were resolved through discussion or consultation with a third reviewer (Khattak R). The included studies are listed in Table 1[3-6].

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram representing breakdown of studies screened and included in the review. PICO: Population intervention comparison outcome. ¹Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Table 1 Studies included in the review.

Ref.	Study region	Type of study	Total study population	Study group (n)	Control group (n)	Sodium-glucose co-transporter-2 inhibitor used
Haehling et al[3]	United States	RCT	1238	614	624	Empagliflozin 10 mg
Anker et al[4]	United States	RCT	707	462	245	Empagliflozin 10 mg
Butt et al[5]	United States	RCT	694	352	342	Dapagliflozin 10 mg
Dewan et al[6]	United States	RCT	585	299	286	Dapagliflozin 10 mg

RCT: Randomized controlled trial.

Data extraction and quality assessment

A standardized data extraction form was used to collect information on study characteristics (author, year, design, sample size, follow-up duration), patient demographics (age, sex, HF phenotype, COPD severity), intervention details (SGLT-2I type, dosage, duration), and reported outcomes (primary and secondary endpoints, AE). The risk of bias for RCTs was assessed using the Cochrane Risk of Bias tool and the RevMan assessment tool (Figure 2)[3-6].

Figure 2  Risk of bias.

Statistical analysis

Meta-analysis was performed using a random-effects model to account for potential heterogeneity across studies. The pooled effect estimate was reported as relative risk (RR) with corresponding 95% confidence interval (CI). Heterogeneity was assessed using the I² statistic, with values above 50% indicating substantial heterogeneity. Publication bias could not be assessed visually in a funnel plot due to the limited number of studies. Similarly, meta-regression or subgroup analyses could not be performed due to the limited number of studies. P < 0.05 was considered statistically significant.

Ethical considerations and registration

As this study involves a systematic review and meta-analysis of published data, ethical approval was not required. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and methodological rigor. The study protocol was registered in the PROSPERO database to enhance reproducibility and avoid duplication of effort.

RESULTS

A total of four RCTs were included in the analysis, encompassing 3224 patients diagnosed with both HF and COPD[3-6]. Among these participants, 1727 (53.6%) received an SGLT-2I, while 1497 (46.4%) received placebo designation.

Primary outcomes

The use of SGLT-2Is was associated with a significant reduction in the composite risk of HHF and CV death compared with placebo (RR = 0.80, 95%CI: 0.70-0.91, P = 0.0006, I² = 0%) (Figure 3A and B)[3-6]. Specifically, SGLT-2Is significantly reduced the risk of HHF (RR = 0.77, 95%CI: 0.67-0.88, P < 0.0001, I² = 0%) and improved time-to-first HHF (RR = 0.75, 95%CI: 0.57-0.99, P = 0.04, I² = 47%) (Figure 3C)[5,6]. However, there was no significant difference between the treatment and placebo groups in terms of CV death (RR = 1.01, 95%CI: 0.84-1.23, P = 0.88, I² = 0%) or all-cause mortality (RR = 0.94, 95%CI: 0.81-1.10, P = 0.46, I² = 0%) (Figure 4A and B)[3-6].

Figure 3 Forest plot comparison of risk of hospitalization for heart failure, composite risk of hospitalization for heart failure cardiovascular death, and time-to-first hospitalization for heart failure. A: Forest plot comparison of risk of hospitalization for heart failure (HHF); B: Forest plot comparison of composite risk of HHF and cardiovascular death; C: Forest plot comparison of time-to-first HHF. SGLT-2: Sodium-glucose co-transporter-2.

Figure 4 Forest plot comparison of cardiovascular death, all-cause mortality, adverse events, and drug discontinuation. A: Forest plot comparison of cardiovascular death; B: Forest plot comparison of all-cause mortality; C: Forest plot comparison of adverse events; D: Forest plot comparison of drug discontinuation. SGLT-2: Sodium-glucose co-transporter-2.

Secondary outcomes

Beyond primary outcomes, the included studies also examined additional clinical parameters. The Dapagliflozin and Prevention of Adverse Outcomes in HF (DAPA-HF) analysis by Dewan et al[6] reported that dapagliflozin significantly improved patient-reported quality of life scores in individuals with COPD and HF, suggesting that SGLT-2Is may provide symptomatic relief beyond reducing hospitalizations[7]. Additionally, improvements in functional capacity, as measured by the Kansas City Cardiomyopathy Questionnaire, were observed in patients receiving dapagliflozin, further supporting the role of SGLT-2Is in improving health status.

Safety outcomes

Our analysis did not identify a significant increase in AE associated with SGLT-2I use. The rate of serious AEs was similar between the two groups (RR = 0.92, 95%CI: 0.80-1.05, P = 0.22, I² = 0%), as were drug discontinuation rates (RR = 1.07, 95%CI: 0.72-1.59, P = 0.73, I² = 52%) (Figure 4C and D)[4-6]. Additionally, there were no significant differences in the incidence of volume depletion (RR = 0.95, 95%CI: 0.67-1.36, P = 0.79, I² = 0%), renal AE (RR = 0.79, 95%CI: 0.57-1.09, P = 0.15, I² = 8%), or major hypoglycemic events (RR = 0.91, 95%CI: 0.73-1.13, P = 0.37, I² = 0%) (Figure 5)[4-6].

Figure 5 Forest plot comparison of volume depletion, renal adverse events, and major hypoglycemia events. A: Forest plot comparison of volume depletion; B: Forest plot comparison of renal adverse events; C: Forest plot comparison of major hypoglycemia events. SGLT-2: Sodium-glucose co-transporter-2.

DISCUSSION

SGLT-2Is have become s a cornerstone therapy for HF with reduced ejection fraction. The purpose of this meta-analysis was to further elucidate the benefit of SGLT-2Is in patients simultaneously suffering from COPD. This study specifically evaluated the efficacy and safety of SGLT-2Is in patients with HF and coexisting COPD, a clinically important but underrepresented subgroup in major HF trials. While prior landmark studies such as EMPEROR-Reduced and DAPA-HF established the benefits of SGLT-2I in broad HF populations, they were not designed to specifically assess outcomes in patients with concomitant COPD[1,2]. The novel contribution of our study lies in the focused analysis of randomized data exclusively in a patient population with both diagnoses. By isolating patients with both HF and COPD, we provide more nuanced evidence that the reduction in HF hospitalizations observed in general HF cohorts is consistent in this higher-risk subgroup, without an increase in AEs. This is clinically relevant, as tolerability and competing risks often complicate therapeutic decisions in such patients[8]. This analysis provides compelling evidence that SGLT-2Is hold significant benefit in reducing the composite risk of HHF and CV death, as well as HHF and time-to-first HHF, in patients with HF and COPD.

The observed reduction in HHF and prolonged time-to-first HHF with SGLT-2Is aligns with the established benefits of these agents in improving hemodynamics and reducing cardiac remodeling, as seen in prior studies of more generalized populations, such as the EMPEROR-Reduced and DAPA-HF trials[1,2]. Furthermore, our results revealed a 20% reduction in the composite risk of HHF and CV death in this population, driven primarily by reductions in HHF rather than CV death alone. A potential mechanism is that the natriuretic and osmotic diuretic effects of SGLT-2Is reduce preload and ventricular filling pressures without significantly activating the renin-angiotensin-aldosterone system, which may particularly beneficial in patients with COPD who already exhibit heightened sympathetic tone. This aligns with prior evidence suggesting that the primary mechanism by which SGLT-2Is benefit HF patients is through enhanced natriuresis, volume re-distribution, and improved hemodynamics[1,2,9]. In doing so, lower filling pressures exist with decreased afterload, improved ventricular-arterial coupling, and downregulation of the renin-angiotensin-aldosterone system.

Further supporting these findings, Chen et al[10] highlighted that COPD patients possess a significantly increased risk of CV events, including HF exacerbations, which may explain why SGLT-2Is yield substantial benefits in this population. Similarly, de Miguel Díez et al[11] emphasized the bidirectional relationship between COPD and HF, suggesting that the inflammatory and hemodynamic interplay between the two conditions contributes to worse CV outcomes. COPD itself has been associated with increased systemic inflammation, heightened sympathetic activation, and greater CV risk[11]. Specifically, COPD can lead to cytokine-mediated endothelial dysfunction and vasoconstriction while simultaneously causing hypoxia-induced sympathetic nervous system activation. This combination can accelerate the development of ischemic heart disease, arrhythmia and cardiac remodeling over time. The ability of SGLT-2Is to reduce HF-related hospitalizations despite this heightened risk underscores their clinical utility in COPD patients. It may provide further support for the hypothesis proposed in the literature that SGLT-2Is improve outcomes in this population, in part through their ability to reduce sympathetic overactivity, systemic inflammation, and oxidative stress[12,13].

While these findings suggest that the benefits highlighted in previous trials apply to patients with COPD, the mortality advantage seen in the broader HF population may not translate to those with coexistent COPD. In fact, the lack of a significant reduction in all-cause mortality or CV death in this meta-analysis is intriguing. The absence of a significant effect on CV death raises the possibility that non-CV comorbidities may contribute disproportionately to mortality in this population, particularly respiratory complications inherent to COPD. Certainly, pulmonary disease may lead to impaired oxygen exchange and cumulative elevation of pulmonary vascular resistance. Escalating pulmonary vascular resistance can lead to increased right ventricular afterload and propagation of venous congestion. Alternatively, exacerbations of COPD may impede the optimal management of HF at both a patient and physician level. Overlapping clinical features, such as exertional shortness of breath, may lead patients to intentionally skip diuretic therapy, inadvertently increasing the risk of HF decompensation. Concerns about beta-blocker-induced bronchospasm may lead to hesitancy in initiating or escalating guideline-directed medical therapy, thereby hindering optimal HF management.

The safety profile of SGLT-2Is in HF patients with COPD is also encouraging. No significant increases in drug discontinuation, serious AE, or specific concerns such as volume depletion, renal AE, or major hypoglycemic events were observed in this study. This is particularly relevant in addressing clinician concerns regarding volume depletion and renal dysfunction in patients with HF and COPD, as these individuals often receive diuretics and other renally active agents in acute care settings[14,15]. These findings reinforce the tolerability of SGLT-2Is, even in a population with a high burden of comorbidities.

Several limitations of this meta-analysis merit discussion. First, the included trials were not primarily designed to evaluate SGLT-2Is in HF patients with COPD, potentially introducing selection bias. Second, the sample size remains relatively modest, necessitating cautious interpretation of subgroup findings. A larger sample size may have led to greater statistical power to detect mortality benefits, though this is an inherent limitation given the specificity of our population. Third, heterogeneity in COPD severity and treatment strategies across studies was not fully accounted for, which may influence outcomes. Future studies with dedicated cohorts of HF-COPD patients that incorporate a more granular assessment of pulmonary function and inflammatory biomarkers are warranted to elucidate the full therapeutic potential of SGLT-2Is in this high-risk population.

The findings of this meta-analysis prompt ongoing consideration in future studies with dedicated attention to patients living with both HF and COPD. Alternate studies could aim to explore the long-term effects of SGLT-2Is on mortality and quality of life. The impact of distinct SGLT-2I agents and varying doses also merit further investigation.

CONCLUSION

It is well known that SGLT-2Is have become a cornerstone of treatment for those with HF. This study aimed to assess whether they are effective in those with HF and concurrent COPD by reducing hospitalization, CV mortality, and drug-related complications. Four trials were included in our analysis, for a total of 3224 participants. Among individuals with HF and COPD, SGLT-2Is significantly reduced the composite risk of HHF and CV. Furthermore, these drugs demonstrated significant benefit over placebo in reducing HHF and improving time-to-first HHF. However, they did not show added benefit in reducing CV death and all-cause death. Additionally, SGLT-2Is did not cause an increase in drug-related AE, renal AE, drug discontinuation, volume depletion, or major hypoglycemia. This provides evidence supporting the use of SGLT-2Is in patients with HF and COPD for reducing HHF and prolonging time-to-first HHF. While the lack of significant mortality benefit warrants further investigation, the favorable safety profile and potential for improving overall HF outcomes make SGLT-2Is a promising therapeutic option for this complex patient population.