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Empagliflozin in patients with type 2 diabetes mellitus and chronic obstructive pulmonary disease

Open AccessPublished:March 18, 2022DOI:https://doi.org/10.1016/j.diabres.2022.109837

      Highlights

      • This research demonstrates that patients with concomitant T2DM and COPD are at high CV risk.
      • Empagliflozin improves cardiac as well as kidney outcomes in this group of patients.
      • These new data may help clinicians in their management of these more complex patients with T2DM.

      Abstract

      Aims

      Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial.

      Methods

      Patients (n = 7,020) with T2DM and CV disease (CVD) were treated with empagliflozin (10 mg or 25 mg) or placebo. Cox regression was used to assess COPD subgroup (placebo only) associations with, and treatment effects of empagliflozin versus placebo on first hospitalization for HF (HHF), CV death, all-cause mortality, incident/worsening nephropathy, and all-cause hospitalization.

      Results

      At baseline, patients with COPD (n = 707) had more HF and used insulin more frequently than those without COPD. During follow-up in the placebo group, those with baseline COPD had increased risk of HHF (HR 2.15 [95% CI 1.32, 3.49]), HHF/CV death (1.60 [1.10, 2.33]), incident/worsening nephropathy (1.68 [1.26, 2.24]), all-cause hospitalization (1.44 [1.19, 1.74]) and all-cause death (1.60 [1.09, 2.35]) compared to those without COPD. Empagliflozin consistently reduced all clinical outcomes, irrespective of COPD status (interaction p-values 0.14 to 0.96), with a confirmed safety profile.

      Conclusions

      In patients with T2DM and CVD, COPD increased the risk of mortality and cardiorenal outcomes, including HF. Empagliflozin consistently reduced these outcomes versus placebo regardless of COPD, suggesting that empagliflozin’s benefits in patients with T2DM and CVD are not mitigated by the presence of COPD.

      Keywords

      1. Introduction

      Co-existence of diabetes mellitus and chronic obstructive pulmonary disease (COPD) is common and carries a worse prognosis than when either disease is present alone [
      • Mannino D.M.
      • Thorn D.
      • Swensen A.
      • Holguin F.
      Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD.
      ,

      Ho T-W, Huang C-T, Ruan S-Y, Tsai Y-J, Lai F, Yu C-J. Diabetes mellitus in patients with chronic obstructive pulmonary disease–The impact on mortality. PLoS One 2017;12:e0175794.

      ,
      • Ehrlich S.F.
      • Quesenberry Jr, C.P.
      • Van Den Eeden S.K.
      • Shan J.
      • Ferrara A.
      Patients diagnosed with diabetes are at increased risk for asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and pneumonia but not lung cancer.
      ]. Furthermore, there is a substantial overlap between COPD and cardiovascular disease (CVD), in particular heart failure (HF), which may pose diagnostic and therapeutic challenges, such as comedication interactions and intolerance, and could also have relevance for treatment efficacy, ultimately impacting prognosis [
      • Hawkins N.M.
      • Petrie M.C.
      • Jhund P.S.
      • Chalmers G.W.
      • Dunn F.G.
      • McMurray J.J.V.
      Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology.
      ]. Thus, managing comorbid conditions is important and recognized as an essential part of a holistic approach to managing patients with COPD [
      • Putcha N.
      • Drummond M.
      • Wise R.
      • Hansel N.
      Comorbidities and chronic obstructive pulmonary disease: prevalence, influence on outcomes, and management.
      ,
      • Recio Iglesias J.
      • Díez-Manglano J.
      • López García F.
      • Díaz Peromingo J.A.
      • Almagro P.
      • Varela Aguilar J.M.
      Management of the COPD patient with comorbidities: an experts recommendation document.
      ].
      Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that inhibits the reabsorption of urinary glucose and sodium in the renal proximal tubule, thereby inducing glucosuria and a transient natriuresis with improved glycemic control in type 2 diabetes mellitus (T2DM). There are numerous potential mechanisms by which SGLT2 inhibitors could benefit patients with COPD including enhanced osmotic diuresis, an increase in haematocrit and beneficial effects on cardiac structure. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of hospitalization for HF (HHF), cardiovascular (CV) death, all-cause mortality, and incident or worsening nephropathy in patients with T2DM and CVD [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ]. Recently the HF and kidney benefits of SGLT2 inhibitors have been extended to individuals without diabetes who have chronic kidney disease and HF with reduced or preserved ejection fraction [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Køber L.
      • Kosiborod M.N.
      • Martinez F.A.
      • et al.
      DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • et al.
      EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.-F.
      • et al.
      DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease.
      ,
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Böhm M.
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      ]. The mechanism of action of SGLT2 inhibitors on CV outcomes remains uncertain, however, and since COPD can both masquerade as and worsen underlying HF, it would be important for clinicians to know whether the benefits of empagliflozin might be mitigated in a COPD population. However, little is known about the use and effects of SGLT2 inhibitors in patients with concomitant T2DM and COPD. We therefore aimed to assess the risk of outcomes in patients with T2DM and COPD included in the EMPA-REG OUTCOME trial, and how empagliflozin impacts on metabolic and cardiorenal outcomes and mortality in this population; we also aimed to evaluate safety of empagliflozin in this group.

      2. Materials and methods

      2.1 Study population and design

      The study design of EMPA-REG OUTCOME (ClinicalTrials.gov number, NCT01131676) is described in detail elsewhere [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Zinman B.
      • Inzucchi S.E.
      • Lachin J.M.
      • Wanner C.
      • Ferrari R.
      • Fitchett D.
      • et al.
      Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME).
      ]. The primary endpoint was 3-point major adverse CV event (3P-MACE), and the trial was designed to continue until at least 691 patients had experienced such an event. In the current analyses we also analyzed the time to first event of the following endpoints: HHF, CV death, the composite of CV death (excluding fatal stroke) or HHF, all-cause mortality, all-cause hospitalization, and incident or worsening nephropathy (defined as the composite of macroalbuminuria > 300 mg/g, doubling of serum creatinine with estimated glomerular filtration rate [eGFR] < 45 ml/min/1.73 m2, need for dialysis or renal transplant, or renal death). In addition, we assessed the risk of total (first and recurrent) all-cause hospitalizations. All CV events were prospectively adjudicated by an independent committee. Moreover, we analyzed the change in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure (SBP) over time as well as adverse events (AEs) as reported by the investigators.
      The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

      2.2 Definition of COPD

      For these post-hoc analyses, patients were considered to have COPD at baseline if the investigator reported them as having a baseline condition coded to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms ‘chronic obstructive pulmonary disease’ or ‘emphysema’, or reported them as using medications for obstructive airways disease (defined as medications belonging to the World Health Organization Anatomical Therapeutic Chemical class R03 with the exception of clenbuterol and cromoglicate sodium).
      As this was a sensitivity analysis, we also performed the analysis with a narrower COPD definition including only patients with a reported diagnosis of COPD or emphysema (MedDRA preferred terms) at baseline, irrespective of the use of medications for obstructive airways disease.
      We reported the use of inhalation medications for obstructive airways disease at baseline grouped by inhaled bronchodilators not containing inhaled corticosteroids (ICS), and ICS alone or in combination.

      2.3 Statistical analysis

      Baseline characteristics are provided by baseline COPD versus no COPD, with continuous variables presented as mean ± standard deviation, and categorical variables as number (n) and proportion (%). Effects on metabolic outcomes (HbA1c, weight, SBP) were evaluated using a mixed model, repeated-measure analysis [

      Verbeke G, Molenberghs G. Linear mixed models for longitudinal data. New York: Springer; 2000.

      ].
      We assessed the risk of first 3P-MACE, CV death, HHF, the composite of CV death or HHF, incident or worsening nephropathy, all-cause mortality, and all-cause hospitalization in those with and without COPD using multivariable Cox regression models [

      Cox DR. Regression models and life tables. J R Stat Soc Series B Stat Methodol 1972;34:187–220.

      ]. We evaluated the treatment effects (pooled empagliflozin doses vs. placebo) on these endpoints in those with and without COPD using Cox regression models and also including the interaction of presence of COPD at baseline by treatment, to evaluate the treatment effect in patients with and without COPD at baseline separately. In addition, we analyzed the number of total all-cause hospitalizations using a multivariable negative binomial model, with 95% confidence intervals (CIs) based on robust error variance estimators [

      Long JS. Regression models for categorical and limited dependent variables. Thousand Oaks, CA: Sage publications; 1997.

      ]. All analyses were post hoc and not adjusted for multiplicity. All statistical analyses were performed using SAS software, version 9.4.
      Additional methods are provided in the online supplementary material.

      3. Results

      In total, 707 (245 in the placebo group; 462 in the empagliflozin group) participants had COPD at baseline. Baseline characteristics, including use of medications at baseline, are given in Table 1. As compared to those without COPD, patients with COPD were slightly older, more often white, current or ex-smokers, and had higher body mass index and waist circumference. They had more comorbidities such as coronary artery disease (84% vs. 75%), HF (17% vs. 9%), and eGFR < 60 ml/min/1.73 m2 (35% vs. 25%); they were also more frequently using loop diuretics (57% vs. 42%), lipid lowering agents (87% vs. 80%), and insulin (56% vs. 47%), but somewhat less metformin (68% vs. 75%) and SU (37% vs. 43%). Seventy-two percent of those with COPD used any medication for obstructive airways disease, 42% used a non-ICS-containing inhaled bronchodilator, and 47% used an ICS-containing inhalation device. Baseline characteristics were balanced across treatment groups within the COPD subgroup.
      Table 1Baseline characteristics in patients with versus without COPD at baseline.
      No COPDCOPD
      Placebo n = 2088EMPA



      n = 4225
      Total



      n = 6313
      Placebo n = 245EMPA n = 462Total



      n = 707
      Female sex588 (28.2)1222 (28.9)1810 (28.7)65 (26.5)129 (27.9)194 (27.4)
      Age, years63.0

      ± 8.8
      62.9



      ± 8.6
      62.9



      ± 8.7
      65.4



      ± 8.7
      65.0



      ± 8.1
      65.1



      ± 8.3
      Race
      White1479 (70.8)3018 (71.4)4497 (71.2)199 (81.2)385 (83.3)584 (82.6)
      Black/African-American105 (5.0)210 (5.0)315 (5.0)15



      (6.1)
      27



      (5.8)
      42



      (5.9)
      Asian484 (23.2)959 (22.7)1443 (22.9)27 (11.0)47 (10.2)74 (10.5)
      Native Hawaian/



      Pacific Islands
      3



      (0.1)
      5



      (0.1)
      8



      (0.1)
      1



      (0.4)
      1



      (0.2)
      2



      (0.3)
      American Indian/Alaska17



      (0.8)
      32



      (0.8)
      49



      (0.8)
      3



      (1.2)
      2



      (0.4)
      5



      (0.7)
      Missing01



      (<0.1)
      1



      (<0.1)
      000
      BMI, kg/m230.41



      ± 5.16
      30.41



      ± 5.23
      30.41



      ± 5.21
      32.74



      ± 5.47
      32.40



      ± 5.29
      32.52



      ± 5.35
      HbA1c, % (mmol/mol)8.1

      ± 0.9

      (65 ± 9)
      8.1

      ± 0.9

      (65 ± 9)
      8.1

      ± 0.9

      (65 ± 9)
      7.9

      ± 0.8

      (63 ± 8)
      8.1

      ± 0.8

      (65 ± 9)
      8.0

      ± 0.8

      (64 ± 9)
      Waist, cm104.2



      ± 13.8
      104.1



      ± 13.6
      104.2



      ± 13.6
      111.2



      ± 13.8
      110.3



      ± 13.6
      110.6



      ± 13.7
      SBP, mmHg135.7



      ± 17.3
      135.3



      ± 16.8
      135.4



      ± 17.0
      136.2



      ± 16.5
      134.8



      ± 18.3
      135.3



      ± 17.7
      DBP, mmHg77.0



      ± 10.2
      76.8



      ± 9.6
      76.8



      ± 9.8
      75.3



      ± 9.5
      75.3



      ± 10.3
      75.3



      ± 10.1
      Cholesterol, mg/dL162.5



      ± 43.5
      163.9



      ± 44.3
      163.4



      ± 44.1
      156.6



      ± 38.7
      159.5



      ± 42.7
      158.5



      ± 41.4
      HDL-C, mg/dL44.3



      ± 11.3
      44.7



      ± 11.8
      44.5



      ± 11.6
      42.2



      ± 11.1
      43.6



      ± 12.5
      43.1



      ± 12.0
      LDL-C, mg/dL85.3



      ± 35.7
      86.4



      ± 36.2
      86.0



      ± 36.0
      80.7



      ± 31.3
      81.7



      ± 33.4
      81.3



      ± 32.7
      Triglycerides, mg/dL170.1



      ± 123.7
      169.5



      ± 125.1
      169.7



      ± 124.6
      175.3



      ± 98.0
      179.3



      ± 165.8
      177.9



      ± 145.7
      Smoking status
      Never897 (43.0)1821 (43.1)2718 (43.1)60 (24.5)104 (22.5)164 (23.2)
      Ex938 (44.9)1874 (44.4)2812 (44.5)136 (55.5)261 (56.5)397 (56.2)
      Currently253 (12.1)530 (12.5)783 (12.4)49 (20.0)97 (21.0)146 (20.7)
      Time since T2DM diagnosis, years
      ≤149



      (2.3)
      122 (2.9)171 (2.7)3



      (1.2)
      6



      (1.3)
      9



      (1.3)
      >1 to 5339 (16.2)653 (15.5)992 (15.7)32 (13.1)59 (12.8)91 (12.9)
      >5 to 10511 (24.5)1039 (24.6)1550 (24.6)60 (24.5)136 (29.4)196 (27.7)
      >101189 (56.9)2411 (57.1)3600 (57.0)150 (61.2)261 (56.5)411 (58.1)
      eGFR, ml/min/1.73 m274.33



      ±20.95
      74.65



      ±21.59
      74.55



      ±21.38
      69.35



      ±21.38
      69.70



      ±21.01
      69.57



      ±21.13
      ≥90452 (21.6)980 (23.2)1432 (22.7)36 (14.7)70 (15.2)106 (15.0)
      60 to < 901116 (53.4)2192 (51.9)3308 (52.4)122 (49.8)231 (50.0)353 (49.9)
      <60520 (24.9)1051 (24.9)1571 (24.9)87 (35.5)161 (34.8)248 (35.1)
      Missing02



      (<0.1)
      2



      (<0.1)
      000
      History of stroke511 (24.5)991 (23.5)1502 (23.8)42 (17.1)93 (20.1)135 (19.1)
      History of CAD1563 (74.9)3155 (74.7)4718 (74.7)200 (81.6)390 (84.4)590 (83.5)
      History of MI976 (46.7)1959 (46.4)2935 (46.5)107 (43.7)231 (50.0)338 (47.8)
      History of PAD414 (19.8)856 (20.3)1270 (20.1)65 (26.5)126 (27.3)191 (27.0)
      History of retinopathy476 (22.8)932 (22.1)1408 (22.3)47 (19.2)91 (19.7)138 (19.5)
      History of heart failure
      Defined by the narrow standardized MedDRA query (SMQ) ‘cardiac failure’; §Without ICS; ¶Belonging to ATC class H02AB; #By definition of subgroup. Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, aspirin; ATC, Anatomical Therapeutic Chemical; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; HbA1c, glycated hemoglobin; HDL-C, high density lipoprotein-cholesterol; ICS, inhaled corticosteroids; LDL-C, low density lipoprotein-cholesterol; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; PAD, peripheral artery disease; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; UACR, urine albumin-to-creatinine-ratio; SU, sulfonyl urea.
      198 (9.5)386 (9.1)584 (9.3)46 (18.8)76 (16.5)122 (17.3)
      UACR normal < 301242 (59.5)2525 (59.8)3767 (59.7)140 (57.1)264 (57.1)404 (57.1)
      Micro 30 to 300600 (28.7)1204 (28.5)1804 (28.6)75 (30.6)134 (29.0)209 (29.6)
      Macro > 300232 (11.1)452 (10.7)684 (10.8)28 (11.4)57 (12.3)85 (12.0)
      Missing14



      (0.7)
      45



      (1.1)
      58



      (0.9)
      2



      (0.8)
      7



      (1.5)
      9



      (1.3)
      Cardiovascular medications
      Beta blocker1338 (64.1)2763 (65.4)4101 (65.0)160 (65.3)293 (63.4)453 (64.1)
      Diuretics846 (40.5)1786 (42.3)2632 (41.7)142 (58.0)261 (56.5)403 (57.0)
      Loop diuretics281 (13.5)578



      (13.7)
      859 (13.6)83



      (33.9)
      147 (31.8)230 (32.5)
      ACEi/ARBs1669 (79.9)3417 (80.9)5086 (80.6)199 (81.2)381 (82.5)580 (82.0)
      Lipid lowering1650 (79.0)3418 (80.9)5068 (80.3)214 (87.3)402 (87.0)616 (87.1)
      Statin1567 (75.0)3248 (76.9)4815 (76.3)206 (84.1)382 (82.7)588 (83.2)
      ASA1725 (82.6)3500 (82.8)5225 (82.8)202 (82.4)376 (81.4)578 (81.8)
      Metformin1559 (74.7)3150 (74.6)4709 (74.6)175 (71.4)309 (66.9)484 (68.4)
      SU901 (43.2)1840 (43.6)2741 (43.4)91 (37.1)174 (37.7)265 (37.4)
      Insulin1003 (48.0)1985 (47.0)2988 (47.3)132 (53.9)267 (57.8)399 (56.4)
      Medications for obstructive airways disease
      Any medication for obstructive airways disease0#0#0#183 (74.7)327 (70.8)510 (72.1)
      Inhaled bronchodilators§0#0#0#112 (45.7)183 (39.6)295 (41.7)
      Inhaled corticosteroids (in combination or as monosubstance)0#0#0#114 (46.5)215 (46.5)329 (46.5)
      Oral or topical corticosteroids4



      (0.2)
      15



      (0.4)
      19



      (0.3)
      41



      (16.7)
      62



      (13.4)
      103 (14.6)
      Data are n (%) unless otherwise indicated; Defined as investigator reported baseline condition coded to the MedDRA preferred terms ‘chronic obstructive pulmonary disease’ or ‘emphysema’, or baseline use of medications for obstructive airways disease (defined as medications belonging to the World Health Organization ATC class R03 with the exception of clenbuterol and cromoglicate sodium);
      Defined by the narrow standardized MedDRA query (SMQ) ‘cardiac failure’; §Without ICS; Belonging to ATC class H02AB; #By definition of subgroup. Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, aspirin; ATC, Anatomical Therapeutic Chemical; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; HbA1c, glycated hemoglobin; HDL-C, high density lipoprotein-cholesterol; ICS, inhaled corticosteroids; LDL-C, low density lipoprotein-cholesterol; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; PAD, peripheral artery disease; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; UACR, urine albumin-to-creatinine-ratio; SU, sulfonyl urea.

      3.1 COPD and clinical outcomes

      Considering the placebo group only, patients with concomitant T2DM and COPD had higher risk of all cardiorenal outcomes as well as mortality (Fig. 1, Fig. 2). There was a doubled risk of HHF (hazard ratio [HR]: 2.15 [95% CI: 1.32, 3.49]), a 60% higher risk of all-cause death (HR: 1.60 [95% CI: 1.09, 2.35]), and 68% higher risk of incident or worsening nephropathy (HR: 1.68 [95% CI: 1.26, 2.24]) as compared with those without COPD. During a median of 3.1 years of follow-up, approximately half of all patients with COPD were hospitalized for any cause, translating into a 44% higher risk among those with COPD than those without COPD in the placebo group (HR: 1.44 [95% CI: 1.19, 1.74]). Among the 245 patients with COPD treated with placebo, there were 318 hospitalizations for any cause during the trial, whereas among the 462 patients with COPD treated with empagliflozin, 498 hospitalizations for any cause occurred. Among the 2,088 patients without COPD treated with placebo, 1,545 hospitalizations for any cause occurred, and among the 4,225 patients without COPD treated with empagliflozin, 2,670 hospitalizations occurred.
      Figure thumbnail gr1
      Fig. 1Incidence rates and HR for outcomes in the placebo group in those with versus without COPD at baseline. †HR (95% CI) for comparison of COPD with no COPD (reference) based on the Cox regression model. ‡Excluding fatal stroke. Abbreviations: 3P-MACE, 3-point major adverse cardiovascular event; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio.
      Figure thumbnail gr2
      Fig. 2Treatment effect of empagliflozin versus placebo in patients with versus without COPD at baseline. HR (95% CI) for time-to-first event analyses based on the Cox regression model. n = number with event, N = number of patients analyzed. †For total all-cause hospitalizations, the number refers to the total number of events. ‡Excluding fatal stroke. §For total hospitalizations, the adjusted rate ratio is based on the negative binomial model. Abbreviations: 3P-MACE, 3-point major adverse cardiovascular event; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio; RR, rate ratio.
      Empagliflozin consistently reduced the risk of all clinical outcomes assessed in those with and without COPD at baseline (Fig. 2) with all interaction P values > 0.1.

      3.2 Metabolic outcomes

      Changes from baseline in HbA1c, weight, and SBP in those with and without COPD are shown in Fig. 3. Empagliflozin reduced HbA1c, weight, and SBP to a similar extent in those with versus those without COPD at baseline.
      Figure thumbnail gr3
      Fig. 3Change from baseline over time for (A) HbA1c, (B) weight, and (C) SBP in empagliflozin and placebo groups in patients with and without COPD at baseline. Abbreviations: COPD, chronic obstructive pulmonary disease; HbA1c, glycated hemoglobin; SBP, systolic blood pressure; SE, standard error.

      3.3 AEs and new onset of COPD

      Table 2 shows AEs by baseline COPD status and treatment. Apart from an increase in genital infections observed with empagliflozin in both subgroups, the proportion of patients who had an AE, a serious AE, a confirmed hypoglycemic episode, volume depletion, or acute renal failure was similar or lower in the empagliflozin group versus the placebo group, both in patients with and in those without baseline COPD.
      Table 2Adverse events in the empagliflozin and placebo groups in patients with versus without COPD at baseline.
      No COPDCOPD
      Placebo (n = 2088)EMPA (n = 4225)Placebo (n = 245)EMPA (n = 462)
      N (%)IR/



      100 PY
      N (%)IR/



      100 PY
      N (%)IR/



      100 PY
      N (%)IR/



      100 PY
      Any AE1906 (91.3)170.253791 (89.7)143.72233 (95.1)300.01439 (95.0)225.61
      Serious AE851 (40.8)21.061555 (36.8)17.83137 (55.9)35.88234 (50.6)29.18
      Confirmed hypoglycemic episode564 (27.0)13.531156 (27.4)13.6186 (35.1)20.39147 (31.8)17.80
      Genital infection34 (1.6)0.66263 (6.2)2.518



      (3.3)
      1.4438 (8.2)3.62
      Volume depletion§94 (4.5)1.84207 (4.9)1.9521 (8.6)3.9132 (6.9)2.97
      Acute renal failure127 (6.1)2.51214 (5.1)2.0128 (11.4)5.2432 (6.9)2.97
      Data are for patients who had one or more event and who had received at least one dose of a study drug. All events occurred within 7 days after the last receipt of the study drug. A plasma glucose level of < 70 mg per deciliter (3.9 mmol per liter) or an event requiring assistance; The definition of genital infection was based on 88 MedDRA preferred terms; §The definition of volume depletion was based on 8 MedDRA preferred terms; The definition of acute renal failure was based on 1 standardized MedDRA query. Abbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; EMPA, empagliflozin; IR, incidence rate; MedDRA, Medical Dictionary for Regulatory Activities; PY, patient years.
      Among those without COPD, 13 (0.6%) patients on placebo and 19 (0.4%) on empagliflozin were reported with a new diagnosis of COPD during the trial.

      3.4 COPD using the narrow definition

      In total, 416 patients fulfilled the narrow diagnosis of COPD at baseline (having investigator-reported diagnosis of either COPD or emphysema as classified by MedDRA preferred terms, irrespective of use of medication; 139 in the placebo group and 277 in the empagliflozin group). A similar pattern to that observed in the main analysis was seen in this analysis. Within the placebo group, those classified with baseline COPD diagnosis had a higher risk of outcomes than those without COPD; for example, they had a 2.6-fold higher risk of HHF (HR: 2.63 [95% CI: 1.52, 4.53]) and a 75% higher risk of all-cause death (HR: 1.75 [95% CI: 1.12, 2.75]) (Supplementary Fig. 1). Empagliflozin also reduced the risk of all outcomes consistently across COPD status at baseline (Supplementary Fig. 2) with all interaction P values > 0.3.

      4. Discussion

      We report in the present study that one in ten patients in the EMPA-REG OUTCOME trial had COPD. Patients with COPD had more co-morbidities, higher use of insulin, diuretics and statins, and a higher risk of mortality, HF, and all-cause hospitalization, as well as incident or worsening nephropathy, compared with patients without COPD. Empagliflozin reduced the risk of these outcomes and improved the metabolic profile to a similar degree in those with and without COPD, with a consistent safety profile.
      Consistent with our findings, other studies have also observed higher risk of hospitalization and mortality in patients with co-existing COPD and diabetes or CVD [
      • Mannino D.M.
      • Thorn D.
      • Swensen A.
      • Holguin F.
      Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD.
      ]. A US study utilizing National Hospital Discharge Survey data (from 1979 to 2001) found that the presence of COPD as a discharge diagnosis was associated with a higher number of comorbid conditions including CV disorders [
      • Holguin F.
      • Folch E.
      • Redd S.C.
      • Mannino D.M.
      Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001.
      ], thereby highlighting the high overall disease burden in the COPD population. They also reported a higher risk of hospitalizations and in-hospital mortality due to HF in those who had a previous COPD discharge diagnosis, suggesting a potential underreporting of comorbidities such as HF, or an elevated risk of new onset HF, in this group. In EMPA-REG OUTCOME, where all patients had T2DM and established CVD, we demonstrated that the risk of HHF was more than double in those with a reported diagnosis of COPD as compared to those without. This underscores the importance of COPD as a potential risk factor for HF: approximately 20% of patients with COPD have a co-existing diagnosis of HF, and around 20 to 35% of patients with HF have a concomitant diagnosis of COPD [
      • Lainscak M.
      • Anker S.D.
      Heart failure, chronic obstructive pulmonary disease, and asthma: numbers, facts, and challenges.
      ,
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ], with a slightly higher prevalence in HF with preserved versus reduced ejection fraction [
      • Mentz R.J.
      • Kelly J.P.
      • von Lueder T.G.
      • Voors A.A.
      • Lam C.S.P.
      • Cowie M.R.
      • et al.
      Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction.
      ]. One possible explanation for this close relationship between COPD and HF with preserved ejection fraction is the pro-inflammatory state induced by COPD that may lead to endothelial dysfunction resulting in myocardial fibrosis and clinical HF with preserved ejection fraction. Additional, or alternative, explanations may be the close link between even mild airway flow limitations and elevated left ventricular filling pressures [
      • Barr R.G.
      • Bluemke D.A.
      • Ahmed F.S.
      • Carr J.J.
      • Enright P.L.
      • Hoffman E.A.
      • et al.
      Percent emphysema, airflow obstruction, and impaired left ventricular filling.
      ], insulin resistance [
      • Machado F.V.C.
      • Pitta F.
      • Hernandes N.A.
      • Bertolini G.L.
      Physiopathological relationship between chronic obstructive pulmonary disease and insulin resistance.
      ], elevated pulmonary pressures and vascular resistance leading to right ventricular dysfunction as observed in advanced COPD [
      • Naeije R.
      Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease.
      ]. The co-existence of HF and COPD poses treatment challenges. Beta blockers are a cornerstone treatment for HF and are not contraindicated in COPD, yet they are often underutilized for the condition due to concern about worsening bronchospasm; and oral corticosteroids, often needed during COPD exacerbations, may cause sodium and water retention, potentially leading to worsening of HF [
      • Canepa M.
      • Franssen F.M.E.
      • Olschewski H.
      • Lainscak M.
      • Böhm M.
      • Tavazzi L.
      • et al.
      Diagnostic and therapeutic gaps in patients with heart failure and chronic obstructive pulmonary disease.
      ].
      COPD is therefore associated with a high comorbidity burden and our results confirm prior findings that this high burden (COPD with T2DM and CVD) drives a poor prognosis. Furthermore, since treatment is challenging, careful assessment of these patients and consideration of morbidity- and mortality-reducing treatments is of the utmost importance. Notably, in this contemporary study, the use of CV medications including beta-blockers, which may improve prognosis in patients with CVD, was largely comparable in those with and those without COPD.
      We observed a consistent treatment effect of empagliflozin on HF outcomes, mortality, all-cause hospitalizations, and nephropathy in patients with and without COPD. Knowing that COPD may both exacerbate and conceal underlying HF, and that the underlying mechanisms of the CV and HF benefits of SGLT2 inhibitors are largely unknown, this is important information for clinicians. Our analysis shows that the CV effects of empagliflozin were not mitigated in a COPD population. This is particularly important given the high prevalence of COPD among patients with T2DM. A recent publication from DAPA-HF reported similar results to ours, with reductions in HF outcomes and mortality, and improvement in quality-of-life measures with dapagliflozin in patients with HF and reduced ejection fraction with and without COPD [
      • Dewan P.
      • Docherty K.F.
      • Bengtsson O.
      • de Boer R.A.
      • Desai A.S.
      • Drozdz J.
      • et al.
      Effects of dapagliflozin in heart failure with reduced ejection fraction, and chronic obstructive pulmonary disease: an analysis of DAPA-HF.
      ]. The current study extends these findings to a population with T2DM and ASCVD (only 10% of whom had HF at baseline) and also by demonstrating a concurrent reduction in nephropathy across these subgroups.
      Despite recent advances in treatments, the evidence for COPD-specific treatments preventing progression of the disease and improving survival is scarce but includes smoking cessation [

      Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2020: https://goldcopd.org/wp-content/uploads/2020/03/GOLD-2020-POCKET-GUIDE-ver1.0_FINAL-WMV.pdf [accessed September 21, 2021].

      ]. Therefore, to improve prognosis in patients with COPD, a holistic approach that includes management of comorbidities with effective treatments is needed. We demonstrate in this study that patients with concomitant T2DM and COPD benefit similarly from empagliflozin treatment to those with T2DM but no COPD in terms of reduced risk of CV, all-cause death, HHF, all-cause hospitalizations, and nephropathy.
      Chronic kidney disease and COPD share several common risk factors such as cigarette smoking and increasing age, and the combination of these two conditions is associated with increased prevalence of CV complications and mortality [
      • Trudzinski F.C.
      • Alqudrah M.
      • Omlor A.
      • Zewinger S.
      • Fliser D.
      • Speer T.
      • et al.
      Consequences of chronic kidney disease in chronic obstructive pulmonary disease.
      ,
      • Fedeli U.
      • De Giorgi A.
      • Gennaro N.
      • Ferroni E.
      • Gallerani M.
      • Mikhailidis D.P.
      • et al.
      Lung and kidney: a dangerous liaison? A population-based cohort study in COPD patients in Italy.
      ,
      • Hasegawa W.
      • Yamauchi Y.
      • Yasunaga H.
      • Sunohara M.
      • Jo T.
      • Matsui H.
      • et al.
      Factors affecting mortality following emergency admission for chronic obstructive pulmonary disease.
      ]. We observed that the proportion of patients with eGFR < 60 ml/min/1.73 m2 at baseline was higher among those with COPD than those without, and that the risk of incident or worsening nephropathy during the trial was approximately 70% higher. Empagliflozin reduced the risk of nephropathy to a similar extent in those with versus those without COPD. Thus, in patients with T2DM, with or without concomitant COPD, empagliflozin mitigates risk through a reduction in risk for both nephropathy and mortality.
      COPD-related hospitalizations are a major driver of the cost of disease management [
      • Iheanacho I.
      • Zhang S.
      • King D.
      • Rizzo M.
      • Ismaila A.S.
      Economic burden of chronic obstructive pulmonary disease (COPD): a systematic literature review.
      ]. In our trial, approximately 50% of the patients with COPD were hospitalized for any cause at least once during follow-up. Among those without COPD, <40% required a hospitalization. These high numbers underscore the disease burden of patients with T2DM, COPD, and CVD. Empagliflozin reduced the risk of both first and total hospitalizations for any cause in those with and without COPD, with no increased risk of AEs apart from genital infection, which is a well-known side effect of the SGLT2-inhibitor class.
      The underlying mechanisms of the cardiorenal and mortality effects of empagliflozin are not yet fully elucidated but are believed to include a reduction in plasma volume through osmotic diuresis, increase in hematocrit, decrease in vascular resistance and improved cardiac remodeling [
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.
      ,
      • Omar M.
      • Jensen J.
      • Ali M.
      • Frederiksen P.H.
      • Kistorp C.
      • Videbæk L.
      • et al.
      ,
      • Verma S.
      • Mazer C.D.
      • Yan A.T.
      • Mason T.
      • Garg V.
      • Teoh H.
      • et al.
      Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial.
      ]. Exploratory mediation analyses of the EMPA-REG OUTCOME trial suggested that changes in markers of plasma volume were the most important mediators of the reduction in CV deaths and as well as hospitalization for heart failure or heart failure death. Additional hypotheses proposed include improved cardiac metabolism and substrate utilization [
      • Ferrannini E.
      • Mark M.
      • Mayoux E.
      CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis.
      ].
      Achieving glycemic control in patients with COPD using oral corticosteroids or ICS may be particularly challenging [
      • Suissa S.
      • Kezouh A.
      • Ernst P.
      Inhaled corticosteroids and the risks of diabetes onset and progression.
      ]. In patients with and without COPD in this trial, HbA1c levels at baseline were comparable, and empagliflozin treatment resulted in similar reductions in HbA1c for both groups.

      5. Limitations

      The most important limitation of our analysis is the lack of verification and characterization of the COPD diagnoses, as the diagnoses were investigator reported and we did not collect data on severity and lung function. We were also not able to report the effects on COPD related hospitalizations separately.

      6. Conclusions

      In EMPA-REG OUTCOME, 10% of patients had concomitant COPD. The COPD patients were at increased risk of cardiorenal events, including HF, as well as all-cause hospitalization and mortality. Empagliflozin consistently reduced these outcomes versus placebo among patients with and without COPD. These data suggest that benefits of empagliflozin treatment in patients with T2DM and CVD are not mitigated by the presence of COPD.

      7. Data statement

      To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stefan D. Anker has received grants from Vifor; has received personal fees from Bayer, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Servier; and has received grants and personal fees from Abbott Vascular, outside the submitted work. David Fitchett has received financial support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck & Co., and Sanofi. Bernard Zinman has received financial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Christoph Wanner has received financial support from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Mundipharma. Subodh Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; receiving honoraria from Sanofi, Sun Pharmaceuticals and the Toronto Knowledge Translation Working Group. He is a member of the scientific excellence committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Silvio Inzucchi has served as a consultant, speaker, or as a member of clinical trial steering committees for Boehringer Ingelheim, AstraZenca, Novo Nordisk, Sanofi/Lexicon Pharmaceuticals, Merck, vTv Therapeutics and Abbott/Alere. Anne Pernille Ofstad and Ola Vedin are employees of Boehringer Ingelheim. Sabine Lauer reports significant consulting fees from Hoffmann La Roche and Boehringer Ingelheim. Leif-Erik Sander and Henry K. Yaggi have no financial conflicts of interest to report.
      Author contributions.
      Concept and design: S.D.A., S.V., S.E.I., B.Z., D.H.F., and C.W. Acquisition, analysis, or interpretation of data: S.E.I., S.L., O.V., and A.P.O. Statistical analysis: S.L. Drafting of the manuscript: S.D.A. and A.P.O. Critical revision of the manuscript for important intellectual content: all authors. All authors approved the final manuscript before publication.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      The authors thank the investigators, coordinators, and patients who participated in this trial. Editorial assistance, limited to the preparation of figures and collation of author comments, and supported financially by Boehringer Ingelheim, was provided by Matthew Smith and Céline Tevlin of Elevate Scientific Solutions.

      Funding

      The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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