Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Pneumonia and Septic Shock

Hang-Long Li; Yi-Kei Tse; Chanchal Chandramouli; Nicole Wing-Lam Hon; Ching-Lung Cheung; Lok-Yee Lam; Meizhen Wu; Jia-Yi Huang; Si-Yeung Yu; Ka-Lam Leung; Yue Fei; Qi Feng; Qingwen Ren; Bernard M. Y. Cheung; Hung-Fat Tse; Subodh Verma; Carolyn S. P. Lam; Kai-Hang Yiu

Disclosures

J Clin Endocrinol Metab. 2022;107(12):3442-3451.

Abstract and Introduction

Abstract

Context: Individuals with type 2 diabetes mellitus (DM) have an increased risk of pneumonia and septic shock. Traditional glucose-lowering drugs have recently been found to be associated with a higher risk of infections. It remains unclear whether sodium-glucose cotransporter 2 inhibitors (SGLT2is), which have pleiotropic/anti-inflammatory effects, may reduce the risk of pneumonia and septic shock in DM.

Methods: MEDLINE, Embase, and ClinicalTrials.gov were searched from inception up to May 19, 2022, for randomized, placebo-controlled trials of SGLT2i that included patients with DM and reported outcomes of interest (pneumonia and/or septic shock). Study selection, data extraction, and quality assessment (using the Cochrane Risk of Bias Assessment Tool) were conducted by independent authors. A fixed-effects model was used to pool the relative risk (RRs) and 95% CI across trials.

Results: Out of 4568 citations, 26 trials with a total of 59 264 patients (1.9% developed pneumonia and 0.2% developed septic shock) were included. Compared with placebo, SGLT2is significantly reduced the risk of pneumonia (pooled RR 0.87, 95% CI 0.78–0.98) and septic shock (pooled RR 0.65, 95% CI 0.44–0.95). There was no significant heterogeneity of effect size among trials. Subgroup analyses according to the type of SGLT2i used, baseline comorbidities, glycemic control, duration of DM, and trial follow-up showed consistent results without evidence of significant treatment-by-subgroup heterogeneity (all P _{heterogeneity} > .10).

Conclusion: Among DM patients, SGLT2is reduced the risk of pneumonia and septic shock compared with placebo. Our findings should be viewed as hypothesis generating, with concepts requiring validation in future studies.

Introduction

The increasing prevalence of type 2 diabetes mellitus (DM) poses a significant public health burden worldwide.^[1] Patients with diabetes have an increased risk of pneumonia: in the United States, the overall incidence rate of pneumonia in 2014 was 1.78-fold higher in patients with diabetes than in individuals without diabetes (34 vs 19 per 1000 person-years).^[2] Among patients admitted for pneumonia, those with pre-existing DM or acute hyperglycemia had approximately 80% higher risk of mortality than normoglycaemic individuals,^[3–6] particularly so in the presence of septic shock.^[7] Paradoxically, glucose lowering using conventional anti-DM drugs, including metformin,^[8] dipeptidyl peptidase-4 inhibitor,^[9] and combination therapy of metformin plus thiazolidinediones,^[10] did not lower the risk of pneumonia, and might in fact be associated with higher risk of pneumonia.^[8–10] Moreover, in patients with DM complicated with sepsis and pneumonia, metformin use was associated higher sepsis severity.^[11] This suggests that glucose lowering per se may not address the excess risk of pneumonia in patients with diabetes.

In recent years, sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged as anti-DM drugs with key cardiorenal benefits beyond glucose lowering.^[12–16] SGLT2is exert pleiotropic and anti-inflammatory effects^[17]—both with plausible benefits in patients with pneumonia. Findings from individual cardiovascular outcome trials on SGLT2is reporting pneumonia or septic shock as secondary outcomes are inconsistent.^[12,18] Compared with placebo, the incidence of pneumonia appeared to be lower with empagliflozin and higher with ertugliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients Removing Excess Glucose (EMPA-REG OUTCOME)^[12] and Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS-CV)^[19] trials, respectively. Preliminary findings from "off-label" SGLT2i usage in subjects infected with severe or critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia suggest benefits in subjects with diabetes,^[20] and no effects in subjects without diabetes.^[21] These may be attributed to the more pronounced anti-inflammatory effects in the context of hyperglycemia, where inflammation is more severe (evidenced by the higher levels of interleukin-6, C-reactive protein, and erythrocyte sedimentation rate) than in the normoglycemic state.^[22–24] We performed a systematic review and meta-analysis of randomized controlled trials to comprehensively evaluate whether SGLT2is reduce the risk of pneumonia and septic shock in patients with DM.

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Table 1. Baseline characteristics of eligible studies
Trial	ClinicalTrials.gov identifier	Age (years), mean	Male, n (%)	HbA1c (%), mean	Baseline condition	Mean eGFR (mL/min/1.73 m²)	Drug	Dose(s) analyzed	Sample size (SGLT2i/placebo)	Median follow-up duration (years)
Bode et al, 2013	NCT01106651	63.6	396 (55.5%)	7.7	DM	77.5	Canagliflozin	100 mg, 300 mg (once daily)	477/237	0.5
Bolinder et al, 2014	NCT00855166	60.7	100 (55.6%)	7.2	DM	84.3	Dapagliflozin	10 mg (once daily)	91/91	2.0
CANTATA-M, 2013	NCT01081834	55.4	258 (44.2%)	8.0	DM	87.1	Canagliflozin	100 mg, 300 mg (once daily)	392/192	1.0
CANTATA-MSU, 2013	NCT01106625	56.8	239 (51%)	8.1	DM	90.1	Canagliflozin	100 mg, 300 mg (once daily)	313/156	1.0
CANVAS Program, 2017	NCT01032629; NCT01989754	63.3	6509 (64.2%)	8.2	DM	76.5	Canagliflozin	100 mg, 300 mg (once daily)	5795/4347	2.4
Cefalu et al, 2015	NCT01031680	62.9	624 (68.3%)	8.1	DM + CVD + HTN	NA	Dapagliflozin	10 mg (once daily)	460/462	1.0
CREDENCE, 2019	NCT02065791	63.0	2907 (66.1%)	8.3	DM + CKD	56.2	Canagliflozin	100 mg (once daily)	2202/2199	2.6
DECLARE-TIMI 58, 2019	NCT01730534	63.9	10 738 (62.6%)	8.3	DM	85.3	Dapagliflozin	10 mg (once daily)	8582/8578	4.2
EMPA-REG EXTEND METSU, 2015	NCT01289990	57.1	339 (50.9%)	8.1	DM	87.2	Empagliflozin	10 mg, 25 mg (once daily)	441/225	1.5
EMPA-REG OUTCOME, 2015	NCT01131676	63.1	5016 (71.5%)	8.1	DM + CVD	74	Empagliflozin	10 mg, 25 mg (once daily)	4691/2337	3.1
EMPA-REG RENAL, 2014	NCT01164501	63.9	430 (58.3%)	8.0	DM + CKD	53.2	Empagliflozin	10 mg, 25 mg (once daily)	420/321	1.0
Ferrannini et al, 2010	NCT00528372	52.0	276 (49.5%)	8.3	DM	NA	Dapagliflozin	2.5 mg, 5 mg, 10 mg (once daily)	484/75	0.5
Jabbour et al, 2014	NCT00984867	54.9	245 (54.8%)	7.9	DM	NA	Dapagliflozin	10 mg (once daily)	225/226	0.9
Ji et al, 2015	NCT01381900	56.3	362 (53.6%)	8.0	DM	94	Canagliflozin	100 mg, 300 mg (once daily)	450/226	0.3
Kohan et al, 2014	NCT00663260	67.0	164 (65.1%)	8.3	DM + CKD	44.6	Dapagliflozin	5 mg, 10 mg (once daily)	168/84	2.0
Rosenstock et al, 2012	NCT00683878	53.5	208 (49.5%)	8.4	DM	NA	Dapagliflozin	5 mg, 10 mg (once daily)	281/139	0.9
Rosenstock et al, 2015	NCT01011868	58.8	276 (55.9%)	8.2	DM	84	Empagliflozin	10 mg, 25 mg (once daily)	324/170	1.5
SOLOIST-WHF, 2020	NCT03521934	70.0^a	810 (66.3%)	7.2	DM + HF	49.7^a	Sotagliflozin	200 mg (once daily)	608/614	0.8
Strojek et al, 2011	NCT00680745	59.8	285 (48.1%)	8.1	DM	81.7	Dapagliflozin	2.5 mg, 5 mg, 10 mg (once daily)	450/146	0.9
Tikkanen et al, 2015	NCT01370005	60.2	495 (60.1%)	7.9	DM + HTN	84	Empagliflozin	10 mg, 25 mg (once daily)	553/272	0.2
VERTIS Asia, 2019	NCT02630706	56.5	281 (55.5%)	8.1	DM	99.3	Ertugliflozin	5 mg, 15 mg (once daily)	339/167	0.5
VERTIS-CV, 2020	NCT01986881	64.4	5769 (70.0%)	8.3	DM + CVD	76	Ertugliflozin	5 mg, 15 mg (once daily)	5499/2747	3.0
VERTIS-RENAL, 2018	NCT01986855	67.3	231 (49.5%)	8.2	DM + CKD	46.6	Ertugliflozin	5 mg, 15 mg (once daily)	314/154	1.0
VERTIS-SITA2, 2018	NCT02036515	59.1	263 (56.9%)	8.0	DM	87.9	Ertugliflozin	5 mg, 15 mg (once daily)	311/153	1.0
Wilding et al, 2012	NCT00673231	59.3	382 (47.8%)	8.5	DM	78.4	Dapagliflozin	2.5 mg, 5 mg, 10 mg (once daily)	610/197	0.9
Yale et al, 2014	NCT01064414	68.5	163 (60.6%)	8.0	DM + CKD	39.4	Canagliflozin	100 mg, 300 mg (once daily)	179/90	1.0

Abbreviations: CVD, cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus type 2; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HF, heart failure; HTN, hypertension; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
^aMedian

Table 2. Results of subgroup analysis for pneumonia
Subgroup		Number of trials	Number of participants	RR (95% CI)	P _hetero
Overall		24	58 584	0.87 (0.78–0.98)
Agent	Canagliflozin	6	16 986	0.83 (0.66–1.03)	.51
	Dapagliflozin	8	20 928	0.88 (0.73–1.06)
	Empagliflozin	5	9764	0.75 (0.53–1.04)
	Others^a	5	10 906	1.02 (0.77–1.36)
Baseline condition	DM only	16	34 479	0.90 (0.77–1.04)	.60
	Others	9	24 105	0.84 (0.70–1.01)
Presence of ASCVD at baseline	Yes	3	16 196	0.90 (0.70–1.14)	.80
	No	21	42 388	0.86 (0.76–0.99)
Mean HbA1c	<median^b	12	14 032	0.83 (0.64–1.08)	.68
	≥median^b	12	44 552	0.88 (0.77–1.00)
Mean FPG	<median^c	10	12 153	0.80 (0.58–1.09)	.39
	≥median^c	10	15 402	0.97 (0.72–1.31)
Mean duration of DM	<median^d	11	12 823	0.81 (0.59–1.11)	.62
	≥median^d	11	44 045	0.88 (0.77–1.00)
Mean eGFR	<median^e	10	34 021	0.86 (0.73–1.01)	.80
	≥median^e	11	22 632	0.89 (0.74–1.06)
Follow-up duration	<1.0 year	9	6355	0.92 (0.57–1.43)	.80
	≥1.0 year	15	52 229	0.87 (0.77–0.98)

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; P_hetero, P-value for between-subgroup heterogeneity; RR, risk ratio.
^aOther SGLT2i, sotagliflozin and ertugliflozin.
^bMedian HbA1c, 8.105%.
^cMedian FPG, 159.75 mg/dL.
^dMedian duration of DM, 8.75 years.
^eMedian eGFR, 81.7 mL/min per 1.73m².

Table 3. Results of subgroup analysis for septic shock
Subgroup		Number of trials	Number of participants	RR (95% CI)	P _hetero
Overall		10	41 854	0.65 (0.44–0.95)
Agent	Canagliflozin	4	15 396	0.46 (0.23–0.91)	.24
	Dapagliflozin	4	18 754	0.88 (0.52–1.51)
	Empagliflozin	2	7704	0.44 (0.16–1.20)
Baseline condition	DM only	6	36 010	0.69 (0.45–1.05)	.56
	Others	4	5844	0.52 (0.22–1.21)
Presence of ASCVD at baseline	Yes	2	7950	0.55 (0.22–1.39)	.72
	No	8	33 904	0.67 (0.44–1.01)
Mean HbA1c	<median^a	5	9479	0.54 (0.23–1.25)	.65
	≥median^a	5	32 375	0.67 (0.44–1.04)
Mean FPG	<median^b	4	8878	0.60 (0.25–1.46)	.88
	≥median^b	4	11 415	0.55 (0.23–1.31)
Mean duration of DM	<median^c	5	25 868	0.73 (0.46–1.18)	.38
	≥median^c	5	15 986	0.51 (0.26–0.98)
Mean eGFR	<median^d	4	11 950	0.43 (0.22–0.86)	.21
	≥ median^d	5	28 562	0.74 (0.46–1.20)
Follow-up duration	<1.0 year	1	420	1.49 (0.06–36.33)	.60
	≥1.0 year	9	41 434	0.64 (0.43–0.94)

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; P_hetero, P-value for between-subgroup heterogeneity; RR, risk ratio.
^aMedian HbA1c, 8.165%.
^bMedian FPG, 161.65 mg/dL.
^cMedian duration of DM, 11.45 years.
^dMedian eGFR, 75.25 mL/min per 1.73 m².

Authors and Disclosures

Hang-Long Li^1,2, Yi-Kei Tse^1,2, Chanchal Chandramouli^3,4, Nicole Wing-Lam Hon^1,2, Ching-Lung Cheung⁵, Lok-Yee Lam^1,2, Meizhen Wu^1,2, Jia-Yi Huang^1,2, Si-Yeung Yu^1,2, Ka-Lam Leung^1,2, Yue Fei⁶, Qi Feng⁷, Qingwen Ren^1,2, Bernard M. Y. Cheung⁶, Hung-Fat Tse^1,2, Subodh Verma⁸, Carolyn S. P. Lam^3,4,9 and Kai-Hang Yiu^1,2

¹Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen 518053, China
²Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong 999077, China
³National Heart Centre Singapore, Singapore 169609, Singapore
⁴Duke-NUS Medical School, Singapore 169857, Singapore
⁵Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong 999077, China
⁶Division of Clinical Pharmacology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong 999077, China
⁷Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong 999077, China
⁸Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada
⁹University Medical Center Groningen, Groningen 9713 GZ, The Netherlands

Correspondence
Kai-Hang Yiu, MD, Division of Cardiology, Department of Medicine, The University of Hong Kong, Room 1929B/K1931, Block K, Queen Mary Hospital, Hong Kong 999077, China. Email: khkyiu@hku.hk.

Author Contributions
H.L.L., C.C., S.V., C.S.P.L., K.H.Y. conceived and designed the study. H.L.L., Y.K.T. acquired the data for analysis. H.L.L., Y.K.T., C.C., N.W.L.H. equally contributed to the analysis and interpretation of data. H.L.L., Y.K.T. drafted the main text, figures and supplementary data. All the other authors equally contributed to revising the manuscript critically for important intellectual content.

Conflict of Interest
C.S.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/ Executive Committee for Abbott, Actelion, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder & non-executive director of Us2.ai. All other authors report no conflict of interest.

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Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Pneumonia and Septic Shock

Abstract and Introduction

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