Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study

Hiddo J.L. Heerspink, Avraham Karasik, Marcus Thuresson, Cheli Melzer-Cohen, Gabriel Chodick, Kamlesh Khunti, John P.H. Wilding, Luis Alberto Garcia Rodriguez, Lucia Cea-Soriano, Shun Kohsaka, Antonio Nicolucci, Giuseppe Lucisano, Fang Ju Lin, Chih Yuan Wang, Eric Wittbrodt, Peter Fenici, Mikhail Kosiborod

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Abstract

Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34–1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35–0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding: AstraZeneca.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalThe Lancet Diabetes and Endocrinology
Volume8
Issue number1
DOIs
Publication statusPublished - 2020 Jan

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Sodium-Glucose Transporter 2
Symporters
Observational Studies
Cohort Studies
Glomerular Filtration Rate
Kidney
Glucose
Pharmaceutical Preparations
Type 2 Diabetes Mellitus
Propensity Score
Chronic Renal Insufficiency
Israel
Taiwan

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3) : a multinational observational cohort study. / Heerspink, Hiddo J.L.; Karasik, Avraham; Thuresson, Marcus; Melzer-Cohen, Cheli; Chodick, Gabriel; Khunti, Kamlesh; Wilding, John P.H.; Garcia Rodriguez, Luis Alberto; Cea-Soriano, Lucia; Kohsaka, Shun; Nicolucci, Antonio; Lucisano, Giuseppe; Lin, Fang Ju; Wang, Chih Yuan; Wittbrodt, Eric; Fenici, Peter; Kosiborod, Mikhail.

In: The Lancet Diabetes and Endocrinology, Vol. 8, No. 1, 01.2020, p. 27-35.

Research output: Contribution to journalArticle

Heerspink, HJL, Karasik, A, Thuresson, M, Melzer-Cohen, C, Chodick, G, Khunti, K, Wilding, JPH, Garcia Rodriguez, LA, Cea-Soriano, L, Kohsaka, S, Nicolucci, A, Lucisano, G, Lin, FJ, Wang, CY, Wittbrodt, E, Fenici, P & Kosiborod, M 2020, 'Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study', The Lancet Diabetes and Endocrinology, vol. 8, no. 1, pp. 27-35. https://doi.org/10.1016/S2213-8587(19)30384-5
Heerspink, Hiddo J.L. ; Karasik, Avraham ; Thuresson, Marcus ; Melzer-Cohen, Cheli ; Chodick, Gabriel ; Khunti, Kamlesh ; Wilding, John P.H. ; Garcia Rodriguez, Luis Alberto ; Cea-Soriano, Lucia ; Kohsaka, Shun ; Nicolucci, Antonio ; Lucisano, Giuseppe ; Lin, Fang Ju ; Wang, Chih Yuan ; Wittbrodt, Eric ; Fenici, Peter ; Kosiborod, Mikhail. / Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3) : a multinational observational cohort study. In: The Lancet Diabetes and Endocrinology. 2020 ; Vol. 8, No. 1. pp. 27-35.
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abstract = "Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50{\%} eGFR decline or end-stage kidney disease. Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9{\%}, 34·1{\%}, 5·7{\%}, 1·4{\%}, 0·5{\%}, and 0·4{\%} of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3{\%}) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71{\%}), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95{\%} CI 1·34–1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95{\%} CI 0·35–0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding: AstraZeneca.",
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TY - JOUR

T1 - Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3)

T2 - a multinational observational cohort study

AU - Heerspink, Hiddo J.L.

AU - Karasik, Avraham

AU - Thuresson, Marcus

AU - Melzer-Cohen, Cheli

AU - Chodick, Gabriel

AU - Khunti, Kamlesh

AU - Wilding, John P.H.

AU - Garcia Rodriguez, Luis Alberto

AU - Cea-Soriano, Lucia

AU - Kohsaka, Shun

AU - Nicolucci, Antonio

AU - Lucisano, Giuseppe

AU - Lin, Fang Ju

AU - Wang, Chih Yuan

AU - Wittbrodt, Eric

AU - Fenici, Peter

AU - Kosiborod, Mikhail

PY - 2020/1

Y1 - 2020/1

N2 - Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34–1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35–0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding: AstraZeneca.

AB - Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34–1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35–0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding: AstraZeneca.

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