Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial

Julio Rosenstock, Vlado Perkovic, Odd Erik Johansen, Mark E. Cooper, Steven E. Kahn, Nikolaus Marx, John H. Alexander, Michael Pencina, Robert D. Toto, Christoph Wanner, Bernard Zinman, Hans Juergen Woerle, David Baanstra, Egon Pfarr, Sven Schnaidt, Thomas Meinicke, Jyothis T. George, Maximilian Von Eynatten, Darren K. McGuire, for the CARMELINA Investigators

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Abstract

Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A 1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m 2 ; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P <.001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P =.62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalJAMA
Volume321
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Rosenstock, Julio ; Perkovic, Vlado ; Johansen, Odd Erik ; Cooper, Mark E. ; Kahn, Steven E. ; Marx, Nikolaus ; Alexander, John H. ; Pencina, Michael ; Toto, Robert D. ; Wanner, Christoph ; Zinman, Bernard ; Woerle, Hans Juergen ; Baanstra, David ; Pfarr, Egon ; Schnaidt, Sven ; Meinicke, Thomas ; George, Jyothis T. ; Von Eynatten, Maximilian ; McGuire, Darren K. ; for the CARMELINA Investigators. / Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk : The CARMELINA Randomized Clinical Trial. In: JAMA. 2019 ; Vol. 321, No. 1. pp. 69-79.
@article{685bb425c16140ce91d738bb802b219a,
title = "Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial",
abstract = "Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A 1c of 6.5{\%} to 10.0{\%}, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95{\%} CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40{\%} or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m 2 ; 80.1{\%} with UACR >30 mg/g) received at least 1 dose of study medication and 98.7{\%} completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4{\%}) and 420 of 3485 (12.1{\%}) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95{\%} CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95{\%} CI, 0.89-1.17; P <.001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4{\%}) and 306 of 3485 (8.8{\%}), respectively (absolute incidence rate difference, 0.22 [95{\%} CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95{\%} CI, 0.89-1.22; P =.62). Adverse events occurred in 2697 (77.2{\%}) and 2723 (78.1{\%}) patients in the linagliptin and placebo groups; 1036 (29.7{\%}) and 1024 (29.4{\%}) had 1 or more episodes of hypoglycemia; and there were 9 (0.3{\%}) vs 5 (0.1{\%}) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.",
author = "Julio Rosenstock and Vlado Perkovic and Johansen, {Odd Erik} and Cooper, {Mark E.} and Kahn, {Steven E.} and Nikolaus Marx and Alexander, {John H.} and Michael Pencina and Toto, {Robert D.} and Christoph Wanner and Bernard Zinman and Woerle, {Hans Juergen} and David Baanstra and Egon Pfarr and Sven Schnaidt and Thomas Meinicke and George, {Jyothis T.} and {Von Eynatten}, Maximilian and McGuire, {Darren K.} and {for the CARMELINA Investigators}",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jama.2018.18269",
language = "English",
volume = "321",
pages = "69--79",
journal = "JAMA",
issn = "0098-7484",
publisher = "American Medical Association (AMA)",
number = "1",

}

Rosenstock, J, Perkovic, V, Johansen, OE, Cooper, ME, Kahn, SE, Marx, N, Alexander, JH, Pencina, M, Toto, RD, Wanner, C, Zinman, B, Woerle, HJ, Baanstra, D, Pfarr, E, Schnaidt, S, Meinicke, T, George, JT, Von Eynatten, M, McGuire, DK & for the CARMELINA Investigators 2019, 'Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial', JAMA, vol. 321, no. 1, pp. 69-79. https://doi.org/10.1001/jama.2018.18269

Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk : The CARMELINA Randomized Clinical Trial. / Rosenstock, Julio; Perkovic, Vlado; Johansen, Odd Erik; Cooper, Mark E.; Kahn, Steven E.; Marx, Nikolaus; Alexander, John H.; Pencina, Michael; Toto, Robert D.; Wanner, Christoph; Zinman, Bernard; Woerle, Hans Juergen; Baanstra, David; Pfarr, Egon; Schnaidt, Sven; Meinicke, Thomas; George, Jyothis T.; Von Eynatten, Maximilian; McGuire, Darren K.; for the CARMELINA Investigators.

In: JAMA, Vol. 321, No. 1, 01.01.2019, p. 69-79.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk

T2 - The CARMELINA Randomized Clinical Trial

AU - Rosenstock, Julio

AU - Perkovic, Vlado

AU - Johansen, Odd Erik

AU - Cooper, Mark E.

AU - Kahn, Steven E.

AU - Marx, Nikolaus

AU - Alexander, John H.

AU - Pencina, Michael

AU - Toto, Robert D.

AU - Wanner, Christoph

AU - Zinman, Bernard

AU - Woerle, Hans Juergen

AU - Baanstra, David

AU - Pfarr, Egon

AU - Schnaidt, Sven

AU - Meinicke, Thomas

AU - George, Jyothis T.

AU - Von Eynatten, Maximilian

AU - McGuire, Darren K.

AU - for the CARMELINA Investigators

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A 1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m 2 ; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P <.001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P =.62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.

AB - Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A 1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m 2 ; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P <.001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P =.62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.

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