Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients with Type 2 Diabetes

The CAROLINA Randomized Clinical Trial

Julio Rosenstock, Steven E. Kahn, Odd Erik Johansen, Bernard Zinman, Mark A. Espeland, Hans J. Woerle, Egon Pfarr, Annett Keller, Michaela Mattheus, David Baanstra, Thomas Meinicke, Jyothis T. George, Maximilian Von Eynatten, Darren K McGuire, Nikolaus Marx

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P <.001 for noninferiority), meeting the noninferiority criterion but not superiority (P =.76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT01243424.

Original languageEnglish (US)
Pages (from-to)1155-1166
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume322
Issue number12
DOIs
StatePublished - Sep 24 2019

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glimepiride
Type 2 Diabetes Mellitus
Randomized Controlled Trials
Metformin
Glycosylated Hemoglobin A
Cardiovascular Diseases
Linagliptin
Dipeptidyl-Peptidase IV Inhibitors
Glucosidases
Thiazolidinediones

ASJC Scopus subject areas

  • Medicine(all)

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Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients with Type 2 Diabetes : The CAROLINA Randomized Clinical Trial. / Rosenstock, Julio; Kahn, Steven E.; Johansen, Odd Erik; Zinman, Bernard; Espeland, Mark A.; Woerle, Hans J.; Pfarr, Egon; Keller, Annett; Mattheus, Michaela; Baanstra, David; Meinicke, Thomas; George, Jyothis T.; Von Eynatten, Maximilian; McGuire, Darren K; Marx, Nikolaus.

In: JAMA - Journal of the American Medical Association, Vol. 322, No. 12, 24.09.2019, p. 1155-1166.

Research output: Contribution to journalArticle

Rosenstock, J, Kahn, SE, Johansen, OE, Zinman, B, Espeland, MA, Woerle, HJ, Pfarr, E, Keller, A, Mattheus, M, Baanstra, D, Meinicke, T, George, JT, Von Eynatten, M, McGuire, DK & Marx, N 2019, 'Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients with Type 2 Diabetes: The CAROLINA Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 322, no. 12, pp. 1155-1166. https://doi.org/10.1001/jama.2019.13772
Rosenstock, Julio ; Kahn, Steven E. ; Johansen, Odd Erik ; Zinman, Bernard ; Espeland, Mark A. ; Woerle, Hans J. ; Pfarr, Egon ; Keller, Annett ; Mattheus, Michaela ; Baanstra, David ; Meinicke, Thomas ; George, Jyothis T. ; Von Eynatten, Maximilian ; McGuire, Darren K ; Marx, Nikolaus. / Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients with Type 2 Diabetes : The CAROLINA Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2019 ; Vol. 322, No. 12. pp. 1155-1166.
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abstract = "Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5{\%} to 8.5{\%}, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47{\%} CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9{\%}] women; mean glycated hemoglobin, 7.2{\%}; median duration of diabetes, 6.3 years; 42{\%} with macrovascular disease; 59{\%} had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8{\%}) in the linagliptin group and 362 of 3010 (12.0{\%}) in the glimepiride group (HR, 0.98 [95.47{\%} CI, 0.84-1.14]; P <.001 for noninferiority), meeting the noninferiority criterion but not superiority (P =.76). Adverse events occurred in 2822 participants (93.4{\%}) in the linagliptin group and 2856 (94.9{\%}) in the glimepiride group, with 15 participants (0.5{\%}) in the linagliptin group vs 16 (0.5{\%}) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6{\%}) participants in the linagliptin group and 1132 (37.7{\%}) in the glimepiride group (HR, 0.23 [95{\%} CI, 0.21-0.26]). Conclusions and Relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT01243424.",
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TY - JOUR

T1 - Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients with Type 2 Diabetes

T2 - The CAROLINA Randomized Clinical Trial

AU - Rosenstock, Julio

AU - Kahn, Steven E.

AU - Johansen, Odd Erik

AU - Zinman, Bernard

AU - Espeland, Mark A.

AU - Woerle, Hans J.

AU - Pfarr, Egon

AU - Keller, Annett

AU - Mattheus, Michaela

AU - Baanstra, David

AU - Meinicke, Thomas

AU - George, Jyothis T.

AU - Von Eynatten, Maximilian

AU - McGuire, Darren K

AU - Marx, Nikolaus

PY - 2019/9/24

Y1 - 2019/9/24

N2 - Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P <.001 for noninferiority), meeting the noninferiority criterion but not superiority (P =.76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT01243424.

AB - Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P <.001 for noninferiority), meeting the noninferiority criterion but not superiority (P =.76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT01243424.

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