Severe HYPO is associated with higher CV and mortality risk. The CAROLINA® trial evaluated the CV safety of linagliptin (LINA) and glimepiride (GLIM) in 6033 subjects with relatively early type 2 diabetes (T2D) and elevated CV risk (mean age 64.0 years, HbA1c 7.2%, median T2D duration 6.3 years) and demonstrated non-inferiority for 3P-MACE and no difference for CV and mortality outcomes. However, a significant lower risk of HYPO was observed with LINA vs. GLIM regardless of severity classification. We assessed, in 6014 participants, the associations between severe HYPO and/or documented HYPO (BG <54 mg/dl), which occurred in 109/3014 (3.6%) and 537/3000 (17.9%) in the LINA and GLIM groups, respectively (HR 0.19 [95% CI 0.15, 0.23]), and CV and mortality outcomes using Cox regression models. HYPO events preceded CV outcomes in 0.0-3.6% of all events with LINA and in 8.0-26.2% events with GLIM. Of note, even when multivariably adjusted, occurrence of HYPO was associated only with higher risk for all-cause mortality (HR 1.49 [1.16, 1.92]), and non-CV mortality (HR 2.16 [1.57, 2.97]) (Fig A). The relative effect of LINA vs. GLIM on any CV or mortality outcome (Fig B) was not influenced by antecedent HYPO.

In conclusion, preceding HYPO was associated with higher risk for all-cause and non-CV mortality, but not with any other outcomes in a relatively early T2D population at elevated CV risk.


J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Mattheus: None. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH.


Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at