Better diabetes control generally reduces development of complications, but those with HbA1c <6.0% have increased cardiovascular (CVD) mortality. Since the cause is unknown, we studied the potential contributions of hypoglycemia, using VA and Medicare databases. 297,263 Veterans with diabetes (ICD-9 codes and diabetes Rx) had ≥4 primary care provider (PCP) visits in 2002-2003, baseline data including age, sex, race, ethnicity, BMI, non-HDL cholesterol, systolic blood pressure (sBP), smoking, ≥1 HbA1c, ≥3 outpatient random plasma glucose (RPG) levels, follow-up through 2012, and survived at least 1 year after A1c measurement. The 40,429 with A1c <6.0% (A1c<6) had mean age 66 year, were 98% male, 16% black and 6.5% Hispanic, had BMI 31, eGFR 71, sBP 139, 81% ever smoked, 51% had CVD at baseline, 48% used sulfonylureas and 13% insulin, with mean HbA1c 5.5%, and RPG 125 mg/dl, while 90,574 with HbA1c 6.0-6.9% (A1c6-6.9) had HbA1c 6.5% and RPG 141 (both p<0.001), but were otherwise clinically comparable. In fully adjusted Cox proportional hazard models, A1c<6 had increased CVD mortality compared to A1c6-6.9 (HR 1.07, p<0.001). However, within 1 year after baseline, A1c<6 also had increased frequency of both outpatient RPG <70 (8.4% vs. 6.0%, p<0.001), outpatient point of care glucose (POCG) <70 (0.34% vs. 0.29%, p=ns), and emergency visits with hypoglycemia (EDHYPO, 0.28% vs. 0.24%, p=ns). Moreover, in Cox models including HbA1c (<6.0 -6.9, -7.9, -8.9, ≥9.0%), hypoglycemia measured by (i) outpatient RPG or POCG levels <70 or (ii) EDHYPO, was independently associated with increased CVD mortality, fully adjusted HR 1.18 and 1.49, both p<0.001. At all HbA1c levels, RPG or POCG <70 predicted CVD mortality more consistently than EDHYPO.

Conclusion: Hypoglycemia-associated CVD mortality occurs in general clinical practice-especially with outpatient glucose <70 mg/dl-and increased mortality with HbA1c <6.0% may be due in part to hypoglycemia. Management should be aimed to optimize control but limit the risk of hypoglycemia.


M. Rhee: None. K.E. Kurgansky: None. Y. Ho: None. D.R. Gagnon: None. S. Raghavan: None. J.L. Vassy: None. K. Cho: None. A. Gonzalez: None. F.N. Khan: None. L.R. Staimez: None. C.N. Ford: None. P.W. Wilson: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..

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