Admission Proinsulin Is Associated with Mortality in Patients with Admission Hyperglycemia during Acute Coronary Syndrome: Results from a Pilot Observational Study Serdar Farhan, 1* Rudolf Jarai, 1 Ioannis Tentzeris, 1 Matthias K. Freynhofer, 1 Ivan Brozovic, 1 Birgit Vogel, 1 A. Kautzky-Willer, 2 Thomas Wascher, 3,4 Johann Wojta, 5 and Kurt Huber 1 1 Third Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria; 2 Third Department of Endocrinology and Metabolism, University of Medicine, Vienna, Austria; 3 First Department of Medicine, Hanusch Hospital, Vienna, Austria; 4 Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5 Depart- ment of Cardiology, University of Medicine, Vienna, Austria; * address correspondence to this author at: Third Department of Medicine, Cardiology and Emer- gency Medicine, Wilhelminenhospital, Montleart- strasse 37, A-1160 Vienna, Austria. Fax +43-1-49150- 2309; e-mail serdarfarhan@yahoo.de. BACKGROUND: Acute hyperglycemia (AHG) is associ- ated with mortality in patients with acute coronary syndrome (ACS). The extent to which hyperproinsu- linemia contributes to worse clinical outcomes for this specific patient population is unknown. METHODS: We included 308 consecutive ACS patients who underwent coronary angioplasty in this pilot ob- servational study. Patients were separated into 3 groups: patients with proven diabetes mellitus (DM group) (n = 55), nondiabetic patients with a normal glucose concentration at admission (NAG group) (n = 175), and nondiabetic patients with AHG at presenta- tion (AHG group) (n = 78). Blood samples for glucose, insulin, and proinsulin measurements were obtained at admission. The primary end point of the study was all-cause mortality, which was assessed at a mean follow-up of 19 months (interquartile range, 12–28 months). RESULTS: Patients in the AHG and DM groups had significantly (P = 0.048) higher all-cause mortality compared with the NAG group. A univariate Cox regression analysis revealed that the proinsulin con- centration was significantly associated with all-cause mortality for all study participants (hazard ratio, 1.013; 95% CI, 1.002–1.024; P = 0.023). AHG patients with increased proinsulin concentrations showed a mortal- ity rate similar to that of DM patients but had a signif- icantly higher mortality rate than patients with AHG and a low proinsulin concentration ( 2 = 7.57; P = 0.006) and patients with NAG (with or without in- creased proinsulin) [ 2 = 7.66 (P = 0.006) and 13.98 (P  0.001), respectively]. A multivariate regression analysis revealed that the concentrations of glucose and proinsulin at admission were significant (P = 0.002) predictors of all-cause mortality. CONCLUSIONS: An increased proinsulin concentration may be a marker for mortality in ACS patients with hyperglycemia at admission and without known diabe- tes. Further studies are needed to evaluate the role of metabolic parameters such as proinsulin. Hyperglycemia is a common sign of glucometabolic stress during acute coronary syndromes (ACSs) 6 (1– 3). Patients with acute hyperglycemia (AHG) during ACS show increased mortality compared with patients with normal glucose concentrations at admission (NAG), independent of the presence or absence of type 2 diabetes mellitus (DM) (1,4–6). AHG in nondia- betic patients has a greater effect on the clinical course than in patients who have preexisting DM (7, 8 ). Hy- perproinsulinemia is a common feature of the insulin resistance (IR) syndrome. Moreover, in the Hoorn Study population (a middle-aged nondiabetic cohort) (9), proinsulin was an independent predictor of all- cause mortality. Furthermore, proinsulin has been shown to activate procoagulatory markers, such as plasminogen activator inhibitor type 1 (PAI-1) (10 ). Therefore, we investigated the role of proinsulin in pa- tients with AHG during ACS. In this single-center observational study, we en- rolled 308 consecutive ACS patients who underwent a diagnostic angiography evaluation followed by percu- taneous coronary intervention and stent implantation. Patients who underwent emergency bypass surgery and ACS patients who did not receive reperfusion therapy were excluded. The diagnosis and treatment of ACS were performed according to the guidelines of the Eu- ropean Society of Cardiology (11, 12 ). Patients were subdivided into an NAG group, a group of patients with an increased glucose concentration on admission (AHG group), and patients with preexisting DM (DM group). All-cause mortality was assessed at a mean follow-up period of 19 months (interquartile range, 12–28 months). Mortality data were collected from 6 Nonstandard abbreviations: ACS, acute coronary syndrome; AHG, acute hyper- glycemia; NAG, normal glucose concentration at admission; DM, diabetes mellitus; IR, insulin resistance; PAI-1, plasminogen activator inhibitor type 1; CK, creatine kinase; GFR, glomerular filtration rate; HR, hazard ratio. Clinical Chemistry 57:10 1456–1460 (2011) Brief Communications 1456