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PP268

ASSOCIATION OF ANTIDIABETIC MEDICATION TO LONG TERM PROGNOSIS AFTER AN ISCHEMIC STROKE

Thursday, 6 October, 2011 - 15:16
Board 14

ASSOCIATION OF ANTIDIABETIC MEDICATION TO LONG TERM PROGNOSIS AFTER AN ISCHEMIC STROKE Vassilios Dragoumanos1, Evangelos Fousteris1, Vivi Gavra2, Maria Vourvou3, Ioannis Kanellos1, Alexandra Gougoutsi2, Andreas Melidonis1, 2 1Diabetes Center, Tzanio General Hospital, Piraeus, Greece, 21st Internal Medicine Clinic, Tzanio General Hospital, Piraeus, Greece, 3Intensive Care Unit, Papageorgiou General Hospital, Thessaloniki, Greece  

Background:Recent data suggest that neuroprotective effects of peroxisome proliferator-activated receptor gamma agonists (PPARc) reduce the risk of recurrent stroke in high-risk diabetic patients and improve functional post stroke recovery. There are no randomized controlled trials, though, on the impact of the rest antidiabeticmedications as insulin (INS), biguanides (BIG),sulfonylureas (SULF), meglitinides (MEG), alpha-glucosidase (αG) inhibitors, dipeptidyl peptidase-4inhibitors (DPP-4), glucagon-like peptide-1 (GLP-1) analogs, and their commonest combinations regarding the prognosis of ischemic stroke diabetic patients. Aims: The aim of the present study was to evaluate and associate the effect of various antidiabetic medications on the long-term outcome after an acute ischemic stroke (IS). Materials and methods : This prospective study was conducted in a tertiary Greek hospital. Two-hundred and sixty six (n=266) consecutive IS diabetic patients, admitted between January 2008 and February 2010, comprised the study population. End points were recurrence of stroke (RS) or death due to primary cause within 2 years following the initial episode. Multivariate analysis was used to identify independent predictors, such as patients' demographics, concomitant medications and other risk factors, regarding study's end points. Variables with a p value ≤0.1 in univariate testing were incorporated into the model using a forward stepwise approach. A p value of ≤0.05 was set as the limit of significance in the multivariate model. Results: After 24 months, 80 (30.1%) out of 266 patients, 31 (11.7%) men and 49 (18.4%) women, suffered RS or died. In particular, RS occurred in 13 (4.9%) patients, 8 (3%) women and 5 (1.9%) men, while 67 (25.2%) patients, 41 (15.4%) women and 26 (9.8%) men died. There was a statistically significant beneficial effect of thiazolidinediones (TZD) (OR=2.95, 95% CI:0.99–8.77, P=0.043), as well as of DPP-4 inhibitor (OR=9.51, 95% CI:1.25–72.19, P=0.008) on RS or death.A multivariate analysis of all risk factors, identified TZD (OR=8.26 95% CI:1.75-39, p=0.008) as the strongest significant negative predictor of RS or death, followed by the use of antiplatelet (OR=5.63, 95% CI: 1.92-16.46, p=0.002) and angiotensin receptor blocker (ARB) (OR=1.04, 95% CI: 1.01-1.18, p<0.001). Diabetes duration (OR=1.85, 95% CI: 1.81-1.91, p<0.001) and admission HbA1c levels (OR=3.45, 95% CI: 2.45-4.85, p<0.001) were also significant predictors of RS or death. Discussion: Neuroprotective properties of TZDs after an ischemic stroke are well reviewed in the literature. Treatment with TZDs in laboratory animals in the acute phase of IS has resulted in the activation of inflammatory cells, reduced leukocyte infiltration and reduced toxic gene inflammatory expression disorders in cerebral tissue. In this way, treatment with TZDs have resulted in less severe IS and better neurological outcome. There are contradictory results regarding DPP4 inhibitor benefits after a stroke. A study reported that DPP4 inhibitors (sitagliptins) are associated with increased degree of inflammation in patients with Rheumatoid Arthritis. DPP4s are also known to eliminate the cytokines, generating inflammation. This inflammation causes a frequent complication of sitagliptins: the headache. However, vildagliptin treatment is related with the prevention or reduction of Parkinson 's disease progress, multiple sclerosis and cerebral ischemia. Another recent study correlates DPP4 inhibition with the normal gene expression of calcium regulatory proteins, BNP and interleykin-6, thereby improving cardiorenal function. Their potential benefits regarding cerebral function, are however, under assessment. Chronic metformin treatment has neuroprotective abilities in stroke rehabilitation. On the contrary, metformin treatment during the acute phase of stroke is not recommended because it exacerbates cerebral ischemia, increases AMPK (Adenosine 5 '-monophosphate-activated protein kinase) and causes metabolic disorder. Up to our knowledge there aren't known results in the literature regarding the combinative treatment of BIGs and DPP4 inhibitors to the outcome of stroke.

Summary and Conclusions:

High-risk diabetic patients that receive TZD or DPP-4 inhibitor in addition to their existing medication significantly reduce the risk of RS or death within 2 years after an acute IS. TZD along with the concomitant use of ARB and antiplatelet agents significantly decrease the long-term risk of RS or death, taking into consideration patients' initial glycemic control and diabetes duration.

 

References:

1. Tureyen K, Kapadia R, Bowen KK, et al. Peroxisome proliferator-activated receptor gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem. 2007 Apr;101(1):41-56. 2. Feinstein DL, Galea E, Gavrilyuk V, et al. Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol. 2002 Jun;51(6):694-702. 3. Sacco RL, Adams R, Albers G, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Circulation.2006; 113: e409-e449. 4. Wilcox R, Bousser MG, Betteridge DJ, et al. Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke. Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke.2007; 38: 865-873. 5. Shimazu T, Inoue I, Araki N, A Peroxisome Proliferator-Activated Receptor-γ Agonist Reduces InfarctSize in Transient but Not in Permanent Ischemia. Stroke. 2005;36:353-359. 6. Nakamura T,Yamamoto E, Kataoka K, et al. Pioglitazone exerts protective effects against stroke in stroke-pronespontaneously hypertensive rats, independently of blood pressure. Stroke. 2007;38:3016-3022. 7. Entee K, Gomez N, Touihri K, et al. Dipeptidyl peptidase IV Inhibition Improves Cardiorenal Function in Pacing-Induced Heart Failure. Circulation. 2010;122:A15196.

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