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Analyze of the risk of cardiovascular disease and mortality in users of oral hypoglycemic patients.

The different types of oral hypoglycemic are associated with different levels of cardiovascular risk or mortality from all causes.

Type 2 diabetes is associated with a doubling in risk of mortality, predominantly cardiovascular type. This may be influenced negatively by oral hypoglycemic agents (OHA) that showed some adverse effects, particularly in patients with a history of heart failure. The risk-benefit equation is still under discussion and for this reason, experts from the Department of Epidemiology and Public Health of the Imperial College London, United Kingdom and other British centers of experimental research, studied the risk of myocardial infarction, heart failure and all-cause mortality associated with the requirement of HO in diabetics of both sexes. Taking into account the results of a previous study, the authors expanded data including a larger group (n= 91,521) and other cardiovascular variables, and analyzes the risks associated with the use of tiazoledinedionas.

Material and methods
The database of general practice in the UK was analyzed, from the period 1990-2005, which included 91,521 diabetics. The main endpoints were incident myocardial infarction, congestive heart failure and mortality from all causes. The time intervals of use of each drug treatment were categorized according to drug type, excluding the periods when HO was not used, or when the use of insulin was recurred.
The incidence of myocardial infarction in the period under review amounted to 3,588 cases, of congestive heart failure to 6,900 episodes, and of death to 18,548. Sulfonylurea monotherapy first or second generation was associated with higher and significant risk (24% to 61%, P <0.001) of mortality from all causes, compared with metformin. The same was observed in the case of second generation sulfonylureas regarding the risk of congestive heart failure: 18% to 30% higher risk (p= 0.01 and p <0.001).
The use of pioglitazone resulted in a reduction of 31% to 39% risk of death from all causes (p= 0.02 p <0.001), compared with metformin. The comparison between rosiglitazone and pioglitazone shoed that the latter was associated with a risk between 34% and 41% lower all-cause mortality (p= 0.14 p = 0.01), than rosiglitazone. For non of the tiazoledinedionas increased risk of myocardial infarction was observed.

Discussion and conclusions
The London study provides an overview of the risks versus benefits in the area of “real” medical practice.
Compared with metformin monotherapy, it faces increased risk of mortality with the use of sulfonylureas of the first or second generation, confirming previous studies. The underlying mechanism has been linked to inhibition of potassium channels, leading to increased intracellular potassium. This is beneficial in pancreatic beta cells and thus that insulin is secreted, but harmful to cardiomyocytes and vascular smooth muscle cells, because it adversely affects ischemic preconditioning, a mechanism that protects against ischemic injury.
The authors did not demonstrate an increased risk of myocardial infarction associated with thiazolidinedione when compared to metformin. Two previous meta-analyses that reported the opposite were challenged by limitations such as short periods of follow up, low event rate, non-registration of time to onset of the event, incomplete results and heterogeneity of effects in combination studies. Overall, there are still no clear or conclusive evidence on potential benefits versus risks in the field of cardiovascular therapy with thiazolidinedione.
In this study, rosiglitazone was associated with lower mortality than metformin; these findings are consistent with the study of
PROspectivePioglitAzoneclinical Trial in macro-Vascular Events Study (PROACTIVE), which is the largest randomized trial of pioglitazone in cardiovascular disease developed to date. The PROACTIVE demonstrated that pioglitazone reduced the overall risk of macro vascular events and significantly decreased risk of mortality from all causes, myocardial infarction or stroke (hazard ratio: 0.84, 95% CI 0.72 to 0.98). That is, despite the increased risk of heart failure, pioglitazone has a possible protective cardiovascular effect. Pioglitazone, that does not share with rosiglitazone its role in the inflammatory response and endothelial liver, shows a associated mortality risk significantly less than the latter.
In summary, the unfavorable risk profile of sulfonylureas explains the preferential use of metformin as initial therapy in type 2 diabetes. The authors confirmed the favorable risk profile of pioglitazone compared to rosiglitazone, associated with reduced risk of mortality from all causes. These findings should be assessed, experts say, when anti-diabetic treatments are prescribed.

Tzoulaki I y col. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database BMJ 339:b4731,2009. Editora Médica Digital