Hypoglycemia that is most likely to affect the elderly those who have worsening renal function and those who have irregular meal schedules [72225 Newer sulfonylurealphonylureasstarlix have less ATPsensitive potassium binding KATP and therefore cause less

"nontraditional" risk factors for cardiovascular disease.

An early trial by the UGDP [23], which explored the effectiveness of oral agents versus insulin, found increased cardiovascular mortality in the cohort of patients that was randomized to sulfonylureas. Widespread criticism of the project's methodology placed the validity of its findings in doubt [24]. Nevertheless, concern about cardiovascular risk remains and the package insert for sulfonylureas that is mandated by the US Food and Drug Administration includes a warning about possible cardiovascular risks. In addition, a retrospective analysis of patients who had diabetes mellitus and underwent balloon angioplasty after myocardial infarction reported increased early mortality (odds ratio 2.7 after adjustment for several covariates) in 67 persons who took sulfonylureas and in 118 who used insulin or lifestyle therapy alone [31].

Concern about cardiovascular risk associated with sulfonylureas has been supported by description of a theoretic underlying mechanism—impairment of myocardial ischemic preconditioning. This is a process by which transitory ischemia "conditions" the myocardium in a protective fashion and allows greater tolerance of subsequent ischemia [25,32].

Ischemic preconditioning is a cardioprotective phenomenon in which short periods of myocar-dial ischemia result in a resistance of the myocardium to a subsequent ischemia [33]. Several studies suggested that preconditioning may result from the activation of KATP channels [34-36]. Gross and Auchampach [34] were the first investigators to show that preconditioning in dogs is mediated by activation of KATP channels because it was prevented by glibenclamide. Ischemic preconditioning was shown to be mediated partly by mitochondrial KATP channels [37]. The opening of these channels may be important in ischemic preconditioning because inhibition of KATP channels with glibenclamide abolished the cardiopro-tective effects of ischemic preconditioning in experimental and clinical studies [38,39], and was used to study this phenomenon [40]. Coronary angioplasty is a useful model for clinical study of ischemic preconditioning because it permits adjustment of ischemic time and measurement of metabolic responses to coronary occlusion [25]; however, much of the data are controversial [4143]. Conflicting evidence largely can be attributed to the use of different species in various studies. Few reports are available about ischemic preconditioning in humans who undergo angioplasty and its effects on cardiovascular events.

This phenomenon was shown experimentally to limit anginal pain, minimize irreversible tissue injury, and protect myocardial function. KATP channels in myocardial cells have an important role in this process [44,45]. Pharmacologic agents that open KATP channels have a protective effect similar to that of previous ischemia; agents that close the channels oppose preconditioning by ischemia. Similar (but not identical) KATP channels also are present in the pancreatic b cell [46,47]. The mechanism of action of sulfonylureas relate to binding to a subunit of the b-cell KATP channel complex (the SUR) that leads to closure of the channel and stimulation or potentiation of insulin secretion [48,49]. Sulfonylureas also bind to cardiovascular KATP channels, although less well than to b-cell KATP channels [47]; presumably, this promotes closure of the channel and opposes ischemic preconditioning. This property of sulfonylureas has the potential to increase cardiovascular risk in patients who have diabetes mellitus.

In addition to animal experiments that support this hypothesis that blockade of ischemic preconditioning may lead to worsening of myocardial ischemia [50,51], several human studies that used glibenclamide tested the clinical relevance of interactions of sulfonylureas with the myocardium. For example, an in vitro study of human atrial tissue compared samples that were obtained during surgery from six diabetic patients who had been taking glibenclamide and one who had been taking glipizide with tissue from a group of four patients who had been taking insulin and six patients who did not have known diabetes melli-tus [52]. The atria from patients who were taking a sulfonylurea had less effective protection of contractility during severe hypoxia by previous exposure to hypoxia. Persons who did not have diabetes mellitus were studied during repeated balloon dilation that was done therapeutically for coronary disease. In one study of this kind, 20 patients were randomized to receive a single oral dose of glibenclamide, 10 mg, or placebo just before the procedure [38]. Protection against electrocardiographic changes and pain that resulted during the second balloon dilation in those who were given placebo was abolished by gliben-clamide pretreatment. In a second study that accompanied angioplasty, pretreatment with a single intravenous dose of glibenclamide or glime-piride was compared with saline infusion [53].

Electrocardiographic evidence of ischemia was more pronounced during the second period of ischemia after glibenclamide administration compared with glimepiride or placebo. Dipyridamole stress led to more severe worsening of echocardio-graphically-determined myocardial function when glibenclamide was given.

Thus, blockade of these channels by glibencla-mide may worsen myocardial ischemia by preventing ischemic preconditioning. Differential response of myocardial KATP channels to sulfonylureas was determined by the SUR isoform because multiple regions of SUR contributed to coupling antagonist-occupied sites with the inward rectifier K+ channel-gating machinery [54]. Glimepiride is pharmacologically distinct from glibenclamide because of differences in receptor-binding properties [55]; this could result in a reduced binding to cardiomyocyte KATP channels as reflected in the lower Katp channel current inhibition activity [51].

Lee and Chou [56] studied the impact of diabetes mellitus and different sulfonylurea administrations on cardioprotective effects in diabetic patients who were undergoing coronary angioplasty. Myocardial ischemia after coronary angioplasty was evaluated in 20 nondiabetic and 23 diabetic patients who were chronically taking either glibenclamide or glimepiride. Glimepiride significantly lowered the ischemic burden that was assessed by an ST-segment shift, chest pain score, and myocardial lactate extraction ratios compared with glibenclamide in nondiabetic patients; this implied that acute administration of glime-piride did not abolish cardioprotection. In the diabetic group that was treated with glibencla-mide, the reduction in the ST-segment shift that was afforded by nicorandil in the first inflation (—58% versus the first inflation in the glibencla-mide group alone) was similar to that afforded by preconditioning (—59% during the second versus the first inflation). In groups that were treated with glimepiride, the magnitude of attenuated lactate production was less in diabetics than nondiabetics at the second inflation; this suggested that diabetes mellitus plays a role in determining lactate production. These results show that diabetes mellitus and sulfonylureas can act in synergism to inhibit activation of KATP channels in patients who are undergoing coronary angioplasty. The degree of inhibition that was assessed by metabolic and electrocardiographic parameters was less severe during treatment with glimepiride than with glibenclamide. Restitution of a preconditioning response in patients who are treated with glimepiride may be the potential beneficial mechanism. Thus, preconditioning leads to protection during subsequent ischemia in nondiabetic patients that is unaffected by glimepiride but impaired by glibenclamide. In the diabetic patients, protection by preconditioning occurred with glimepiride but not with gly-buride. In addition, the values for lactate balance suggested that diabetes itself may have impaired preconditioning.

It is possible that whatever effect that gliben-clamide has on ischemic preconditioning is counterbalanced by other effects that are beneficial. The most obvious of these is improvement of glycemic control, as in the UKPDS. Another possible protective effect is an antiarrhythmic action of glyburide that seems to occur under certain circumstances [57]. Thus, the effects of glibenclamide on cardiovascular outcomes may remain neutral or favorable despite an undesirable interaction with ischemic preconditioning.

The peak level that is required for adequate duration of action from this short-acting agent might have been high enough to favor significant binding to the lower-affinity myocardial KATP channel complex and the b-cell channels. Longer-acting sulfonylureas, such as glimepiride, extended-release glipizide, and extended-release gliclazide, lack such prominent peak blood levels, and thus, may be more b-cell specific for phar-macokinetic reasons.

In addition to having effects on the myocardium that set it apart, glibenclamide also may have a greater tendency to cause hypoglycemia than other sulfonylureas [8,58]. As with the myocardial effects, the mechanism of glibencla-mide tendency to cause hypoglycemia is not well-defined. Differences in pharmacokinetics, binding properties, and formation and clearance of metabolites may all contribute, particularly in patients who have renal insufficiency. The increased hypoglycemia may pose a problem in patients who are at risk for cardiovascular events. Desouza et al [59] performed continuous glucose monitoring and simultaneous cardiac holter monitoring for ischemia in patients who had type 2 diabetes mellitus that was treated with insulin. Hypoglyce-mia was more likely to be associated with cardiac ischemia and symptoms than normoglycemia and hyperglycemia and was particularly common in patients who experienced considerable swings in blood glucose. Thus, it may be advisable to avoid drugs that cause hypoglycemia in patients who have established coronary artery disease.

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