Cardiovascular Implications

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SUs bind to a subunit of the KATP channel complex inducing closure of the channel. In the past years, different cross-reactivity with cardiovascular KATP channels have been investigated [50]. Particular attention has been set on the phenomenon of ischemic preconditioning, which (self)protects the myocardial cells from ischemia and reduces infarct size [51]. As preconditioning is a result of opening the KATP channels, it could be opposed by closing these channels, a fact that raised concerns about possibly increased cardiovascular complications and mortality during SU therapy [9]. In a recent study, left ventricular myocardial function was determined in type 2 diabetic patients with known coronary artery disease after therapy with either insulin or glibenclamide. Stress conditions were provoked by dipyridamole infusion. Patients treated with glibenclamide showed much worse myocardial function assessed with echocardiogra-phy. This effect could be restored when therapy was changed to insulin [52].

Clinical and epidemiological data on the impact of SU use on myocardial infarction are controversial. In 1970, concerns about cardiovascular safety were raised upon results of the University Group Diabetes Program, in which treatment with tolbu-tamide increased cardiovascular mortality compared with insulin and placebo [53]. In diabetic patients undergoing direct balloon angioplasty for acute myocardial infarction, sulfonylurea drug use was associated with an increased risk of in-hospital mortality [54]. However, no detailed information on the specific SUs is given in that study. As data were collected between 1985 and 1994, probably first or early second-generation SUs have been used. In another study, treatment with glibenclamide or glipizide was associated with an attenuated magnitude of ST-elevation during myocardial infarction, resulting in failure to meet the criteria for throm-bolytic therapy and as a consequence leading to inappropriate withholding therapy in those patients [55]. Some other studies yielded similar results [56,57], whereas others even suggested decreased cardiac mortality on treatment with SUs [58,59]. In the UKPDS and other studies, SU treatment seemed to be neutral [11,60,61]. It is of note that most of those data are based on the use of "older" SUs.

In the ADOPT-study [42] glibenclamide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (p < 0.05), and the risk associated with metformin was similar to that with rosiglita-zone (Table 2). This observation differs from the UKPDS findings, which suggested that metformin reduces overall mortality and may reduce coronary events. This difference may be related to the facts that patients in the ADOPT-study were younger and had a shorter follow-up period than did the British study. The lower cardiovascular risk associated with glibenclamide compared with rosiglita-zone or metformin in the early phase of type 2 diabetes needs further confirmation, but could be related to better postprandial glucose lowering induced by glibenclamide, since HbA1c values were only slightly different, whereas fasting glucose levels were significantly higher in the SU group (Fig. 2).

Few data about new SU agents are available. Recently, in an epidemiologic study, the association between the use of SUs and other antidiabetic drugs and the risk of cardiovascular complications has been investigated [62] in a population-based case-control study. From those data, the risk of myocar-dial infarction appeared higher among users of "old" SUs like glibenclamide, glipizide and tolbutamide [adjusted odds ratio (OR), 2.07; 95% confidence interval (CI), 1.81-2.37] than among users of glimepiride and gliclazide (adjusted OR, 1.36; CI, 1.01-1.84). If diabetes was not treated with pharmacotherapy, the OR was 3.51 (CI 2.92-4.22).

In a study with type 2 diabetic patients undergoing coronary angioplasty, inhibition of ischemic preconditioning assessed by metabolic and electrocardiographic parameters was less severe during treatment with glimepiride than with glibenclamide. Restitution of a preconditioning response in glimepiride-treated patients may be the potential beneficial mechanism [63]. Other studies confirm different selectivity of SUs for beta cell versus cardiovascular KATP channels and therapeutic benefits of glimepiride in comparison with glibenclamide [64-66].

This epidemiological and observational approach evaluating the effect of "old" versus "new SUs" was recently enlarged in a Danish nationwide population-based study [67]. Altogether, 72,913 patients with first-time admissions with myocar-dial infarction were followed up including 6,644 patients with type 2 diabetes, 3,992 of them were treated with SUs (1,438 were on "new SUs" and 2,554 on "old SUs"). Remarkably, 30-day mortality was significantly lower in patients on "new SUs" (19%; gliclazide: 17.4%; glimepiride: 19.4%) compared with patients treated with old SUs (25.9%). The relative risk ratio for mortality after myocardial infarction associated with the use of "new SUs" was 0.75 (p = 0.009). The data observed in Danish patients with myocardial infarction are in agreement with a recent report from Italy [68], which evaluated the 3-year mortality in 696 diabetic patients treated with different combinations of insulin secretagogues and metformin. The yearly mortality was 8.7%, when metformin was combined with glibenclamide, but only 3.1%, 2.1% or 0.4% when the biguanide was combined with repaglinide, gliclazide or glim-piride. The risk ratio for mortality associated with glibenclamide versus other SUs was significantly increased: 2.09 (CI: 1.07; 4.11).

Table 2. Vascular serious adverse events during treatment with rosiglitazone, metformin or glibenclamide in the ADOPT-study population (for details see text and ref. 42).

Table 2. Vascular serious adverse events during treatment with rosiglitazone, metformin or glibenclamide in the ADOPT-study population (for details see text and ref. 42).

Rosiglitazone

Metformin

Glibenclamide

(n = 1,456)

(n = 1,454)

(n = 1,441)

Cardiovascular disease, n (%)

49 (3.4%)

46 (3.2%)

26 (1.8%)a

Myocardial infarction

Fatal, n (%)

2 (0.1%)

2 (0.1%)

3 (0.2%)

Non-fatal, n (%)

22 (1.5%)

18 (1.2%)

11 (0.8%)

CHF, n (%)

12 (0.8%)

12 (0.8%)

3 (0.2%)a

Stroke, n (%)

13 (0.9%)

17 (1.2%)

12 (0.8%)

Peripheral vascular disease, n (%)

7 (0.5%)

6 (0.4%)

4 (0.3%)

ap < 0.05 versus rosiglitazone.

ap < 0.05 versus rosiglitazone.

In addition to coronary heart disease, other effects of modern SUs have been investigated: In a recent study, the effects of treatment with gliben-clamide and gliclazide on forearm post-ischemic reactive hyperaemia were investigated. Four-week treatment with glibenclamide but not gliclazide resulted in sustained reduction of post-ischaemic reactive hyperaemia. The authors concluded that this difference was most probably based on different SU-receptor binding [69].

However, other mechanisms could contribute to such effects: gliclazide could also possess haemor-rheologic properties [70,71]. It reduces platelet reactivity, increases prostacyclin synthesis and increases fibrinolysis [9]. In one study, administration of either modified release or standard gliclazide to type 2 diabetic patients resulted in a fall in 8-isoprostanes, a marker of lipid oxidation, and an increase in total plasma antioxidant capacity, superoxide dismutase and thiols, all of them antioxidant parameters [72]. In a similar study, where these data were confirmed, gliclazide, but not glibenclamide reduced systolic and diastolic blood pressure [73]. Following that data, gliclazide possesses antioxidant properties that produce measurable clinical effects at therapeutic doses. In another study, gliclazide, but not glibenclamide treatment was able to lower serum ICAM-1 levels in poorly controlled type 2 diabetic patients, which typically have elevated serum ICAM-1 as a marker of endothelial dysfunction [74].

Similarly, glimepiride, but not glibenclamide, has been shown to improve insulin resistance and TNF-alpha, interleukin-6, high sensitive-CRP, lipoprotein(a), homocystein and plasminogen activator inhibitor-1 (PAI-1) levels, all markers of atherosclerotic disorder [75,76]. In vitro studies suggest that glimepiride, and to a lesser extent gliclazide are more potent inhibitors of platelet aggregation than gliquidone and glibenclamide [77].

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