Tolbutamide

Oral sulfonylureas, particularly the cost-effective first generation agents, are a mainstay of treatment for patients with type 2 diabetes mellitus. Yet, data are conflicting as to whether oral sulfonylureas increase the incidence of new coronary events in these patients.

More than 30 years ago, the University Group Diabetes Program (UGDP) found that sulfonylureas increased cardiovascular (CV) mortality in persons with diabetes mellitus. (1) In this study, compared with a placebo group of 205 diabetic patients, a standard insulin dose group of 210 diabetic patients, and a variable insulin dose group of 204 diabetic patients, tolbutamide administered to 204 diabetic patients caused an increased incidence of CV mortality (4.9% for the placebo group, 6.2% for the standard insulin dose group, 5.9% for the variable insulin dose group, and 12.7% for the tolbutamide group). These findings led the U.S. Food and Drug Administration to require a blackbox warning in sulfonylurea packaging. Despite the FDA action, conclusions of the UGDP were criticized (2) and the findings' significance were downplayed. Yet, the warning remains (box).

Ten years ago, findings from the much larger United Kingdom Prospective Diabetes Study (UKPDS) countered those of the UGDP. This study of 3,867 patients with newly diagnosed diabetes mellitus (mean age 54) found that treatment with oral sulfonylureas was not harmful. (3)

What sulfonylureas do Sulfonylureas induce the pancreas to release insulin by preventing the opening of adenosine triphosphate-sensitive potassium ([K.sub.ATP]) channels. Sulfonylureas also inhibit membrane-associated potassium channels in the heart and have been found to impair ischemic preconditioning4 and prevent coronary vasodilation in response to myocardial ischemia. (5) Sulfonylurea drug action within the myocardium may increase its vulnerability to ischemia. (6) Sulfonylureas also impair ischemic preconditioning during coronary angioplasty, resulting in increased clinical manifestations of myocardial ischemia. (7) By preventing the opening of myocardial KATP channels, sulfonylureas would appear to have the potential to increase the consequences of myocardial ischemia. (8)

Khawaja et al (9) studied 14 diabetic patients with coronary artery disease (CAD) treated with insulin and/or glucophage (group 1) and 14 diabetic patients with CAD treated with sulfonylureas (group 2) by exercise nuclear treadmill testing. Exercise-induced myocardial ischemia occurred in 14% of group 1 patients versus 92% of group 2 patients. Exercise-induced myocardial ischemia detected by a nuclear scan was present in 22% of group 1 patients versus 64% of group 2 patients. Exercise-induced chest pain occurred in 14% of group 1 patients versus 50% of group 2 patients. Exercise capacity was 8.8 METS in group 1 patients versus 7.8 METS in group 2 patients, meaning diabetics with CAD treated with insulin and/or glucophage can exercise longer than diabetics with CAD treated with sulfonylureas.

Mocanu et al (10) showed that the sulfonylurea glibenclamide abolished myocardial protection afforded by either ischemic preconditioning or diazoxide in the isolated rat heart. However, these investigators demonstrated that the novel sulfonylurea glimepiride did not block the beneficial effects of mitochondrial [K.sub.ATP] channel opening in the isolated rat heart. Therefore, the effects of glimepiride on CV events needs further investigation.

Animal studies have also demonstrated that opening of [K.sub.ATP] channels in the myocardium results in ST-segment elevation during acute MI, and that pretreatment with sulfonylureas blunts these ST-segment changes. (11-13)

In a retrospective study with 88 diabetic patients hospitalized with acute MI over a 4-year period, Huizar et al demonstrated that sulfonylurea therapy attenuated the magnitude of ST-segment elevation during acute MI. (14) This resulted in failure to meet criteria for administration of thrombolytic therapy and consequently led to inappropriately withholding therapy in this group of diabetic patients. Non-diagnostic ST-segment elevation was present in 53% of patients treated with sulfonylureas versus 29% of patients in the control group in this study. Thrombolytic therapy was administered to 20% of diabetics treated with sulfonylureas versus 40% of diabetics in the control group. These investigators concluded that if additional studies confirm their findings, the criteria for thrombolytic therapy should be reconsidered or the use of other hypoglycemic drug therapy considered in diabetics with acute MI. Whereas this study raises several interesting points, questions have been raised about its statistical validity and relevance to the population at large.

Other coronary events Clinical outcomes after direct coronary angioplasty for acute MI were evaluated in 67 diabetic patients taking oral sulfonylurea drugs and in 118 diabetic patients not taking sulfonylureas. (15) Hospital mortality was significantly higher among patients with diabetes mellitus treated with oral sulfonylurea drugs (24%) versus those treated with insulin or diet (11%). Logistic regression analysis found sulfonylurea drug use to be a significant independent predictor of hospital mortality (odds ratio = 2.77).

O'Keefe et al demonstrated that oral sulfonylureas exerted an independent adverse outcome after elective coronary angioplasty in diabetic patients with CAD. (16) Elsewhere, O'Keefe et al pointed out that sulfonylureas induce vasoconstriction and worsen vascular reactivity. By promoting weight gain and increasing insulin levels, sulfonylureas may increase atherogenesis and cardiovascular events. (17)

Of 636 older persons, mean age 80, with diabetes mellitus and prior MI, 278 persons (44%) were treated with sulfonylureas, 272 persons (43%) with insulin, 9 persons (1%) with metformin, and 77 persons (12%) with diet alone. (18) Mean follow-up was 30 months. In this study, use of sulfonylureas was associated with a significant independent increase in the incidence of new coronary events with a risk ratio of 1.4.

However, Jollis et al (19) did not find an association between sulfonylurea therapy and adverse events in older persons who had diabetes mellitus and acute MI. As noted earlier, the UKPDS also found that treatment with sulfonylureas was not harmful. (3)

Conclusions

This brief review confirms that there are conflicting data as to whether sulfonylureas increase CV mortality. A large-scale, prospective, randomized study needs to be performed to investigate whether sulfonylureas increase the incidence of new coronary events in persons with CAD. Such a study also needs to investigate whether sulfonylureas attenuate the magnitude of ST-segment elevation during acute MI.

Data show that glimepiride is a more selective potassium ion channel blocker. (20) Whether glimepiride is safer than other sulfonylureas in causing cardiovascular events still needs to be proven.

On the basis of the available data, it would seem prudent to minimize the use of sulfonylureas in diabetics with coronary artery disease when feasible. And data would appear to support switching diabetics with CAD who are receiving sulfonylureas to other hypoglycemic therapy at the time of an acute MI or coronary angioplasty.

References

(1.) University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of phenformin therapy. Diabetes 1975; 24(suppl 1):65-184.

(2.) Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes 1972; 21(9):976-9.

(3.) Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):837-53.

(4.) Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 1997; 96(1):29-32.

(5.) Narishige T, Egashira K, Akatsuka Y, et al. Glibenclamide prevents coronary vasodilation induced by beta 1-adrenoceptor stimulation in dogs. Am J Physiol 1994; 266(1 Pt 2):H84-92.

(6.) Engler RL, Yellon DM. Sulfonylurea [K.sub.ATP] blockade in type II diabetes and preconditioning in cardiovascular disease. Time for reconsideration. Circulation 1996; 94(9):2297-301.

(7.) Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation 1994; 90(2):700-5.

(8.) Brady PA, Terzic A. The sulfonylurea controversy: More questions from the heart. J Am Coll Cardiol 1998; 31(5):950-6.

(9.) Khawaja U, Campeau R, Tenaglia A, et al. Prevention of ischemic preconditioning in diabetic patients with CAD treated with sulfonylureas (abstract). J Am Coll Cardiol 2000; 35:339A.

(10.) Mocanu MM, Maddock HL, Baxter GF, Lawrence CL, Standen NB, Yellon DM. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation 2001; 103(25):3111-6.

(11.) Wilde AA. ATP-sensitive potassium channels, transmural ischemia and the ECG implications for the non-insulin dependent diabetic patient? Cardiovasc Res 1996; 31(5):688-90.

(12.) Kubota I, Yamaki M, Shibata T, Ikeno E, Hosoya Y, Tomoike H. Role of ATP-sensitive K+ channel on ECG ST segment elevation during a bout of myocardial ischemia. Circulation 1993; 88(4 Pt 1):1845-51.

(13.) Kondo T, Kubota I, Tachibana H, Yamaki M, Tomoike H. Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia. Cardiovasc Res 1996; 31(5):683-7.

(14.) Huizar JF, Gonzalez LA, Alderman J, Smith HS. Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetics. J Am Coll Cardiol 2003; 42(6):1017-21.

(15.) Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 1999; 33(1):119-24.

(16.) O'Keefe JH, Blackstone EH, Sergeant P, McCallister BD. The optimal mode of coronary revascularization for diabetics. A risk-adjusted long-term study comparing coronary angioplasty and coronary bypass surgery. Eur Heart J 1998; 19(11):1696-703.

(17.) O'Keefe JH Jr, Miles JM, Harris WH, Moe RM, McCallister BD. Improving the adverse cardiovascular prognosis of type 2 diabetes. Mayo Clin Proc 1999; 74(2):171-80.

(18.) Aronow WS, Ahn C. Incidence of new coronary events in older persons with diabetes mellitus and prior myocardial infarction treated with sulfonylureas, insulin, metformin, and diet alone. Am J Cardiol 2001; 88(5):556-7.

(19.) Jollis JG, Simpson RJ Jr, Cascio WE, Chowdhury MK, Crouse JR 3rd, Smith SC Jr. Relation between sulfonylurea therapy, complications, and outcome for elderly patients with acute myocardial infarction. Am Heart J 1999; 138(5 Pt 1):S376-80.

(20.) Muller G, Satoh Y, Geisen K. Extrapancreatic effects of sulfonylureas--a comparison between glimepiride and conventional sulfonylureas. Diabetes Res Clin Pract 1995; 28(suppl):S115-37.

Dr. Aronow is clinical professor of medicine, department of medicine, divisions of cardiology and geriatrics, New York Medical College, Valhalla, NY. Disclosure: The author has no real or apparent conflicts of interest related to the subject under discussion.

FDA mandated sulfonylurea warning:

Administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared with treatment with diet alone or diet plus insulin. Despite controversy regarding its interpretation, this warning is based on the study conducted by the University Group Diabetes Program (UGDP). This long-term prospective clinical trial involving 823 patients evaluated the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. (Diabetes 1970; 19[suppl 2]:747-830.)

Patients treated for 5 to 8 years with diet plus tolbutamide (1.5 g/d) had a rate of CV mortality 2.5 times that of patients treated with diet alone. A significant increase in total mortality was not observed. Consider this for other sulfonylureas as well.

Sulfonylurea binding to ATP-dependent K+ channels has been shown to inhibit the response to ischemia, potentially delaying the recovery of contractile function and increasing infarct size during a MI. However, prevention of channel opening during ischemia could reduce the occurrence of ventricular fibrillation during ischemia. Inform the patient of potential risks, advantages, and alternative modes of therapy.

Take Home

* Based on current data, the author recommends that clinicians exercise prudence by minimizing use of sulfonylureas in diabetics with coronary artery disease.

* Data appears to support switching diabetics with CAD who are receiving sulfonylureas to other hypoglycemic therapy at the time of an acute MI or coronary angioplasty.

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