NDC Issues Warning Against the Use of Higher Sulfonylurea Doses - Particularly When Used in Combination with Metformin

Click here for the Sulfonylurea Dose-Responsive and Sulfonylurea-Metformin Combination Mortality SlideShow
Click here for The Pathophysiology Underlying Cardiovascular Mortality Results in a Worsening of Glycemic Control SlideShow

 

Olney, MD (03 May 2000)

c.f. meta-analysis

The National Diabetes Center - a not-for-profit patient advocacy group for physicians located north of DC - announced today that a meta-analysis of diabetes studies suggested that higher doses of a class of drugs known as sulfonylureas are associated with increased mortality. This mortality appears to correlate with risk of hypoglycemia and with metformin combination.

Sulfonylureas represent a class of drugs which bind to receptors controlling the ATP-sensitive "potassium channel" - the major regulator of voltage differences across the cellular membrane. Identified previously as "SUR-1" [for "SulfonylUrea Receptor-1" found initially in the insulin-producing cells of the pancreas and also in the hypothalamus] this receptor is the physiological leptin response element. Leptin is a hormone released by fat cells in direct proportion to cell size (or degree of adiposity) and when leptin binds to this receptor in the pancreas, it opens the potassium channel thereby inhibiting insulin release. This is likely the major mechanism whereby obesity causes type 2 diabetes.

The major pharmacologic response to this abnormality has been the use of sulfonylureas, which close these same potassium channels thereby offsetting the leptin inhibition and increasing insulin release.

Unfortunately other sulfonylurea receptors ["SUR-2a", "SUR-2b", and "mito -kATP") also exists in the myocardial sarcolemma, vascular smooth muscle cells, and myocardial mitochondrial membranes, respectively. SUR-2b potassium channels control blood flow to the heart and other muscles based on metabolic demand. The effect of closing these channels is to diminish blood flow to the heart. Although sulfonylurea agents differ in their affinity to bind to these SUR-2b receptors, the binding of all agents is increased at higher concentrations. The question set out to answer by epidemiologists at the National Diabetes Center was therefore, "Are higher doses of sulfonylureas associated with increased cardiovascular mortality?"

The NDC has reviewed data now from 11 major studies - (1) the UGDP study in the United States (2) the UKPDS study in Great Britain (3) the metformin pivotal trials for registration with the FDA (4) the Digami study of patients with myocardial infarction in Sweden (5) the Bezafibrate Infarction Prevention study in Israel [6] the Swedish [metformin+sulfonylurea] Surveillance Study in Uppsala, Sweden (7) the Garratt study of angioplasties at the Mayo Clinic (8) the Campbell studies of sulfonylurea-induced hypoglycemic mortality{(9) the Serafimerlassarettet Study (10) the Bedford [Intervention ] Study and (11) the Malmohus County [Intervention] Study.
The result of this meta-analysis is that mortality was seen to associate most strongly with sulfonylurea dosage. The further enhancement of mortality seen in combination of sulfonylureas with metformin - another class of potent oral hypoglycemic agents - was seen to correlate not only with sulfonylurea dosage, but also with degree of control and other likely-surrogates for hypoglycemia.

The National Diabetes Center has therefore issued a warning this day not to utilize any of the agents which close ATP-sensitive potassium channels in doses higher than 2.5 mg/day equivalent glipizide activity [or daily doses of 2.5 mg glyburide, 100 mg chlorpropamide, 1 mg glimepiride, 1.5 mg repaglinide.]

ReReferences [Partial List]

Abbud Z.A., Shindler D.M., Wilson A.C. and Kostis J.B. Effect of diabetes mellitus on short- and long-term mortality rates of patients with acute myocardial infarction: a statewide study. Myocardial Infarction Data Acquisition System Study Group. Am Heart J 1995, 130:51-58.[Medline]

Ambrose J.A. and Weinrauch M. Thrombosis in ischemic heart disease. Arch Intern Med 1996, 156:1382-1394.[Medline]

Ashcroft S.J. and Ashcroft F.M. The sulphonylurea receptor. Biochim Biophys Acta 1992, 1175:45-59.[Medline]

BARI Investigators, Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996, 335:217-225.[Medline]

Brady P.A. and Terzic A. The sulfonylurea controversy: more questions from the heart. J Am Coll Cardiol 1998, 31:950-956.[Medline, ]

Brady P.A., Al-Suwaidi J., Kopecky S.L. and Terzic A. Sulphonylureas and mortality in diabetic patients with myocardial infarction. Circulation 1998, 97:709-710.[Medline]

Brady P.A., Alekseev A.E., Aleksandrova L.A., Gomez L.A. and Terzic A. A disrupter of actin microfilaments impairs sulfonylurea-inhibitory gating of cardiac KATP channels. Am J Physiol 1996, 271:H2710-H2716.[Medline]

Brady P.A., Alekseev A.E. and Terzic A. Operative condition-dependent response of cardiac KATP channels towards sulfonylureas. Circ Res 1998, 82:272-278.[Medline]

Brady P.A., Zang S., Lopez J.R., Jovanovic A., Alekseev A.E. and Terzic A. Dual effect of glyburide, an antagonist of KATP channels, on metabolic inhibition-induced Ca2+ loading in cardiomyocytes. Eur J Pharmacol 1996, 308:343-349.[Medline]

Campbell I.W. Metformin and the sulphonylureas: the comparative risk. : Horm Metab Res Suppl 1985;15:105-11 .[Medline]

Cleveland J.C. Jr, Meldrum D.R., Cain B.S., Banerjee A. and Harkem A.H. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited. Circulation 1997, 96:29-32.[Medline]

Edwards G. and Weston A. The pharmacology of ATP-sensitive potassium channels. Annu Rev Pharmacol Toxicol 1993, 33:597-637.[Medline]

Engler R.L. and Yellon D.M. Sulphonylurea KATP blockade in type II diabetes and preconditioning in cardiovascular disease: time for reconsideration. Circulation 1996, 94:2297-2301.[Medline]

Findlay I. Inhibition of ATP-sensitive K+ channels in cardiac muscle by the sulphonylurea drug glibenclamide. J Pharmacol Exp Ther 1992, 261:540-545.[Medline]

Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro Mn . Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology 1999;91(3):195-202.[NDC]

Fosset M., De Weille J.R., Green R.D., Schmid-Antomarchi H. and Lazdunski M. Antidiabetic sulphonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels. J Biol Chem 1988, 263:7933-7936.[Medline]

Garratt KN, Brady PA, Hassinger NL, D Grill DE, Terzic A and Holmes DR Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 1999, 33:119-124.[AdobeAcrobatPDF]

Gerich J.E. Oral hypoglycemic agents. N Engl J Med 1989, 321:1231-1245.[Medline]

Gray R.P., Yudkin J.S. and Patterson D.L. Enzymatic evidence of impaired reperfusion in diabetic patients after thrombolytic therapy for acute myocardial infarction: a role for plasminogen activator inhibitor? Br Heart J 1993, 70:530-536.[Medline]

Groop L. Sulphonylureas in NIDDM. Diabetes Care 1992, 15:737-754.[Medline]

Gross G.J. and Auchampach J.A. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992, 70:223-233.[Medline]

Gross G.J. ATP-sensitive potassium channels and myocardial preconditioning. Basic Res Cardiol 1995, 90:85-88.[Medline]

Grover G.J. Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia. J Cardiovasc Pharmacol 1994, 24:S18-S27.[Medline]

Hamada E., Takikawa R. and Ito H. et al. Glibenclamide specifically blocks ATP-sensitive K+ channel current in atrial myocytes of guinea pig heart. Jpn J Pharmacol 1990, 54:473-477.[Medline]

Hasdai D., Garratt K.N., Holmes D.R. Jr, Berger P.B., Schwartz R.S. and Bell M.R. Coronary angioplasty and intracoronary thrombolysis are of limited efficacy in resolving early intracoronary stent thrombosis. J Am Coll Cardiol 1996, 28:361-367.[Medline]

Heine R.J. Role of sulfonylureas in non-insulin-dependent diabetes mellitus: Part II—''The cons'' Horm Metab Res 1996, 28:522-526.[Medline]

Innerfield R.J. Metformin-Associated Mortality in U.S. Studies. New Eng J Med 1996,334:1611-1613.[NDC]

Ito Y., Okeda T., Sato Y., Ito M. and Sakata T. Plasminogen activator inhibitor-1 in nonobese subjects with non-insulin-dependent diabetes mellitus. Proc Soc Exp Biol Med 1996, 211:287-291.[Medline]

Jackson W.F. Arteriolar tone is determined by activity of ATP-sensitive potassium channels. Am J Physiol 1993, 265:H1797-H1803.[Medline]

Juhan-Vague I., Alessi M.C. and Vague P. Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med 1996, 28:371-380.[Medline]

Klimt C.R., Knatterud G.L., Meinert C.L. and Prout T.E. A study of the effects of hypoglycemic agents in vascular complications in patients with adult-onset diabetes. Diabetes 1970, 19:747-830.[Medline]

Mak K.H., Moliterno D.J. and Granger C.B. et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol 1997, 30:171-179.[Medline]

Malmberg K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512-1515. [FullTextOnline]
 
Malmberg K. and Ryden L. Myocardial infarction in patients with diabetes mellitus. Eur Heart J 1988, 9:259-264.[Medline]

Mansfield M.W., Stickland M.H. and Grant P.J. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995, 74:842-847.[Medline]

McGill J.B., Schneider D.J., Arfken C.L., Lucore C.L. and Sobel B.E. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994, 43:104-109.[Medline]

Melander A. Increased risk of cardiovascular events, including death, among overweight patients who use metformin and sulfonylureas in combination. reported from EASD Annual Meeting in Brussels, September, 1999 by Johnston C. EASD: Controversy Remains Over Sulfonylurea-Metformin Combination Therapy. Doctors Guide to the Internet, 1 October 1999. [NDC]

Ming Z., Parent R. and Lavallee M. beta2-Adrenergic dilation of resistance coronary vessels involves KATP channels and nitric oxide in conscious dogs. Circulation 1996, 95:1568-1576.[Medline]

Morishita E., Asakura H. and Jokaji H. et al. Hypercoagulability and high lipoprotein(a) levels in patients with type II diabetes mellitus. Atherosclerosis 1996, 120:7-14.[Medline]

Murray C., Jennings R. and Reimer K. Preconditioning with ischemia: a delay in lethal injury in ischaemic myocardium. Circulation 1986, 74:1124-1136.[Medline]

Narishige T., Egashira K., Akatsuka Y., Takahashi T., Kasuya H. and Takeshita A. Glibenclamide prevents coronary vasodilation induced by beta1-adrenoceptor stimulation in dogs. Am J Physiol 1994, 266:H84-H92.[Medline]

Nordt T.K., Schneider D.J. and Sobel B.E. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease. Circulation 1994, 89:321-330.[Medline]

Nordt T.K., Sawa H., Fujii S. and Sobel B.E. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation 1995, 91:764-770.[Medline]

O'Murchu B., Gersh B.J., Reeder G.S., Bailey K.R. and Holmes D.R. Jr Late outcome after percutaneous transluminal coronary angioplasty during acute myocardial infarction. Am J Cardiol 1993, 72:634-639.[Medline]

Oltrona L., Eisenberg P.R., Lasala J.M., Sewall D.J., Shelton M.E. and Winters K.J. Association of heparin-resistant thrombin activity with acute ischemic complications of coronary interventions. Circulation 1996, 94:2064-2071.[Medline]

Olsson J., Lindberg G., Gottsäter M., Lindwall K., Sjöstrand Å., Tisell A., .Melander A. Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study Diabetologia 2000,43:558-560 [NDC]

Panten U., Schwanstecher M. and Schwanstecher C. Sulfonylurea receptors and mechanism of sulfonylurea action. Exp Clin Endocrinol Diabetes 1996, 104:1-9.[Medline]

Rytter L., Troelsen S. and Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 1985, 8:230-234.[Medline]

Stein B., Weintraub W.S. and Gebhart S.P. et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 1995, 91:979-989.[Medline]

Terzic A., Jahangir A. and Kurachi Y. Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and potassium opening drugs. Am J Physiol 1995, 38:C525-C545.[Medline]

Testa R., Bonfigli A.R., Piantanelli L., Manfrini S., Testa I. and Gregorio F. Relationship between plasminogen activator inhibitor type-1 plasma levels and the lipoprotein(a) concentrations in non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1996, 33:111-118.[Medline]

Tomai F., Crea F., Gaspardone A., Versaci F. and De Paulis R. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation 1994, 90:700-705.[Medline]

Turner R. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53 .[LancetOnline]

Zaret B.L., Wackers F.J. and Terrin M.L. et al. Value of radionuclide rest and exercise left ventricular ejection fraction in assessing survival of patients after thrombolytic therapy for acute myocardial infarction: results of Thrombolysis in Myocardial Infarction (TIMI) phase II study. The TIMI Study Group. J Am Coll Cardiol 1995, 26:73-79.[Medline]



Reload The National Diabetes Center Frames
Home Page