Cardiovascular Drugs and Therapy

, Volume 9, Issue 2, pp 295–304 | Cite as

Association between serum lipids, glucose tolerance, and insulin sensitivity during 12 months of celiprolol treatment

  • Kimmo Malminiemi
Beta-Blockers

Summary

The study was undertaken to evaluate the development and association of parameters related to the metabolic syndrome during celiprolol treatment. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed on 25 nondiabetic patients with controlled hypertension and dyslipidemia. The tests were carried out during the patients' previous antihypertensive monotherapy (beta- or Ca-blocker, or an ACE inhibitor), and after 6 and 12 months of celiprolol treatment. About one third of patients were randomized to a control group in which treatment was kept unchanged. Insulin sensitivity index (ISI), measured by the euglycemic clamp test, increased 35% in the celiprolol group at 6 months and remained at that level at 12 months, independent of the previous treatment (p=0.03, compared to the change in the control group). During a 2 hour OGTT, incremental glucose area under the curve (AUC) decreased from 4.5 to 1.9 hr × mmol/l during 6 months of celiprolol treatment, and decreased further to 1.5 hr × mmol/l at 12 months (p<0.001). Insulin AUC decreased from 113 to 72 hr × mU/l, and decreased further to 68 hr × mU/l (p<0.01). All insulin parameters in OGTT were highly significant (p<0.0001) and inversely associated with ISI. Insulin AUC had the best linear correlation with ISI (r=−0.682, p<0.0001). Glucose parameters in OGTT correlated only weakly and inversely with insulin sensitivity. From the fasting serum lipids, triglycerides showed an inverse (p<0.001) and HDL a weak (p<0.05) positive association with ISI. Four out of 20 metabolic, clinical, and demographic parameters proved to be independently significant predictors for ISI in multiple regression analysis. These were insulin AUC, fasting insulin levels, triglyceride values, and age. The coefficient of determination in this four-parameter linear model was 69%. In this preliminary, observer-masked trial with a limited control group, celiprolol improved the impaired insulin sensitivity and glucose tolerance of dyslipidemic hypertensive patients. A fairly predictive model can be formulated to evaluate the peripheral insulin sensitivity of hypertensive patients with suspected metabolic syndrome using OGTT with serum insulin determinations.

Key Words

metabolic syndrome celiprolol insulin sensitivity euglycemic clamp dyslipidemia hypertension 

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References

  1. 1.
    Reaven GM. Role of insulin resistance in human disease (Syndrome X): An expanded definition.Annu Rev Med 1993;44:121–131.Google Scholar
  2. 2.
    Botker HE, Moller N, Ovesen P, et al. Insulin resistance in microvascular angina (syndrome X).Lancet 1993;342:136–140.Google Scholar
  3. 3.
    Black HR. The coronary artery disease paradox: The role of hyperinsulinemia and insulin resistance and implications for therapy.J Cardiovasc Pharmacol 1990;15(Suppl 5):S26-S38.Google Scholar
  4. 4.
    Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics.Metabolism: Clin Exp 1988;37:338–345.Google Scholar
  5. 5.
    Fuh MM-T, Shieh S-M, Wu D-A, Chen YDI, Reaven GM. Abnormalities of carbohydrate and lipid metabolism in patients with hypertension.Arch Intern Med 1987;147:1035–1038.Google Scholar
  6. 6.
    Chen Y-DI, Jeng C-Y, Reaven GM. HDL metabolism in diabetes.Diabetes Metab Rev 1987;3:653–668.Google Scholar
  7. 7.
    Jarrett RJ, Keen H, McCartney M, et al. Glucose tolerance and blood pressure in two population samples: Their relation to diabetes mellitus and hypertension.Int J Epidemiol 1978;7:15–24.Google Scholar
  8. 8.
    Smith U, Gudbjörnsdottir S, Landin K. Hypertension as a metabolic disorder—an overview.J Intern Med 1991;229(Suppl 2):1–7.Google Scholar
  9. 9.
    Moller DE, Flier JS. Insulin resistance—mechanisms, syndromes, and implications.N Engl J Med 1991;325:938–948.Google Scholar
  10. 10.
    DeFronzo RA, Ferrannini E. Insulin resistance; a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease.Diab Care 1991;14:173–194.Google Scholar
  11. 11.
    Sheu WSS, Shieh SM, Fuh MMT, et al. Insulin resistance, glucose intolerance and hyperinsulinemia; hypertriglyceridemia versus hypercholesterolemia.Arterioscl Thromb 1993;13:367–370.Google Scholar
  12. 12.
    Pollare T, Lithell H, Berne C. Insulin resistance is characteristic feature of primary hypertension independent of obesity.Metabolism: Clin Exp 1990;39:167–174.Google Scholar
  13. 13.
    Pyörälä K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: Results from two population studies in Finland.Diab Care 1979;2:131–141.Google Scholar
  14. 14.
    Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: The key feature of a cardiovascular and metabolic syndrome.Diabetologia 1991;149:1514–1520.Google Scholar
  15. 15.
    Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context.Lancet 1990;335:827–838.Google Scholar
  16. 16.
    Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance.Ann Intern Med 1993;118:529–539.Google Scholar
  17. 17.
    Lithell HO. Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.Diab Care 1991;14:203–209.Google Scholar
  18. 18.
    Milne RJ, Buckley MMT. Celiprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease.Drugs 1991;41:941–969.Google Scholar
  19. 19.
    Opie LH. Qualities of an ideal beta adrenergic antagonist and comparison of existing agents with a new cardioselective hydrophilic vasodilator beta adrenergic antagonist, celiprolol.Am J Cardiol 1988;61:8C-13C.Google Scholar
  20. 20.
    Riddell JG, Shanks RG, Brogden RN. Celiprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris.Drugs 1987;34:438–458.Google Scholar
  21. 21.
    Vyssoulis GP, Karpanou EA, Pitsavos CE, Skoumas JN, Paleologos AA, Toutouzas PK. Differentiation of betablocker effects on serum lipids and apolipoproteins in hypertensive patients with normolipidaemic and dyslipidamic profiles.Eur Heart J 1992;13:1506–1513.Google Scholar
  22. 22.
    Fogari R, Zoppi A, Tettamanti F, Malamani G, Pasotti C. The effect of celiprolol on the blood lipid profile in hypertensive patients with high cholesterol levels.Cardiovasc Drugs Ther 1991;4(Suppl 6):1287–1290.Google Scholar
  23. 23.
    Herrmann JM, von Heyman F, Freischutz M. Lipid profile improvement following celiprolol.J Int Med Res 1988;16(Suppl 1):39A-46A.Google Scholar
  24. 24.
    Nordic Guidelines for Good Clinical Trial Practice. Stockholm: Nordic Council on Medicines, December 1989.Google Scholar
  25. 25.
    DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: A method for quantifying insulin secretion and resistance.Am J Physiol 1979;237:E214-E223.Google Scholar
  26. 26.
    McGuire EAH, Helderman JH, Tobin JD, Andres R, Berman M. Effects of arterial versus venous sampling on analysis of glucose kinetics in man.J Appl Physiol 1976;41:565–73.Google Scholar
  27. 27.
    Stein EA. Lipids, lipoproteins and apolipoproteins. In: Tietz NA, ed.Fundamentals in Clinical Chemistry, 3rd ed. Philadelphia: WB Saunders, 1987:476–477.Google Scholar
  28. 28.
    Cederholm J, Wibell L. Evaluation of insulin release and relative peripheral resistance with use of the oral glucose tolerance test: A study in subjects with normoglycaemia, glucose intolerance and non-insulin-dependent diabetes mellitus.Scand J Clin Lab Invest 1985;45:741–751.Google Scholar
  29. 29.
    Gottesman I, Mandarino L, Gerich J. Use of glucose uptake and glucose clearance for the evaluation of insulin action in vivo.Diabetes 1984;33:184–91.Google Scholar
  30. 30.
    Sherwin RS, Kramer KJ, Tobin JD, et al. A model of kinetics of insulin in man.J Clin Invest 1974:53:1481–92.Google Scholar
  31. 31.
    Zar JH.Biostatistical analysis, 2nd ed. London: Prentice-Hall, 1984; ANOVA: 162–169, confidence intervals: 170–171, power: 171–176.Google Scholar
  32. 32.
    Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension.Lancet 1981;2:539–543.Google Scholar
  33. 33.
    Starke AAR. Determination of insulin sensitivity: Methodological considerations.J Cardiovasc Pharmacol 1992;20(Suppl 11):S17-S21.Google Scholar
  34. 34.
    Campbell IT, Jarrett RJ, Keen H. Diurnal and seasonal variation in oral glucose tolerance: Studies in the Antarctic.Diabetologia 1975;11:139–145.Google Scholar
  35. 35.
    Yki-Järvinen H. Action of insulin on glucose metabolism in vivo.Bailliere's Clin Endocrinol Metab 1993;7:903–927.Google Scholar
  36. 36.
    Rudenski AS, Matthews DR, Levy JC, Turner RC. Understanding “insulin resistance”: Both glucose resistance and insulin resistance are required to model human diabetes.Metabolism: Clin Exp 1991;40:908–917.Google Scholar
  37. 37.
    Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.J Clin Invest 1990;85:1844–1852.Google Scholar
  38. 38.
    Shmueli E, Alberti KGMM, Record CO. Diacylglycerol/protein kinase C signalling: A mechanism for insulin resistance?J Intern Med 1993;234:397–400.Google Scholar
  39. 39.
    Häring HU, Mehnert H. Pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: Candidates for a signal transmitter defect causing insulin resistance of the skeletal muscle.Diabetologia 1993;36:176–182.Google Scholar
  40. 40.
    Clauser E, Leconte I, Auzan C. Molecular basis of insulin resistance.Horm Res 1992;38:5–12.Google Scholar
  41. 41.
    Tung LH, Jackman G, Campbell B, Louis S, Iakovidis D, Louis WJ. Partial agonist activity of celiprolol.J Cardiovasc Pharmacol 1993;21:484–488.Google Scholar
  42. 42.
    Wheeldon NM, McDevitt DG, Lipworth BJ. Selectivity of antagonist and partial agonist activity of celiprolol in normal subjects.Br J Clin Pharmacol 1992;34:337–343.Google Scholar
  43. 43.
    Mann WS, Sales EF, Van Inwegen RG, Barrett JA, Smith RD, Wolf PS. Celiprolol, a compound possessing weak alpha-2-adrenoceptor antagonist properties in the dog.Arch Int Pharmacodyn Ther 1986;284:53–71.Google Scholar
  44. 44.
    Champigny O, Ricquier D, Blondel O, Mayers RM, Briscoe MG, Holloway BR. Beta-3-adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial uncoupling protein in adult dogs.Proc Natl Acad Sci USA 1991;88:10774–10777.Google Scholar
  45. 45.
    Fitzgerald JD. Do partial agonist beta-blockers have improved clinical utility?Cardiovasc Drugs Ther 1993;7:303–310.Google Scholar
  46. 46.
    Kritz H, Najemnik C, Irsigler K. Beta-receptor blockade and diabetes mellitus: Effect of celiprolol on blood sugar level and insulin in type I and type II diabetes.Arzneim Forsch 1983;33:72–76.Google Scholar
  47. 47.
    Fogari R, Lazzari P, Zoppi A, Tettamanti F, Malamani G, Boari L. The effects of celiprolol in the short-term treatment of hypertensive patients with type 2 diabetes.Curr Ther Res 1990;47:879–888.Google Scholar
  48. 48.
    Bassett DR, Block WD, Dean EN, White AA. Recognition of borderline carbohydrate-lipid metabolism disturbance: An incipient form of type IV hyperlipoproteinemia.J Cardiovasc Pharmacol 1990;15(Suppl 5):S8-S17.Google Scholar
  49. 49.
    Laakso M, Sarlund H, Mykkanen L. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.Arteriosclerosis 1990;10:223–231.Google Scholar
  50. 50.
    Ronnemaa T, Laakso M, Kallio V, Pyörälä K, Marniemi J, Puukka P. Serum lipids, lipoproteins and apolipoproteins and the excessive occurrence of coronary heart disease in non-insulin-dependent diabetic patients.Am J Epidemiol 1989;130:632–645.Google Scholar
  51. 51.
    Enzi G, Pavan M, Digito M, et al. Clustering of metabolic abnormalities and other risk factors for cardiovascular disease in visceral obesity.Diab Nutr Metab 1993;6:47–55.Google Scholar
  52. 52.
    Björntorp P. Classification of obese patients and complications related to the distribution of surplus fat.Am J Clin Nutr 1987;45:1120–1125.Google Scholar
  53. 53.
    Björntorp P. Abdominal obesity and the metabolic syndrome.Ann Med 1992;24:465–468.Google Scholar
  54. 54.
    DeFronzo RA. Insulin resistance, hyperinsulinemia, and coronary artery disease: A complex metabolic web.J Cardiovasc Pharmacol 1992;20(Suppl 11):S1-S16.Google Scholar
  55. 55.
    Swales JD. New antihypertensive agents: Benefits of treatment.J Cardiovasc Pharmacol 1992;20(Suppl 11):S70-S73.Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Kimmo Malminiemi
    • 1
  1. 1.Department of MedicineUniversity of TampereTampereFinland

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