Summary
The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Kannel WB, McGee DL (1979) Diabetes and cardiovascular disease. The Framingham study. JAMA 241: 2035–2038
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H (1983) Mortality from coronary heart disease and stroke in relation to degree of glycaemia: The Whitehall Study. BMJ 287: 867–870
Rosengren A, Welin L, Tsipogianni A, Wilhelmsen L (1989) Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study. BMJ 299: 1127–1131
Manson JE, Colditz GA, Stampfer MJ et al. (1991) A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 151: 1141–1147
Stamler J, Vaccaro O, Neaton J, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group (1993) Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 16: 434–449
Krolewski AS, Kosinski EI, Warram JH et al. (1987) Magnitude and determinants of coronary artery disease in juvenile-onset, insulin dependent diabetes mellitus. Am J Cardiol 59: 750–755
Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T (1987) Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without nephropathy: incidence and risk factors. Diabetologia 30: 144–148
Pyörälä K, Laakso M, Uusitupa M (1987) Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 3: 463–524
Jarrett JH, Shipley MJ (1985) The Whitehall Study: comparative mortality rates and indices of risk in diabetes. Acta Endocrinol (Copenh) 110 [Suppl 272]: 21–26
Brownlee M (1992) Glycation products and the pathogenesis of diabetic complications. Diabetes Care 15: 1835–1843
Schonfeld G, Birge E, Miller JP, Kessler G, Santiago J (1974) Apolipoprotein B levels and altered lipoprotein composition in diabetes. Diabetes 23: 825–833
Taskinen M-R, Kuusi T, Helve E, Nikkilä E, Yki-Järvinen H (1988) Insulin therapy induces antiatherogenic changes of serum lipoproteins in non-insulin-dependent diabetes. Arteriosclerosis 8: 168–177
Howard BV (1987) Lipoprotein metabolism in diabetes mellitus. J Lipid Res 28: 613–628
Stout RW (1981) The role of insulin in atherosclerosis in diabetics and non-diabetics. Diabetes 30 [Suppl 2]: 54–57
Reaven GM (1988) Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 37: 1595–1607
Uusitupa M, Siitonen O, Aro A, Pyörälä K (1985) Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects. Diabetologia 28: 22–27
Uusitupa M, Siitonen O, Pyörälä K et al. (1985) The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed type 2 (non-insulin-dependent) diabetes. Diabetologia 28: 653–659
Uusitupa M, Siitonen O, Voutilainen E et al. (1986) Serum lipids and lipoproteins in newly diagnosed non-insulin-dependent (type II) diabetic patients, with special reference to factors influencing HDL cholesterol and triglyceride levels. Diabetes Care 9: 17–22
WHO Expert Committee on Diabetes Mellitus (1980) Second report. Technical Report Series, No 646, Geneva
Laakso M, Honkonen E, Kauppinen U, Pyörälä K (1983) Diagnostic criteria used for the definition of diabetes in the district of University Central Hospital of Kuopio (Finnish). Suom Lääkäril 10: 862–865
Uusitupa M (1983) Coronary heart disease and left ventricular performance in newly diagnosed non-insulin-dependent diabetics (academic dissertation). Series original reports 6/1983, University of Kuopio, Kuopio
Rose GA (1962) The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull WHO 27: 645–658
Rose GA, Blackburn H (1968) Cardiovascular survey methods. WHO Monograph Series No 56, World Health Organization, Geneva
Penttilä IM, Voutilainen E, Laitinen O, Juutilainen P (1981) Comparison of different analytical and precipitation methods for the direct estimation of serum high-density lipoprotein cholesterol. Scand J Clin Lab Invest 41: 353–360
Röschlau P, Bernt E, Gruber W (1974) Enzymatische Bestimmung des Gesamtcholesterins im Serum. Z Klin Chem Biochem 12: 403–407
Wahlefield AW (1974) Triglycerides. Determination after enzymatic hydrolysis. In: Bergmeyer HU (ed) Methods in enzymatic analysis. Academic Press, New York, pp 1831–1835
Uusitupa M, Siitonen O, Penttilä I, Aro A, Pyörälä K (1987) Proteinuria in newly diagnosed type II diabetic patients. Diabetes Care 10: 191–194
Niskanen L, Uusitupa M, Sarlund H et al. (1990) Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed type 2 (noninsulin-dependent) diabetic patients. Diabetologia 33: 237–243
Niskanen LK, Uusitupa MI, Sarlund H, Siitonen O, Pyörälä K (1990) A five year follow-up study on plasma insulin levels in newly diagnosed non-insulin-dependent diabetic patients and non-diabetic subjects. Diabetes Care 13: 41–48
Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyörälä K (1990) 5-year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects. Circulation 82: 27–36
West KM, Ahuja MMS, Bennett PH et al. (1983) The role of circulating glucose and triglyceride concentrations and their interactions with other “risk factors” as determinants of arterial disease in nine diabetic population samples from the WHO Multinational study. Diabetes Care 6: 361–369
Standl E, Janka HU (1985) High serum insulin concentrations in relation to other cardiovascular risk factors in macrovascular disease of type 2 diabetes. Horm Metab Res [Suppl] 15: 46–51
Fontbonne A, Eschwege E, Cammbien F et al. (1989) Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Diabetologia 32: 300–304
Welin L, Eriksson H, Larsson B, Ohlson L-O, Svärdsudd K, Tibblin G (1992) Hyperinsulinemia is not a major coronary risk factor in elderly men. Diabetologia 35: 766–770
Kissebach AH, Alfarsi S, Evans DJ, Adams PW (1982) Integrated regulation of very low density lipoproteins, triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes 31: 217–225
Tatami R, Mabuchi H, Ueda K et al. (1981) Intermediate-density lipoprotein and cholesterol-rich very low density lipoprotein in angiographically determined coronary artery disease. Circulation 64: 1174–1184
Tilly-Kiesi M, Syvänne M, Kuusi T, Lahdenperä S, Taskinen M-R (1992) Abnormalities of low density lipoproteins in normolipidemic type II diabetic and nondiabetic patients with coronary artery disease. J Lipid Res 33: 333–342
Regnström J, Nilsson J, Tornvall P, Landou C, Hamsten A (1992) Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet 339: 1183–1186
Hiramatsu K, Bierman EL, Chait A (1985) Metabolism of lowdensity lipoprotein from patients with diabetic hypertriglyceridemia by cultured human skin fibroblasts. Diabetes 34: 8–14
Zilversmit DB (1978) Relative atherogeneticity of different plasma lipoproteins. Adv Exp Med Biol 109: 45–49
Austin MA, Breslow JL, Hennekins CH, Buring JE, Willett WC, Krauss RM (1988) Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 260: 1917–1921
Kesäniemi YA, Witztum JL, Steinbrecher UP (1983) Receptor-mediated catabolism of low density lipoprotein in man: quantitation using glucosylated low density lipoprotein. J Clin Invest 71: 950–959
Gordon DJ, Rifkind BM (1989) High-density lipoprotein — the clinical implications of recent studies. N Engl J Med 321: 1311–1316
Stout RW, Bierman EL, Ross R (1975) Effect of insulin on the proliferation of cultural primate arterial smooth muscle cells. Circ Res 36: 319–327
Oppenheimer MJ, Sundquist K, Bierman EL (1989) Downregulation of high-density lipoprotein receptor in human fibroblasts by insulin and IGF-I. Diabetes 38: 117–122
Welborn TA, Knuiman M, McCann V, Stanton K, Constable IJ (1984) Clinical macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia 27: 568–573
Schneider DJ, Nordt TK, Sobel BE (1993) Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes 42: 1–7
Uusitupa M, Pyörälä K, Laakso M (1992) Metabolic control and macrovascular disease. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds) International textbook of diabetes mellitus. John Wiley & Sons Ltd., Chichester, pp 1471–1485
Mogensen CE (1984) Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310: 356–360
Jarrett RJ, Viberti GC, Argyropoulos A et al. (1984) Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabetic Med 1: 17–19
Mattock MB, Morrish NJ, Viberti G et al. (1992) Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 47: 736–741
Stehouwer CD, Nauta JJ, Zeldenrust GC et al. (1992) Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 340: 319–323
Deckert T, Feldt-Rasmussen B, Borch-Johnsen T, Kofoed-Enevoldsen A (1989) Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 32: 219–226
Wing RR, Koeske R, Epstein LH, Nowalk MP, Gooding W, Becker D (1987) Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 147: 1749–1975
Uusitupa M, Laitinen J, Siitonen O, Vanninen E, Pyörälä K (1993) Maintenance of improved metabolic control after intensified diet therapy in recent type 2 diabetes. Diab Res Clin Pract 19: 227–238
Dunn FL (1990) Hyperlipidemia in diabetes mellitus. Diabetes Metab Rev 6: 47–61
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Uusitupa, M.I.J., Niskanen, L.K., Siitonen, O. et al. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 36, 1175–1184 (1993). https://doi.org/10.1007/BF00401063
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00401063