Risk Factors for Coronary Heart Disease in Diabetes Mellitus R.J. JARRETT
A review of the putative risk factors associat >d with the development of coronary heart disease in diabetes is presented. Emphasis is given to the effect of nephropathy (persistent proteinuria) and hypertension on cardiovascular mortality in IDDM. Risk factors associated with CHD in NIDDM are also reviewed. Finally, possible reasons to explain the increased incidence of CHD associated with proteinuria in IDDM patients, including lipoprotein abnormalities, increased fibrinogen levels, increased platelet adhesiveness, and altered hemostatic variables, are discussed. Diabetes 41(Suppl. 2):1-3, 1992
A
risk factor is an attribute or exposure that is associated with an increased probability of a specified outcome, such as the occurrence of a disease. A risk factor is not necessarily a causal factor. The principal problem in attempting to relate coronary heart disease in people with diabetes to putative risk factors is that of accurately establishing CHD. Most data are from mortality studies that rely to a large extent on death certification, albeit sometimes supplemented by additional information. Apart from the usual uncertainties surrounding death certificates, there is the potential of bias in that CHD is widely known to be associated with diabetes so that other causes of death might be wrongly attributed to CHD. This mistake could apply in particular to diabetic people with renal failure, in whom a "metabol-
From the United Medical and Dental Schools, of Guy's and St. Thomas's Hospital, London SE1 9RT, United Kingdom. Address correspondence and reprint requests to R. John Jarrett, MD, Guy's Hospital, Medicai School Building, London Bridge SE1 9RT, UK. Received for publication 3 April 1992 and accepted 12 May 1992. CHD, coronary heart disease; IDDM, insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes; LDL, low-density lipoprotein; apoB, apolipoprotein B; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; ICD, International Classification of Diseases; BP, blood pressure.
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
ic" death might be wrongly attributed to CHD. Persons found dead, in whom the cause is nocturnal hypdglycemia or arrhythmia due to autonomic neuropathy or to factors unknown, may also be wrongly assigned to CHD. In practice, many studies do not report CHD specifically, but subsume it within cardiovascular or circulatory disease. IDDM The Steno Memorial cohort study (1-3) clearly demonstrated the effect of nephropathy (persistent proteinuria) on relative all-cause mortality rates and on cardiovascular mortality. An increased incidence of CHD in people with proteinuria was also reported from the Joslin Clinic (4). It remains an open question whether the incidence of CHD is increased over that in the general population in diabetic people who do not develop renal abnormalities. Incidence was apparently increased in both the Joslin and Steno studies, though numbers were small and this possibility of biased attribution was not addressed. Further, in neither study was microalbuminuria identified in those without proteinuria. Microalbuminuria is a precursor of proteinuria (5), though it is not known whether mortality is increased within the phase of microalbuminuria. The reasons for the increased incidence of CHD associated with proteinuria remain speculative, but proteinuria is associated with increased levels of cholesterol and blood pressure (3) and with increased levels of LDL cholesterol, triglycerides, and apoB, with lower levels of HDL cholesterol (6). Significant lipoprotein abnormalities are also associated with microalbuminuria. Watts et al. (7) found higher levels of total and LDL cholesterol and apoB, with lower levels of HDL cholesterol, while Jones et al. (8) observed higher levels of LDL cholesterol, VLDL cholesterol, triglycerides, and apoB, with lower levels of HDL cholesterol. Several studies demonstrated higher blood-pressure levels in diabetic people with microalbuminuria (9,10). Plasma fibrinogen is significantly higher in
RISK FACTORS FOR CHD IN DIABETES
TABLE 1 Prospective risk-factor studies inNIDDM Risk factor Reference
End point
15 29
Circulatory mortality Cardiovascular mortality CHD mortality and morbidity Cardiovascular mortality CHD mortality CHD mortality CHD mortality
30 16 31 32 19
Sample size
Cholesterol
Triglyceride
Blood pressure
Smoking
Obesity
Proteinuria
3463 229 232 246 191 689 943
+ , Significant; - , not significant; •, not studied, impaired glucose tolerance and NIDDM.
association with both microalbuminuria (8,11) and proteinuria (11,12). Platelet adhesiveness also significantly increases in proteinuric patients (12,13). Thus, there are many potentially atherogenic or hemostatic variables that could contribute to the increased CHD risk associated with increased protein excretion. To these may be added increased vascular permeability (14). However, very few prospective studies have examined the associations of putative risk factors and morbidity or mortality. In the WHO Multinational Study, 10 of the 14 centers participated in a 6- to 7-yr follow-up recording mortality data (15). Blood pressure, hypertension, and proteinuria were examined in relation to circulatory mortality (ICD codes 390-459 and 798.1). In insulin-dependent patients (n = 1277), hypertension (systolic BP > 160 or diastolic BP > 95 or on treatment) was significantly related to mortality, as was proteinuria. The effect of hypertension appeared to be independent of its relationship with proteinuria. In the London cohort of the Multinational Study, there were 240 insulin-dependent patients. Mortality was studied over a 10- to 12-yr follow-up (16). Cardiovascular mortality was significantly associated with hypertension in univariate analysis, but not with plasma cholesterol or cigarette smoking. The relative risk for proteinuria was 2.4, which just escaped conventional statistical significance. Thus, although proteinuria and hypertension are established risk factors in IDDM, other putative risk factors remain to be investigated.
results. In the three studies in which it was measured, proteinuria was significantly associated. Only one of five studies found obesity (defined by body mass index) to be a significant variable. In a mixed population of men with impaired glucose tolerance or NIDDM, plasma triglycerides were significantly predictive and were the only significant variable after multivariate analysis (19). No prospective study of NIDDM reported on HDL cholesterol, but several cross-sectional studies had a significant negative association between the level of HDL cholesterol and the prevalence of cardiovascular disease (2022). The inconsistent results of the prospective studies clearly do not allow any confident statements about the role of classical risk factors for CHD and cardiovascular disease in NIDDM. Of interest, however, is the consistent association of CHD mortality with proteinuria supplemented by the positive and significant association of microalbuminuria and all-cause mortality (23,24). These associations are unexplained (25) but clearly deserve further study. Whatever the role of risk factors after the diagnosis of diabetes, in two populations, several atherogenic traits (for example, blood pressure and lipid variables) are more evident in those with normal glucose tolerance who later develop diabetes (26,27). Thus, the higher cardiovascular risk associated with NIDDM may be due largely, if not entirely, to a long prediabetic exposure to several atherogenic factors (28).
NIDDM
REFERENCES
People with NIDDM have age-specific all-cause mortality rates approximately double those of the general population or of nondiabetic control subjects (17). The increment varies somewhat among populations and tends to diminish with increasing age at onset of diabetes (17,18). In most, but not all (for example, indigenous Japanese, Native Americans of the Pima tribe), the excess mortality risk is due principally to CHD (18). Prospective studies with risk factor analyses are summarized in Table 1. The three classical risk factors—blood pressure, plasma cholesterol, and cigarette smoking—yield inconsistent
1. Borch-Johnsen K, Kragh Andersen P, Deckert T: The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 28:590-96, 1985 2. Borch-Johnsen K, Kreiner S: Proteinuria: value as predictor of cardiovascular mortality in insulin-dependent diabetes mellitus. Br MedJ 294:1651-54, 1987 3. Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T: Coronary heart disease in young type I (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 30:144-48, 1987 4. Krolewski AS, Kosinski EJ, Warram JH, Leland S, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR: Magnitude and determinants of coronary artery disease in juvenile-onset, insulindependent diabetes mellitus. Am J Cardiol 59:750-55, 1987 5. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H:
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
6. 7.
8.
9. 10. 11.
12. 13. 14. 15.
16.
17. 18. 19.
Microalbuminuria as a predictor of clinical nephropathy in insulindependent diabetes mellitus. Lancet 1:1430-32, 1982 Vannini P, Ciavarella A, Flammini M, Bargossi AM, Forlani G, Borgnino LC, Orsoni G: Lipid abnormalities in insulin-dependent diabetic patients with albuminuria. Diabetes Care 7:151-54, 1984 Watts GF, Naumova R, Slavin BM, Morris RW, Houlston R, Kubal C, Shaw KM: Serum lipids and lipoproteins in insulin-dependent diabetic patients with persistent microalbuminuria. Diabetic Med 6:2530, 1989 Jones SL, Close CF, Mattock MB, Jarrett RJ, Keen H, Viberti GC: Plasma lipid and coagulation factor concentrations in insulin-dependent diabetes with microalbuminuria. Br Med J 298:487-90, 1989 Wiseman M, Viberti GC, MacKintosh D, Jarrett RJ, Keen H: Glycaemia, arterial pressure and microalbuminuria in type I (insulin dependent) diabetes mellitus. Diabetologia 26:401-405, 1984 Mathiesen ER, Oxenboll B, Johansen K, Svendsen PA, Decked T: Incipient nephropathy in type I (insulin-dependent) diabetes. Diabetologia 26:406-10, 1984 Jensen T, Stender S, Decked T: Abnormalities in plasma concentrations of lipoproteins and fibrinogen in type I (insulin-dependent) diabetic patients with increased albumin excretion. Diabetologia 31:142-45, 1988 Valdorf-Hansen F, Jensen T, Borch-Johnsen K, Decked T: Cardiovascular risk factors in type I (insulin-dependent) diabetic patients with and without proteinuria. Acta Med Scand 222:439-44, 1987 Fuller JH, Keen H, Jarrett RJ: Haemostatic variables associated with diabetes and its complications. Br Med J 2:964-66, 1979 Decked T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albuminuria reflects widespread vascular damage: the Steno hypothesis. Diabetologia 32:219-26, 1989 Fuller JH, Head J, and the WHO Multinational Study Group: Blood pressure, proteinuria and their relationship with circulatory modality: the WHO Multinational Study of Vascular Disease in Diabetics. Diabete Metab 15:273-77, 1989 Morrish NJ, Stevens LK, Head J, Fuller JH, Jarrett RJ, Keen H: A prospective study of modality among middle-aged diabetic patients (the London cohqd of the WHO Multinational Study of Vascular Disease in Diabetics) II; associated risk factors. Diabetologia 33: 542-48, 1990 Panzram G: Modality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30:123-31, 1987 Jarrett RJ: Epidemiology and public health aspects of non-insulindependent diabetes mellitus. Epidemiol Rev 11:151-71, 1989 Fontbonne A, Eschwege E, Cambien F: Hypedriglyceridaemia as a risk factor of coronary head disease modality in subjects with
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
20.
21. 22.
23. 24. 25. 26.
27.
28. 29. 30.
31. 32.
impaired glucose tolerance or diabetes. Diabetologia 32:300-304, 1989 Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW, Fujimoto WY: Association of plasma triglyceride and C-peptide with coronary head disease in Japanese-American men with a high prevalence of glucose intolerance. Diabetologia 33:489-96, 1990 Knuiman MW, Welborn TA, McCann VJ, Stanton KG, Constable IJ: Prevalence of diabetic complications in relation to risk factors. Diabetes 35:1332-39, 1986 Allawi J, Jarrett RJ: Male-type fat distribution is associated with cardiovascular risk factors and the prevalence of cardiovascular disease in non-insulin treated diabetics. J Diabet Complications 4:150-53, 1990 Jarrett RJ, Vibedi GC, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ: Microalbuminuria predicts modality in non-insulin dependent diabetics. Diabetic Med 1:17-19, 1984 Schmitz A, Vaeth M: Microalbuminuria: a major risk factor in noninsulin dependent diabetes. A 10 year follow-up study of 503 diabetic patients. Diabetic Med 5:126-34, 1988 Allawi J, Jarrett RJ: Microalbuminuria and cardiovascular risk factors in type 2 diabetes mellitus. Diabetic Med 7:115-18, 1990 McPhillips JB, Barrett-Connor E, Wingard DL: Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol 131:443-53, 1990 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK: Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary head disease stad ticking before the onset of clinical diabetes? JAMA 263:2893-98, 1990 Jarrett RJ: Type 2 (non-insulin-dependent) diabetes mellitus and coronary head disease: chicken, egg or neither? Diabetologia 26:99-102, 1984 Suarez L, Barrett-Connor E: Interaction between cigarette smoking and diabetes mellitus in the prediction of death attributed to cardiovascular disease. Am J Epidemiol 120:670-75, 1984 Rosengren A, Welin L, Tsipogianni A, Wilhelmsen L: Impact of cardiovascular risk factors on coronary head disease and modality among middle-aged diabetic men: a general population study. Br Med J 299:1127-31, 1989 Fitzgerald AP, Jarrett RJ: Are conventional risks factors for modality relevant in type 2 diabetes? Diabetic Med 8:475-80, 1991 Nelson RG, Sievers ML, Knowler WC, Swinburn BA, Pettitt DJ, Saad MF, Liebow IM, Howard BV, Bennett PH: Low incidence of fatal coronary head disease in Pima Indians despite high prevalence of non-insulin-dependent diabetes. Circulation 81:987-95, 1990
A review of the putative risk factors associat >d with the development of coronary heart disease in diabetes is presented. Emphasis is given to the effect of nephropathy (persistent proteinuria) and hypertension on cardiovascular mortality in IDDM. Risk factors associated with CHD in NIDDM are also reviewed. Finally, possible reasons to explain the increased incidence of CHD associated with proteinuria in IDDM patients, including lipoprotein abnormalities, increased fibrinogen levels, increased platelet adhesiveness, and altered hemostatic variables, are discussed. Diabetes 41(Suppl. 2):1-3, 1992
A
risk factor is an attribute or exposure that is associated with an increased probability of a specified outcome, such as the occurrence of a disease. A risk factor is not necessarily a causal factor. The principal problem in attempting to relate coronary heart disease in people with diabetes to putative risk factors is that of accurately establishing CHD. Most data are from mortality studies that rely to a large extent on death certification, albeit sometimes supplemented by additional information. Apart from the usual uncertainties surrounding death certificates, there is the potential of bias in that CHD is widely known to be associated with diabetes so that other causes of death might be wrongly attributed to CHD. This mistake could apply in particular to diabetic people with renal failure, in whom a "metabol-
From the United Medical and Dental Schools, of Guy's and St. Thomas's Hospital, London SE1 9RT, United Kingdom. Address correspondence and reprint requests to R. John Jarrett, MD, Guy's Hospital, Medicai School Building, London Bridge SE1 9RT, UK. Received for publication 3 April 1992 and accepted 12 May 1992. CHD, coronary heart disease; IDDM, insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes; LDL, low-density lipoprotein; apoB, apolipoprotein B; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; ICD, International Classification of Diseases; BP, blood pressure.
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
ic" death might be wrongly attributed to CHD. Persons found dead, in whom the cause is nocturnal hypdglycemia or arrhythmia due to autonomic neuropathy or to factors unknown, may also be wrongly assigned to CHD. In practice, many studies do not report CHD specifically, but subsume it within cardiovascular or circulatory disease. IDDM The Steno Memorial cohort study (1-3) clearly demonstrated the effect of nephropathy (persistent proteinuria) on relative all-cause mortality rates and on cardiovascular mortality. An increased incidence of CHD in people with proteinuria was also reported from the Joslin Clinic (4). It remains an open question whether the incidence of CHD is increased over that in the general population in diabetic people who do not develop renal abnormalities. Incidence was apparently increased in both the Joslin and Steno studies, though numbers were small and this possibility of biased attribution was not addressed. Further, in neither study was microalbuminuria identified in those without proteinuria. Microalbuminuria is a precursor of proteinuria (5), though it is not known whether mortality is increased within the phase of microalbuminuria. The reasons for the increased incidence of CHD associated with proteinuria remain speculative, but proteinuria is associated with increased levels of cholesterol and blood pressure (3) and with increased levels of LDL cholesterol, triglycerides, and apoB, with lower levels of HDL cholesterol (6). Significant lipoprotein abnormalities are also associated with microalbuminuria. Watts et al. (7) found higher levels of total and LDL cholesterol and apoB, with lower levels of HDL cholesterol, while Jones et al. (8) observed higher levels of LDL cholesterol, VLDL cholesterol, triglycerides, and apoB, with lower levels of HDL cholesterol. Several studies demonstrated higher blood-pressure levels in diabetic people with microalbuminuria (9,10). Plasma fibrinogen is significantly higher in
RISK FACTORS FOR CHD IN DIABETES
TABLE 1 Prospective risk-factor studies inNIDDM Risk factor Reference
End point
15 29
Circulatory mortality Cardiovascular mortality CHD mortality and morbidity Cardiovascular mortality CHD mortality CHD mortality CHD mortality
30 16 31 32 19
Sample size
Cholesterol
Triglyceride
Blood pressure
Smoking
Obesity
Proteinuria
3463 229 232 246 191 689 943
+ , Significant; - , not significant; •, not studied, impaired glucose tolerance and NIDDM.
association with both microalbuminuria (8,11) and proteinuria (11,12). Platelet adhesiveness also significantly increases in proteinuric patients (12,13). Thus, there are many potentially atherogenic or hemostatic variables that could contribute to the increased CHD risk associated with increased protein excretion. To these may be added increased vascular permeability (14). However, very few prospective studies have examined the associations of putative risk factors and morbidity or mortality. In the WHO Multinational Study, 10 of the 14 centers participated in a 6- to 7-yr follow-up recording mortality data (15). Blood pressure, hypertension, and proteinuria were examined in relation to circulatory mortality (ICD codes 390-459 and 798.1). In insulin-dependent patients (n = 1277), hypertension (systolic BP > 160 or diastolic BP > 95 or on treatment) was significantly related to mortality, as was proteinuria. The effect of hypertension appeared to be independent of its relationship with proteinuria. In the London cohort of the Multinational Study, there were 240 insulin-dependent patients. Mortality was studied over a 10- to 12-yr follow-up (16). Cardiovascular mortality was significantly associated with hypertension in univariate analysis, but not with plasma cholesterol or cigarette smoking. The relative risk for proteinuria was 2.4, which just escaped conventional statistical significance. Thus, although proteinuria and hypertension are established risk factors in IDDM, other putative risk factors remain to be investigated.
results. In the three studies in which it was measured, proteinuria was significantly associated. Only one of five studies found obesity (defined by body mass index) to be a significant variable. In a mixed population of men with impaired glucose tolerance or NIDDM, plasma triglycerides were significantly predictive and were the only significant variable after multivariate analysis (19). No prospective study of NIDDM reported on HDL cholesterol, but several cross-sectional studies had a significant negative association between the level of HDL cholesterol and the prevalence of cardiovascular disease (2022). The inconsistent results of the prospective studies clearly do not allow any confident statements about the role of classical risk factors for CHD and cardiovascular disease in NIDDM. Of interest, however, is the consistent association of CHD mortality with proteinuria supplemented by the positive and significant association of microalbuminuria and all-cause mortality (23,24). These associations are unexplained (25) but clearly deserve further study. Whatever the role of risk factors after the diagnosis of diabetes, in two populations, several atherogenic traits (for example, blood pressure and lipid variables) are more evident in those with normal glucose tolerance who later develop diabetes (26,27). Thus, the higher cardiovascular risk associated with NIDDM may be due largely, if not entirely, to a long prediabetic exposure to several atherogenic factors (28).
NIDDM
REFERENCES
People with NIDDM have age-specific all-cause mortality rates approximately double those of the general population or of nondiabetic control subjects (17). The increment varies somewhat among populations and tends to diminish with increasing age at onset of diabetes (17,18). In most, but not all (for example, indigenous Japanese, Native Americans of the Pima tribe), the excess mortality risk is due principally to CHD (18). Prospective studies with risk factor analyses are summarized in Table 1. The three classical risk factors—blood pressure, plasma cholesterol, and cigarette smoking—yield inconsistent
1. Borch-Johnsen K, Kragh Andersen P, Deckert T: The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 28:590-96, 1985 2. Borch-Johnsen K, Kreiner S: Proteinuria: value as predictor of cardiovascular mortality in insulin-dependent diabetes mellitus. Br MedJ 294:1651-54, 1987 3. Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T: Coronary heart disease in young type I (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 30:144-48, 1987 4. Krolewski AS, Kosinski EJ, Warram JH, Leland S, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR: Magnitude and determinants of coronary artery disease in juvenile-onset, insulindependent diabetes mellitus. Am J Cardiol 59:750-55, 1987 5. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H:
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
6. 7.
8.
9. 10. 11.
12. 13. 14. 15.
16.
17. 18. 19.
Microalbuminuria as a predictor of clinical nephropathy in insulindependent diabetes mellitus. Lancet 1:1430-32, 1982 Vannini P, Ciavarella A, Flammini M, Bargossi AM, Forlani G, Borgnino LC, Orsoni G: Lipid abnormalities in insulin-dependent diabetic patients with albuminuria. Diabetes Care 7:151-54, 1984 Watts GF, Naumova R, Slavin BM, Morris RW, Houlston R, Kubal C, Shaw KM: Serum lipids and lipoproteins in insulin-dependent diabetic patients with persistent microalbuminuria. Diabetic Med 6:2530, 1989 Jones SL, Close CF, Mattock MB, Jarrett RJ, Keen H, Viberti GC: Plasma lipid and coagulation factor concentrations in insulin-dependent diabetes with microalbuminuria. Br Med J 298:487-90, 1989 Wiseman M, Viberti GC, MacKintosh D, Jarrett RJ, Keen H: Glycaemia, arterial pressure and microalbuminuria in type I (insulin dependent) diabetes mellitus. Diabetologia 26:401-405, 1984 Mathiesen ER, Oxenboll B, Johansen K, Svendsen PA, Decked T: Incipient nephropathy in type I (insulin-dependent) diabetes. Diabetologia 26:406-10, 1984 Jensen T, Stender S, Decked T: Abnormalities in plasma concentrations of lipoproteins and fibrinogen in type I (insulin-dependent) diabetic patients with increased albumin excretion. Diabetologia 31:142-45, 1988 Valdorf-Hansen F, Jensen T, Borch-Johnsen K, Decked T: Cardiovascular risk factors in type I (insulin-dependent) diabetic patients with and without proteinuria. Acta Med Scand 222:439-44, 1987 Fuller JH, Keen H, Jarrett RJ: Haemostatic variables associated with diabetes and its complications. Br Med J 2:964-66, 1979 Decked T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albuminuria reflects widespread vascular damage: the Steno hypothesis. Diabetologia 32:219-26, 1989 Fuller JH, Head J, and the WHO Multinational Study Group: Blood pressure, proteinuria and their relationship with circulatory modality: the WHO Multinational Study of Vascular Disease in Diabetics. Diabete Metab 15:273-77, 1989 Morrish NJ, Stevens LK, Head J, Fuller JH, Jarrett RJ, Keen H: A prospective study of modality among middle-aged diabetic patients (the London cohqd of the WHO Multinational Study of Vascular Disease in Diabetics) II; associated risk factors. Diabetologia 33: 542-48, 1990 Panzram G: Modality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30:123-31, 1987 Jarrett RJ: Epidemiology and public health aspects of non-insulindependent diabetes mellitus. Epidemiol Rev 11:151-71, 1989 Fontbonne A, Eschwege E, Cambien F: Hypedriglyceridaemia as a risk factor of coronary head disease modality in subjects with
DIABETES, VOL. 41, SUPPL. 2, OCTOBER 1992
20.
21. 22.
23. 24. 25. 26.
27.
28. 29. 30.
31. 32.
impaired glucose tolerance or diabetes. Diabetologia 32:300-304, 1989 Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW, Fujimoto WY: Association of plasma triglyceride and C-peptide with coronary head disease in Japanese-American men with a high prevalence of glucose intolerance. Diabetologia 33:489-96, 1990 Knuiman MW, Welborn TA, McCann VJ, Stanton KG, Constable IJ: Prevalence of diabetic complications in relation to risk factors. Diabetes 35:1332-39, 1986 Allawi J, Jarrett RJ: Male-type fat distribution is associated with cardiovascular risk factors and the prevalence of cardiovascular disease in non-insulin treated diabetics. J Diabet Complications 4:150-53, 1990 Jarrett RJ, Vibedi GC, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ: Microalbuminuria predicts modality in non-insulin dependent diabetics. Diabetic Med 1:17-19, 1984 Schmitz A, Vaeth M: Microalbuminuria: a major risk factor in noninsulin dependent diabetes. A 10 year follow-up study of 503 diabetic patients. Diabetic Med 5:126-34, 1988 Allawi J, Jarrett RJ: Microalbuminuria and cardiovascular risk factors in type 2 diabetes mellitus. Diabetic Med 7:115-18, 1990 McPhillips JB, Barrett-Connor E, Wingard DL: Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol 131:443-53, 1990 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK: Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary head disease stad ticking before the onset of clinical diabetes? JAMA 263:2893-98, 1990 Jarrett RJ: Type 2 (non-insulin-dependent) diabetes mellitus and coronary head disease: chicken, egg or neither? Diabetologia 26:99-102, 1984 Suarez L, Barrett-Connor E: Interaction between cigarette smoking and diabetes mellitus in the prediction of death attributed to cardiovascular disease. Am J Epidemiol 120:670-75, 1984 Rosengren A, Welin L, Tsipogianni A, Wilhelmsen L: Impact of cardiovascular risk factors on coronary head disease and modality among middle-aged diabetic men: a general population study. Br Med J 299:1127-31, 1989 Fitzgerald AP, Jarrett RJ: Are conventional risks factors for modality relevant in type 2 diabetes? Diabetic Med 8:475-80, 1991 Nelson RG, Sievers ML, Knowler WC, Swinburn BA, Pettitt DJ, Saad MF, Liebow IM, Howard BV, Bennett PH: Low incidence of fatal coronary head disease in Pima Indians despite high prevalence of non-insulin-dependent diabetes. Circulation 81:987-95, 1990
