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HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE IN TYPE 2 DIABETES
~~~~~~
DIABETES
0095-4543/99 $8.00 + .OO
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE IN TYPE 2 DIABETES Markku Laakso, MD
Macrovascular complications, coronary heart disease, stroke, and peripheral vascular disease are major contributors to early death and chronic They account for about 70% of illness in patients with type 2 all mortality, and the most important of these complications, coronary heart disease, is twofold to fourfold more common in patients with type 2 diabetes than in normoglycemiccontrol ~ u b j e c t s . ' ~The ~ *risk ~ , ~for ~ stroke and peripheral vascular disease is also substantially increased in patients with type 2 d i a b e t e ~ . ' ~ , ~ , ~ ~ Cardiovascular complications are frequent at the diagnosis of type 2 diabetes. Therefore, the period of asymptomatic hyperglycemia preceeding the frank diabetic state must be important for the development of macrovascular disease. This prediabetic state was first recognized in 1980, when the World Health Organization (WHO) revised diagnostic criteria for diabetes and impaired glucose tolerance (IGT), a category between normal glucose tolerance and diabetes.37Indeed, IGT has been shown to be associated with an approximate twofold increase in the risk of macrovascular disease, giving direct evidence for the hypothesis that the prediabetic state is a risk factor for atheroscleotic complication^.^^,^ How can a mild abnormality in glucose metabolism that leads to an excess risk of macrovascular disease be explained? Several studies have indicated that both type 2 diabetes and IGT are associated with an unfavorable cardiovascular risk factor profile, high blood pressure, low highdensity lipoprotein (HDL) cholesterol, high triglycerides, obesity, central
From the Department of Medicine, University of Kuopio, Kuopio, Finland
PRIMARY CARE VOLUME 26 'NUMBER 4 'DECEMBER 1999
829
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LAAKSO
obesity, and abnormalities in hemostatic These risk factors, however, do not completely explain the excess of cardiovascular complications in type 2 diabetes. This implies that the diabetic state itself, or factors associated with it, have to increase the risk for cardiovascular disease in type 2 diabetes. To decrease or to prevent the burden of cardiovasculardisease in type 2 diabetes, a crucial question is whether or not type 2 diabetes and coronary heart disease share common antecedents, which could explain the strong association between them. If a common soil hypothesis is c0rrect,2~ then the correction of hyperglycemia is not enough to normalize the cardiovascular risk of type 2 diabetic patients. If, on the other hand, hyperglycemia itself is responsible for the increase in the risk of cardiovascular disease, then the major focus in the treatment should be on the correction of glycemic control. GLUCOSE LEVEL AS A CARDIOVASCULAR RISK FACTOR IN SUBJECTS WITHOUT DIABETES
Evidence that hyperglycemia can affect the development of macrovascular complications, even in nondiabetic individuals, has been published in epidemiologic and autopsy studies. Results from the first crosssectional, population-based studies that suggested a relationship between elevated blood glucose in an oral glucose tolerance test and cardiovascular disease in subjects without clinically manifest diabetes were published in 196.5 from the United Kingdom (the Bedford study) and from the United States (the Tecumseh S t ~ ~ d yFollow-up ) . ~ ~ of these two cohorts verified the positive association between glucose level and coronary heart disease mortality. In 1979, the International Collaborative Group published the first extensive evaluation of nondiabetic glucose levels to predict cardiovascular disease based on 4 to 15years of follow-up data from 11different ~ t u d i e s . ~ Cardiovascular and coronary heart disease mortality rates in the highest blood glucose quintile compared to those observed in the lowest quintile were greater than 2.0 in only three of the nine studies. Only one study indicated a positive association of coronary heart disease mortality and glucose level after adjustment for confounding factors. Inconsistenciesbetween the studies could be related to a short follow-up period and to a lesser degree of standardization of the oral glucose tolerance test. The authors concluded that the 11studies did not show any consistent, strong, and graded association between asymptomatic hyperglycemia and coronary heart disease? In 1980, the Whitehall Study, one of the studies included in the International Collaborative Group report, indicated that there was a 1.5-fold to twofold increase in coronary heart disease and stroke mortality independent of age, smoking, blood pressure, and cholesterol level after 7.5 years follow-up for individuals with 2-hour glucose as low as 5.4mmol/L after a 50 g glucose load.”
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
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During the last 10 years, a new interest in glucose level as a predictor of macrovascular complications has developed. The results of the 12-year follow up of the Honolulu Heart Study that included 6394 nondiabetic men of Japanese ancestry, aged 45 to 70 years at baseline, indicated that the risk of fatal and nonfatal coronary heart disease events increased continuously as 1-hour glucose levels after 50 g glucose challenge increased (P < 0.001), with no apparent glycemic threshold? In the Framingham Study,38the British Regional Heart Study,= and the Rancho Bernard0 Study,= nondiabetic subjects had elevated risk for coronary heart diseasee death with increasing baseline glucose level. Recently, the results of a 20-year follow-up study of nondiabetic men aged 44 to 55 years from the three studies originally included in the International Collaborative Group (the Whitehall Study (n = 10 025), the Paris Prospective Study (n = 6629), and the Helsinki Policemen Study (n = 631) were published.2 These studies indicated that men in the upper 20% of the 2-hour glucose distributions and those in the upper 2.5% for fasting glucose had a significantly higher risk, with an age-adjusted hazards ratio for coronary heart disease of 1.8 (1.4-2.4) and 2.7 (1.7-4.4), respectively. The Chicago Heart Study assessed the relationship of asymptomatic hyperglycemia at baseline to the risk of cardiovascular disease in over 11544white and 666 African American middle-aged men.I7Coronary heart disease mortality was increased in subjects with asymptomatic hyperglycemia (the relative risk and its 95% confidence intervals: 1.18 i1.011.371). In the Framingham study, glycated hemoglobin A,, (HbA,,) predicted cardiovascular disease events, but the subjects were not classified as nondiabetic and diabetic; consequently, the effect of glycemic control on cardiovascular disease could be attributed to a higher prevalence of diabetes in subjects with high HbA,,.27 McGill et all9investigated the incidence of fatty streaks in the arteries of individuals who had died from a variety of causes, mainly accidents. The occurrence of both fatty streaks and raised lesions was significantly elevated in the group with high HbA,, levels (X%) compared with those with lower HbA,, levels (58%).In the high HbA,, group, fatty streaks were seen in 47.9% and raised lesions in 16.7%, whereas in the lower HbA,, group, the corresponding percentages were 23% and 5.2% ( P = 0.009 and P = 0.02, respectively). This study, although cross-sectional, gives evidence that the atherosclerosis process is affected by hyperglycemia. Similarly, recent cross-sectional studies have indicated that HbA,, associates positively with carotid artery stenosis3and that asymptomatic hyperglycemia is associated with increased intima-media thickness of the carotid a~tery.3~ A meta-analysis of all published cohort studies of mainly nondiabetic populations has reported that the risk for cardiovascular events increased continuously with glucose levels above 4.2 mmol/L.5 This implies that there seems to be a graded relationship between glucose levels and the risk of macroangiopathy within the nondiabetic range.
HYPERGLYCEMIA AS A CARDIOVASCULAR RISK FACTOR IN SUBJECTS WITH TYPE 2 DIABETES
Until recent years, glycemic control was not believed to be an important risk factor for cardiovascular disease in type 2 diabetes. This conclusion was based on small studies and on scanty and inconsistent In the large cross-sectionalWHO Multinational Study of Vascular Disease in Diabetes, including 3000 diabetic patients from nine different countries, high fasting plasma glucose was associated with an increased prevalence of previous stroke, intermittent claudication, and previous leg amputations, but not with the prevalence of coronary heart disease assessed by the presence of major Q-waves on electr~cardiogram.~~ Since 1993, several large, prospective studies on newly-detected and previously-diagnosed type 2 diabetic patients have indicated that glycemic control is important for cardiovascular risk, including the risk for coronary heart disease in type 2 diabetic patients. Only a few recent crosssectional studies have not reported an association between glycemic control and cardiovascular
Newly Diagnosed Patients With Type 2 Diabetes
Uusitupa et a P showed that among 133 middle-aged subjects with newly diagnosed type 2 diabetes, 10-year cardiovascular mortality increased three-fold by tertiles of blood glucose and hbA,, (Table 1).In the same study, hyperglycemia was a constant predictor for 15-year cardiovascular mortality assessed at the time of diagnosis or at 5- or 10-year examinations.21In the study by Anderson and Svardsudd,' an average fasting blood glucose level predicted cardiovascular and coronary heart disease mortality in an unselected cohort of 411 subjects aged 23 to 94 years. In the Diabetes Intervention Study8postprandial blood glucose at entry determined 1 hour after the subject's normal breakfast, but not fasting glucose, predicted subsequent development of myocardial infarction. In the United Kingdom Prospective Diabetes Study (UKPDS),which included 2693 subjects with newly-detected type 2 diabetes aged 25 to 65 years, fasting plasma glucose and I-IbA,, were significantly associated with the risk of coronary heart disease (fatal and nonfatal myocardial infarction, angina pectoris) and fatal myocardial infarction during the fol10w-up.~~ They also evaluated the significance of other cardiovascular risk factors for coronary heart disease by stepwise multivariate Cox analysis. The most important risk factors for coronary heart disease were high low density lipoprotein cholesterol followed by low high density lipoprotein cholesterol and HbA,,, and high low density lipoprotein cholesterol, diastolic blood pressure, smoking, low high density lipoprotein cholesterol followed by HbA,, for nonfatal and fatal myocardial infarction, respectively. These results emphasize the significance of classic risk factors for the risk of coronary heart disease in type 2 diabetic patients.
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
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Table 1. PROSPECTIVE STUDIES SHOWING AN ASSOCIATION BETWEEN CARDIOVASCULAR EVENTS AND GLYCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES No. Patients
Study
Age (years)
Length of Follow-up (years)
Newly diagnosed type 2 diabetes Uusitupa et alY 133 Andersson and 411 Svardsuddl Hanefeld et als 1139
45-64 23-94
10 7
30-55
11
Turner et aP’
25-65
8
2693
Previously diagnosed type 2 diabetes Kuusisto et all2 229 65-74
3.5 3.5 10
Kuusisto et all3 Heinlo
229 1370
65-74
Gall et a17 Stand1 et al” Lehto et all5
328 290 1059
20-65 <76 45-64
5 10
Lehto et all6
1059
45-64
7
471
25-64
7.5
Wei et al” CHD
=
>30
7
Endpoint Cardiovascular mortality CHD mortality and morbidity Incidence of myocardial infarction CHD mortality and morbidity CHD mortality and morbidity Stroke incidence CHD mortality. Stroke incidence Cardiovascular mortality Cardiovascular mortality CHD mortality and morbidity Stroke mortality and morbidity Cardiovascular mortality
coronary heart disease
Previously Diagnosed Patients With Type 2 Diabetes
In our prospective population-based study including 229 subjects with type 2 diabetes aged 65 to 74 years at baseline and followed for 3.5 years, HbA,, was the most powerful predictor of coronary heart disease events.12 In the same subjects, fasting glucose levels, 2-hour plasma glucose levels, and HbA,, predicted fatal or nonfatal ~tr0ke.I~ The Wisconsin EpidemiologicStudy of Diabetic Retinopathy assessed the significance of glycemic control for micro- and macrovascular complications in 1370 subjects with late-onset diabetes during 10 years of follow-up.10HbA,,. predicted not only microangiopathic but also macroangiopathic complications. A 1%increase in HbA,, resulted in a 70% increase in proliferative retinopathy, but only a 10% increase in coronary heart disease events. The results of this study imply that hyperglycemia is a much stronger risk factor for microvascular complications than it is for ischemic heart disease. In a 5-year follow-up study from Denmark? glycemic control measured by HbA,, predicted both all-cause and cardiovascular mortality in 328 patients with type 2 diabetes. In a 10-year follow-up study from Munich, Germany, HbA,, predicted cardiovascular death in 290 subjects with
type 2 diabetes.’B In the authors 7-year follow-up study on 1059 Finnish patients with type 2 diabetes aged 45 to 64 years at baseline, high fasting plasma glucose predicted coronary heart disease event^,'^ and lugh fasting plasma glucose and HbA,, predicted fatal and nonfatal stroke.Ib The association between poor glycemic control and stroke was much stronger than the association with poor glycemic control and coronary heart disease events. The San Antonio Heart Study, which included 471 patients with type 2 diabetes, demonstrated a dose-response relationship between the level of hyperglycemia and mortality.35Patients belonging to the highest quartile of fasting plasma glucose (>11.5 mmol/L) had 4.9-fold higher total and 4.9-fold h g h e r cardiovascular mortality than patients belonging to the two lowest fasting plasma quarhles (<8.0mmol/L). T h s study demonstrated that hyperglycemia is not only a risk factor in whites but also in other ethnic groups. CLINICAL TRIALS Although several recent, prospective, population-based studies including newlydetected or previously diagnosed patients with type 2 diabetes suggest that hyperglycemia is associated with cardiovascular disease, they do not prove causality between these two. Clinical mals are needed to provide a definite answer to this crucial question. Unfortunately, information from clinical trials aiming to investigate the effect of the reduction of hyperglycemia on cardiovascular end points in type 2 diabetes is h t e d . The Ihabetes Control and Complications Trial convincingly demonstrated that intensive insulin treatment reduced microvascular complications but because of a low number of incident cases, intensive treatment did not signdicantly reduce cardiovascular eventsw Moreover, we can not be sure whether or not trial evidence based on type 1 diabetic patients can be applied to type 2 diabetic patients. The University Group Diabetes Program (UGDP) randomized 619 patients to the following treatment regimens: placebo, phenformin, tolbutamide, a fixed insuhn dose, and a variable insulin dose.” The study began in 1961 and was completed in 1975. Patients treated with phenformin and tolbutamide had inmased cardiovascular mortality, and these study arms were stopped. At the end of the study, average fasting blood glucose was 2.0 mmol/L lower in the variable insulin group than in the placebo group or in the b e d insulin group, corresponding roughly to 1% of HbA,,. Insulin treatment groups and the placebo group had similar cardiovascular mortality (20.6% versus 20.2%,respectively). The suspicion that oral agents are harmful in the treatment of patients with type 2 diabetes has persisted since the results of this study were published. The UGDP did not solve the problem of whether or not the improvement of glycemic control could prevent diabetic complications. The Veterans Affairs Cooperative Study in Glycemia Control randomized 153 men with type 2 diabetes to standard therapy (1 -2 insulin inpc-
HYFERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
835
tions daily) or to intensive therapy4 Intensive treatment resulted in a reduction of HbA,, by an average of 2.1% (7.3% versus 9.4%, P < 0.001). coronary heart disease event rate was somewhat higher in the intensive treatment group than in the conventional treatment group (21.3% versus 11.5%,P = NS). The Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) triaP6 (n = 620) showed that in subjects with an acute myocardial infarction, intensive insulin treatment was associated with a lower case fatality rate than placebo treatment (18.6% versus 26.1%, P = 0.03). Whether the beneficial effect resulted from insulin infusion at acute phase or from improved long-term control cannot be determined from this trial. The UKPDS, begun in 1977, was designed to investigate whether intensive blood glucose control could reduce the risk of macrovascular or microvascular complicationsin subjects with type 2 diabetes, and whether any particular therapy was advantageous for these subjects (see article by Yudkin elsewhere in this issue).32Microvascular complications (retinopathy, nephropathy) were reduced by 25% ( P = 0.0099) and myocardial infarction was reduced by 16%( P = 0.052) with intensive treatment (Table 2). There was no evidence of any glycemic threshold for any of the microvascular and cardiovascular complications above the normal glucose levels (HbA,, > 6.0%). Table 2 shows the results from the intensive blood pressure trial of the UKPDS study, which included 1148 type 2 diabetic subjects with hyperten~ion.3~ Interestingly, blood pressure reduction was more effective than was tight glucose control, with respect to all end-points including microvascular complications. The glucose control and blood pressure control studies cannot be directly compared, because these two studies were not based on the same study subjects. Implications for Therapy
According to several prospective population-based studies, glycemic control influences the risk for cardiovascular disease, including coronary heart disease, independently of conventional risk factors in patients with type 2 diabetes. Recent evidence from the UKPDS has convincingly shown that long-term complications in patients with type 2 diabetes can be prevented by the correction of glycemic control. In the UKPDS, none of the treatment modalities was particularly effective in reducing complications, but the study did remove any residual suspicion that treatment with insulin or sulphonylureas is harmful at least in diabetic patients without macrovascular disease at baseline. Diet treatment, weight reduction, and exercise remain the cornerstones for treatment of type 2 diabetic patients. Aggressive treatment of hyperglycemia is undoubtedly indicated to retard the development of microvascular complications, but it also prevents, although to a lesser extent, macrovascular complications. The management of hyperglycemia should not outweigh other cardiovascular risk factors, particularly high cholesterol and elevated blood pressure, because
w QI
m
35% 25%
ll%7
12% 10% 6% 16% 0.0099
0.029 NS NS 0.052 NS NS
P Value
? = increase in the risk;NS = not statistically sigruhcant;PVD = peripheral vascular disease. Data from references 32 and 33.
Any diabetes-relatedendpoint Deaths related to diabetes All-cause mortality Myocardial infarction Stroke Amputation or death from PVD Microvascular disease
Endpoint
Glucose Control Risk Reduction
49% 37%
44%
24% 32% 18% 21 %
0.0046 0.019 NS NS 0.013 NS 0.0092
Blood Pressure Control Risk Reduction P Value
~~~~~~
Table 2. RISK REDUCTIONWITH INTENSIVE GLUCOSE TREATMENT AND BLOOD PRESSURE CONTROL FOR DIFFERENT ENDPOINTS IN THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
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recent trials have indicated that the lowering of total cholesterol levelz4 and blood pressure3 is beneficial in the treatment of cardiovascular disease in patients with type 2 diabetes. Therefore, in the prevention and treatment of cardiovascular disease in type 2 diabetes, all known cardiovascular risk factors should be attacked simultaneously.
References 1. Andersson BKG, Svardsudd K: Long-term glycemic control relates to mortality in type 11 diabetes. Diabetes Care 18:1534-1543, 1995 2. B a k u B, Shipley M, Jarrett RJ, et al: High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care 21:360-366,1998 3. Beks PH, Mackaay AJ, de Vries H, et al: Carotid artery stenosisis related to blood glucose level in an elderly Caucasian population: The Hoom Study. Diabetologia 40:290-298, 1997 4. Colwell JA, Clark CM: Forum two: Unanswered research questions about metabolic control in non-insulin dependent diabetes mellitus. Ann Intern Med 124178-179,1996 5. Coutinho M, Wang Y, Gerstein HC, et al: Continuous relationship of glucose with cardiovascular events in nondiabetic subjects: A meta regression analysis of 18 studies in 88,000 individuals [abstract]. Circulation 94 (suppl8):1-214, 1996 E', Abbott RD, Reed DM, et al: Postchallenge glucose concentration and cor6. Donahue R
onary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 36~689-692,1987 7. Gall M-A, Borch-JohnsenK, Hougaard P, et a1 Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 44:1303-1309,1995 8. Hanefeld M, Fischer S, Julius U, et al: Risk factors for myocardial infarction and death in newly detected NIDDM The Diabetes Intervention Study: 11-year follow-up. Diabetologia 39:1577-1583, 1996 9. International Collaborative Group: Asymptomatic hyperglycemia and coronary heart disease: A series of papers by the International Collaborative Group based on studies in fifteen populations. J Chronic Dis 32829-837,1979 10. Klein R Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 18258-268,1995 11. Knatterud GL, Klimt CR, Levin ME, et al: Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VI. Mortality and selected nonfatal events with insulin treatment. JAMA 240:37-42,1978 12. Kuusisto J, Mykkanen L, Pyorala K, et al: NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 43:960-967,1994 13. Kuusisto J, Mykkanen L, Pyorala K, et a1 Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects: Stroke 251157-1164, 1994 14. Laakso M, Lehto S: Epidemiology of macrovascular disease in diabetes.DiabetesReview 5~294-315,1997 15. Lehto S, Ronnemaa T, Haffner SM, et al: Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes483354-1359, 1997 16. Lehto S, Ronnemaa T, Pyorala K, et al: Predictors of stroke in middle-aged patients with non-insulin dependent diabetes. Stroke 2763-68,1996 17. Lowe LP, Liu K, Greenland P, et a1 Diabetes, asymptomatichyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care 20:163-169,1997 18. Malmberg K, Ryden L, Hamsten A, et al: Effects of insulin treahnent on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J 171337-1344,1996
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LAAGO
19. McGill HC Jr, McMahon CA, Malcom GT, et al: Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Pathological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Atheroscl Thromb Vasc Biol15:431-440,1995 20. Meigs JB, Singer DE, Sullivan LM, et a 1 Metabolic control and prevalent cardiovascular disease in non-insulin-dependent diabetes mellitus (NIDDM):The NIDDM Patient Outcome Research team. Am J Med 10238-47,1997 21. Niskanen L, Turpeinen A, Penttila I, et al: Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: A 15-year follow-up from the time of diagnosis. Diabetes Care 21:1861-1869,1998 22. Perry IJ, Wannamethee SG, Whincup PH, et al: Asymptomatic hyperglycaemia and major ischaemic health disease events in Britain. J Epidemiol Community Health 48:538543,1994 23. Pyorala K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: An epidemiologic view. Diabetes Metab Rev 3:463-524,1987 24. Pyorala K, Pedersen TR, Kjekshus J, et al: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 20:614620,1997 25. Scheidt-Nave C, Barrett-Connor E, Wingard DL, et a 1 Sex differences in fasting glycemia as a risk factor for ischemic heart death. Am J Epidemiol133:565-576,1991 26. Siitonen 01, Niskanen LK, Laakso M, et al: Lower-extremity amputations in diabetic and nondiabetic patients. Diabetes Care 1616-20,1993 27. Singer DE, Nathan DM, Anderson KM, et al: Association of GHbA,, with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes 41~202-208,1992 28. Stand1 E, Balletshofer B, Dahl B, et a 1 Predictors of 10-year macrovascular and overall mortality in patients with NIDDM The Munich General Practioner Project. Diabetologia 39:1540-1545,1996 29. Stem MI? Diabetes and cardiovascular disease. The 'common soil' hypothesis. Diabetes 44:369-374,1995 30. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986,1993 31. Turner RC, Millns H, Neil HAW, et al: Risk factors for coronary artery disease in noninsulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS 23). Br Med J 316823-828,1998 32. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). Lancet 352837-853,1998 33. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 317703-713,1998 34. Uusitupa MIJ, Niskanen LK, Voutilainen E, et al: Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition,in type 2 (noninsulin-dependent) diabetic and non-diabetic subjects. Diabetologia 361175-1184,1993 35. Wei M, Gaskill SP, Haffner SM, et al: Effect of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 21:1167-1172, 1998 36. West KM, Ahuja MMS, Bennett PH, et al: 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 6:361-369,1983 37. WHO Expert Committee on Diabetes Mellitus: Second report. World Health Organization technical report series 646. Geneva: World Health Organization, 1980 38. Wilson PWF, Cupples LA, Kannel WB: Is hyperglycemia associated with cardiovascular disease? The Framingham Study. Am Heart J 121:586-590,1991
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39. Yamasaki Y, Kawamori R, Matsushima H, et a l Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery. Diabetologia 38585-591,1995 Address reprint requests to Markku Laakso, MD Department of Medicine University of Kuopio 70210 Kuopio, Finland e-mail [email protected]
DIABETES
0095-4543/99 $8.00 + .OO
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE IN TYPE 2 DIABETES Markku Laakso, MD
Macrovascular complications, coronary heart disease, stroke, and peripheral vascular disease are major contributors to early death and chronic They account for about 70% of illness in patients with type 2 all mortality, and the most important of these complications, coronary heart disease, is twofold to fourfold more common in patients with type 2 diabetes than in normoglycemiccontrol ~ u b j e c t s . ' ~The ~ *risk ~ , ~for ~ stroke and peripheral vascular disease is also substantially increased in patients with type 2 d i a b e t e ~ . ' ~ , ~ , ~ ~ Cardiovascular complications are frequent at the diagnosis of type 2 diabetes. Therefore, the period of asymptomatic hyperglycemia preceeding the frank diabetic state must be important for the development of macrovascular disease. This prediabetic state was first recognized in 1980, when the World Health Organization (WHO) revised diagnostic criteria for diabetes and impaired glucose tolerance (IGT), a category between normal glucose tolerance and diabetes.37Indeed, IGT has been shown to be associated with an approximate twofold increase in the risk of macrovascular disease, giving direct evidence for the hypothesis that the prediabetic state is a risk factor for atheroscleotic complication^.^^,^ How can a mild abnormality in glucose metabolism that leads to an excess risk of macrovascular disease be explained? Several studies have indicated that both type 2 diabetes and IGT are associated with an unfavorable cardiovascular risk factor profile, high blood pressure, low highdensity lipoprotein (HDL) cholesterol, high triglycerides, obesity, central
From the Department of Medicine, University of Kuopio, Kuopio, Finland
PRIMARY CARE VOLUME 26 'NUMBER 4 'DECEMBER 1999
829
830
LAAKSO
obesity, and abnormalities in hemostatic These risk factors, however, do not completely explain the excess of cardiovascular complications in type 2 diabetes. This implies that the diabetic state itself, or factors associated with it, have to increase the risk for cardiovascular disease in type 2 diabetes. To decrease or to prevent the burden of cardiovasculardisease in type 2 diabetes, a crucial question is whether or not type 2 diabetes and coronary heart disease share common antecedents, which could explain the strong association between them. If a common soil hypothesis is c0rrect,2~ then the correction of hyperglycemia is not enough to normalize the cardiovascular risk of type 2 diabetic patients. If, on the other hand, hyperglycemia itself is responsible for the increase in the risk of cardiovascular disease, then the major focus in the treatment should be on the correction of glycemic control. GLUCOSE LEVEL AS A CARDIOVASCULAR RISK FACTOR IN SUBJECTS WITHOUT DIABETES
Evidence that hyperglycemia can affect the development of macrovascular complications, even in nondiabetic individuals, has been published in epidemiologic and autopsy studies. Results from the first crosssectional, population-based studies that suggested a relationship between elevated blood glucose in an oral glucose tolerance test and cardiovascular disease in subjects without clinically manifest diabetes were published in 196.5 from the United Kingdom (the Bedford study) and from the United States (the Tecumseh S t ~ ~ d yFollow-up ) . ~ ~ of these two cohorts verified the positive association between glucose level and coronary heart disease mortality. In 1979, the International Collaborative Group published the first extensive evaluation of nondiabetic glucose levels to predict cardiovascular disease based on 4 to 15years of follow-up data from 11different ~ t u d i e s . ~ Cardiovascular and coronary heart disease mortality rates in the highest blood glucose quintile compared to those observed in the lowest quintile were greater than 2.0 in only three of the nine studies. Only one study indicated a positive association of coronary heart disease mortality and glucose level after adjustment for confounding factors. Inconsistenciesbetween the studies could be related to a short follow-up period and to a lesser degree of standardization of the oral glucose tolerance test. The authors concluded that the 11studies did not show any consistent, strong, and graded association between asymptomatic hyperglycemia and coronary heart disease? In 1980, the Whitehall Study, one of the studies included in the International Collaborative Group report, indicated that there was a 1.5-fold to twofold increase in coronary heart disease and stroke mortality independent of age, smoking, blood pressure, and cholesterol level after 7.5 years follow-up for individuals with 2-hour glucose as low as 5.4mmol/L after a 50 g glucose load.”
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
831
During the last 10 years, a new interest in glucose level as a predictor of macrovascular complications has developed. The results of the 12-year follow up of the Honolulu Heart Study that included 6394 nondiabetic men of Japanese ancestry, aged 45 to 70 years at baseline, indicated that the risk of fatal and nonfatal coronary heart disease events increased continuously as 1-hour glucose levels after 50 g glucose challenge increased (P < 0.001), with no apparent glycemic threshold? In the Framingham Study,38the British Regional Heart Study,= and the Rancho Bernard0 Study,= nondiabetic subjects had elevated risk for coronary heart diseasee death with increasing baseline glucose level. Recently, the results of a 20-year follow-up study of nondiabetic men aged 44 to 55 years from the three studies originally included in the International Collaborative Group (the Whitehall Study (n = 10 025), the Paris Prospective Study (n = 6629), and the Helsinki Policemen Study (n = 631) were published.2 These studies indicated that men in the upper 20% of the 2-hour glucose distributions and those in the upper 2.5% for fasting glucose had a significantly higher risk, with an age-adjusted hazards ratio for coronary heart disease of 1.8 (1.4-2.4) and 2.7 (1.7-4.4), respectively. The Chicago Heart Study assessed the relationship of asymptomatic hyperglycemia at baseline to the risk of cardiovascular disease in over 11544white and 666 African American middle-aged men.I7Coronary heart disease mortality was increased in subjects with asymptomatic hyperglycemia (the relative risk and its 95% confidence intervals: 1.18 i1.011.371). In the Framingham study, glycated hemoglobin A,, (HbA,,) predicted cardiovascular disease events, but the subjects were not classified as nondiabetic and diabetic; consequently, the effect of glycemic control on cardiovascular disease could be attributed to a higher prevalence of diabetes in subjects with high HbA,,.27 McGill et all9investigated the incidence of fatty streaks in the arteries of individuals who had died from a variety of causes, mainly accidents. The occurrence of both fatty streaks and raised lesions was significantly elevated in the group with high HbA,, levels (X%) compared with those with lower HbA,, levels (58%).In the high HbA,, group, fatty streaks were seen in 47.9% and raised lesions in 16.7%, whereas in the lower HbA,, group, the corresponding percentages were 23% and 5.2% ( P = 0.009 and P = 0.02, respectively). This study, although cross-sectional, gives evidence that the atherosclerosis process is affected by hyperglycemia. Similarly, recent cross-sectional studies have indicated that HbA,, associates positively with carotid artery stenosis3and that asymptomatic hyperglycemia is associated with increased intima-media thickness of the carotid a~tery.3~ A meta-analysis of all published cohort studies of mainly nondiabetic populations has reported that the risk for cardiovascular events increased continuously with glucose levels above 4.2 mmol/L.5 This implies that there seems to be a graded relationship between glucose levels and the risk of macroangiopathy within the nondiabetic range.
HYPERGLYCEMIA AS A CARDIOVASCULAR RISK FACTOR IN SUBJECTS WITH TYPE 2 DIABETES
Until recent years, glycemic control was not believed to be an important risk factor for cardiovascular disease in type 2 diabetes. This conclusion was based on small studies and on scanty and inconsistent In the large cross-sectionalWHO Multinational Study of Vascular Disease in Diabetes, including 3000 diabetic patients from nine different countries, high fasting plasma glucose was associated with an increased prevalence of previous stroke, intermittent claudication, and previous leg amputations, but not with the prevalence of coronary heart disease assessed by the presence of major Q-waves on electr~cardiogram.~~ Since 1993, several large, prospective studies on newly-detected and previously-diagnosed type 2 diabetic patients have indicated that glycemic control is important for cardiovascular risk, including the risk for coronary heart disease in type 2 diabetic patients. Only a few recent crosssectional studies have not reported an association between glycemic control and cardiovascular
Newly Diagnosed Patients With Type 2 Diabetes
Uusitupa et a P showed that among 133 middle-aged subjects with newly diagnosed type 2 diabetes, 10-year cardiovascular mortality increased three-fold by tertiles of blood glucose and hbA,, (Table 1).In the same study, hyperglycemia was a constant predictor for 15-year cardiovascular mortality assessed at the time of diagnosis or at 5- or 10-year examinations.21In the study by Anderson and Svardsudd,' an average fasting blood glucose level predicted cardiovascular and coronary heart disease mortality in an unselected cohort of 411 subjects aged 23 to 94 years. In the Diabetes Intervention Study8postprandial blood glucose at entry determined 1 hour after the subject's normal breakfast, but not fasting glucose, predicted subsequent development of myocardial infarction. In the United Kingdom Prospective Diabetes Study (UKPDS),which included 2693 subjects with newly-detected type 2 diabetes aged 25 to 65 years, fasting plasma glucose and I-IbA,, were significantly associated with the risk of coronary heart disease (fatal and nonfatal myocardial infarction, angina pectoris) and fatal myocardial infarction during the fol10w-up.~~ They also evaluated the significance of other cardiovascular risk factors for coronary heart disease by stepwise multivariate Cox analysis. The most important risk factors for coronary heart disease were high low density lipoprotein cholesterol followed by low high density lipoprotein cholesterol and HbA,,, and high low density lipoprotein cholesterol, diastolic blood pressure, smoking, low high density lipoprotein cholesterol followed by HbA,, for nonfatal and fatal myocardial infarction, respectively. These results emphasize the significance of classic risk factors for the risk of coronary heart disease in type 2 diabetic patients.
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
833
Table 1. PROSPECTIVE STUDIES SHOWING AN ASSOCIATION BETWEEN CARDIOVASCULAR EVENTS AND GLYCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES No. Patients
Study
Age (years)
Length of Follow-up (years)
Newly diagnosed type 2 diabetes Uusitupa et alY 133 Andersson and 411 Svardsuddl Hanefeld et als 1139
45-64 23-94
10 7
30-55
11
Turner et aP’
25-65
8
2693
Previously diagnosed type 2 diabetes Kuusisto et all2 229 65-74
3.5 3.5 10
Kuusisto et all3 Heinlo
229 1370
65-74
Gall et a17 Stand1 et al” Lehto et all5
328 290 1059
20-65 <76 45-64
5 10
Lehto et all6
1059
45-64
7
471
25-64
7.5
Wei et al” CHD
=
>30
7
Endpoint Cardiovascular mortality CHD mortality and morbidity Incidence of myocardial infarction CHD mortality and morbidity CHD mortality and morbidity Stroke incidence CHD mortality. Stroke incidence Cardiovascular mortality Cardiovascular mortality CHD mortality and morbidity Stroke mortality and morbidity Cardiovascular mortality
coronary heart disease
Previously Diagnosed Patients With Type 2 Diabetes
In our prospective population-based study including 229 subjects with type 2 diabetes aged 65 to 74 years at baseline and followed for 3.5 years, HbA,, was the most powerful predictor of coronary heart disease events.12 In the same subjects, fasting glucose levels, 2-hour plasma glucose levels, and HbA,, predicted fatal or nonfatal ~tr0ke.I~ The Wisconsin EpidemiologicStudy of Diabetic Retinopathy assessed the significance of glycemic control for micro- and macrovascular complications in 1370 subjects with late-onset diabetes during 10 years of follow-up.10HbA,,. predicted not only microangiopathic but also macroangiopathic complications. A 1%increase in HbA,, resulted in a 70% increase in proliferative retinopathy, but only a 10% increase in coronary heart disease events. The results of this study imply that hyperglycemia is a much stronger risk factor for microvascular complications than it is for ischemic heart disease. In a 5-year follow-up study from Denmark? glycemic control measured by HbA,, predicted both all-cause and cardiovascular mortality in 328 patients with type 2 diabetes. In a 10-year follow-up study from Munich, Germany, HbA,, predicted cardiovascular death in 290 subjects with
type 2 diabetes.’B In the authors 7-year follow-up study on 1059 Finnish patients with type 2 diabetes aged 45 to 64 years at baseline, high fasting plasma glucose predicted coronary heart disease event^,'^ and lugh fasting plasma glucose and HbA,, predicted fatal and nonfatal stroke.Ib The association between poor glycemic control and stroke was much stronger than the association with poor glycemic control and coronary heart disease events. The San Antonio Heart Study, which included 471 patients with type 2 diabetes, demonstrated a dose-response relationship between the level of hyperglycemia and mortality.35Patients belonging to the highest quartile of fasting plasma glucose (>11.5 mmol/L) had 4.9-fold higher total and 4.9-fold h g h e r cardiovascular mortality than patients belonging to the two lowest fasting plasma quarhles (<8.0mmol/L). T h s study demonstrated that hyperglycemia is not only a risk factor in whites but also in other ethnic groups. CLINICAL TRIALS Although several recent, prospective, population-based studies including newlydetected or previously diagnosed patients with type 2 diabetes suggest that hyperglycemia is associated with cardiovascular disease, they do not prove causality between these two. Clinical mals are needed to provide a definite answer to this crucial question. Unfortunately, information from clinical trials aiming to investigate the effect of the reduction of hyperglycemia on cardiovascular end points in type 2 diabetes is h t e d . The Ihabetes Control and Complications Trial convincingly demonstrated that intensive insulin treatment reduced microvascular complications but because of a low number of incident cases, intensive treatment did not signdicantly reduce cardiovascular eventsw Moreover, we can not be sure whether or not trial evidence based on type 1 diabetic patients can be applied to type 2 diabetic patients. The University Group Diabetes Program (UGDP) randomized 619 patients to the following treatment regimens: placebo, phenformin, tolbutamide, a fixed insuhn dose, and a variable insulin dose.” The study began in 1961 and was completed in 1975. Patients treated with phenformin and tolbutamide had inmased cardiovascular mortality, and these study arms were stopped. At the end of the study, average fasting blood glucose was 2.0 mmol/L lower in the variable insulin group than in the placebo group or in the b e d insulin group, corresponding roughly to 1% of HbA,,. Insulin treatment groups and the placebo group had similar cardiovascular mortality (20.6% versus 20.2%,respectively). The suspicion that oral agents are harmful in the treatment of patients with type 2 diabetes has persisted since the results of this study were published. The UGDP did not solve the problem of whether or not the improvement of glycemic control could prevent diabetic complications. The Veterans Affairs Cooperative Study in Glycemia Control randomized 153 men with type 2 diabetes to standard therapy (1 -2 insulin inpc-
HYFERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
835
tions daily) or to intensive therapy4 Intensive treatment resulted in a reduction of HbA,, by an average of 2.1% (7.3% versus 9.4%, P < 0.001). coronary heart disease event rate was somewhat higher in the intensive treatment group than in the conventional treatment group (21.3% versus 11.5%,P = NS). The Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) triaP6 (n = 620) showed that in subjects with an acute myocardial infarction, intensive insulin treatment was associated with a lower case fatality rate than placebo treatment (18.6% versus 26.1%, P = 0.03). Whether the beneficial effect resulted from insulin infusion at acute phase or from improved long-term control cannot be determined from this trial. The UKPDS, begun in 1977, was designed to investigate whether intensive blood glucose control could reduce the risk of macrovascular or microvascular complicationsin subjects with type 2 diabetes, and whether any particular therapy was advantageous for these subjects (see article by Yudkin elsewhere in this issue).32Microvascular complications (retinopathy, nephropathy) were reduced by 25% ( P = 0.0099) and myocardial infarction was reduced by 16%( P = 0.052) with intensive treatment (Table 2). There was no evidence of any glycemic threshold for any of the microvascular and cardiovascular complications above the normal glucose levels (HbA,, > 6.0%). Table 2 shows the results from the intensive blood pressure trial of the UKPDS study, which included 1148 type 2 diabetic subjects with hyperten~ion.3~ Interestingly, blood pressure reduction was more effective than was tight glucose control, with respect to all end-points including microvascular complications. The glucose control and blood pressure control studies cannot be directly compared, because these two studies were not based on the same study subjects. Implications for Therapy
According to several prospective population-based studies, glycemic control influences the risk for cardiovascular disease, including coronary heart disease, independently of conventional risk factors in patients with type 2 diabetes. Recent evidence from the UKPDS has convincingly shown that long-term complications in patients with type 2 diabetes can be prevented by the correction of glycemic control. In the UKPDS, none of the treatment modalities was particularly effective in reducing complications, but the study did remove any residual suspicion that treatment with insulin or sulphonylureas is harmful at least in diabetic patients without macrovascular disease at baseline. Diet treatment, weight reduction, and exercise remain the cornerstones for treatment of type 2 diabetic patients. Aggressive treatment of hyperglycemia is undoubtedly indicated to retard the development of microvascular complications, but it also prevents, although to a lesser extent, macrovascular complications. The management of hyperglycemia should not outweigh other cardiovascular risk factors, particularly high cholesterol and elevated blood pressure, because
w QI
m
35% 25%
ll%7
12% 10% 6% 16% 0.0099
0.029 NS NS 0.052 NS NS
P Value
? = increase in the risk;NS = not statistically sigruhcant;PVD = peripheral vascular disease. Data from references 32 and 33.
Any diabetes-relatedendpoint Deaths related to diabetes All-cause mortality Myocardial infarction Stroke Amputation or death from PVD Microvascular disease
Endpoint
Glucose Control Risk Reduction
49% 37%
44%
24% 32% 18% 21 %
0.0046 0.019 NS NS 0.013 NS 0.0092
Blood Pressure Control Risk Reduction P Value
~~~~~~
Table 2. RISK REDUCTIONWITH INTENSIVE GLUCOSE TREATMENT AND BLOOD PRESSURE CONTROL FOR DIFFERENT ENDPOINTS IN THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY
HYPERGLYCEMIA AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE
837
recent trials have indicated that the lowering of total cholesterol levelz4 and blood pressure3 is beneficial in the treatment of cardiovascular disease in patients with type 2 diabetes. Therefore, in the prevention and treatment of cardiovascular disease in type 2 diabetes, all known cardiovascular risk factors should be attacked simultaneously.
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onary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 36~689-692,1987 7. Gall M-A, Borch-JohnsenK, Hougaard P, et a1 Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 44:1303-1309,1995 8. Hanefeld M, Fischer S, Julius U, et al: Risk factors for myocardial infarction and death in newly detected NIDDM The Diabetes Intervention Study: 11-year follow-up. Diabetologia 39:1577-1583, 1996 9. International Collaborative Group: Asymptomatic hyperglycemia and coronary heart disease: A series of papers by the International Collaborative Group based on studies in fifteen populations. J Chronic Dis 32829-837,1979 10. Klein R Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 18258-268,1995 11. Knatterud GL, Klimt CR, Levin ME, et al: Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VI. Mortality and selected nonfatal events with insulin treatment. JAMA 240:37-42,1978 12. Kuusisto J, Mykkanen L, Pyorala K, et al: NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 43:960-967,1994 13. Kuusisto J, Mykkanen L, Pyorala K, et a1 Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects: Stroke 251157-1164, 1994 14. Laakso M, Lehto S: Epidemiology of macrovascular disease in diabetes.DiabetesReview 5~294-315,1997 15. Lehto S, Ronnemaa T, Haffner SM, et al: Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes483354-1359, 1997 16. Lehto S, Ronnemaa T, Pyorala K, et al: Predictors of stroke in middle-aged patients with non-insulin dependent diabetes. Stroke 2763-68,1996 17. Lowe LP, Liu K, Greenland P, et a1 Diabetes, asymptomatichyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care 20:163-169,1997 18. Malmberg K, Ryden L, Hamsten A, et al: Effects of insulin treahnent on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J 171337-1344,1996
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39. Yamasaki Y, Kawamori R, Matsushima H, et a l Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery. Diabetologia 38585-591,1995 Address reprint requests to Markku Laakso, MD Department of Medicine University of Kuopio 70210 Kuopio, Finland e-mail [email protected]