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Hypertension and macrovascular disease—the killing fields of NIDDM
Diabetes Research and Clinical Practice 39 Suppl. (1998) S27 – S33
Hypertension and macrovascular disease—the killing fields of NIDDM Markku Laakso * Department of Medicine, Uni6ersity of Kuopio, 70210 Kuopio, Finland
Abstract Diabetes mellitus and particularly non-insulin-dependent diabetes mellitus (NIDDM) increases the risk for all manifestations of: (a) atherosclerotic vascular disease; (b) coronary heart disease (CHD); (c) cerebrovascular disease; and (d) peripheral vascular disease. NIDDM is known to be associated with several adverse cardiovascular risk factors, including: (i) hypertension; (ii) obesity; (iii) central obesity; (iv) hyperinsulinemia; and (v) serum lipid and lipoprotein abnormalities, characterized mainly by elevated serum total triglycerides and low high-density lipoprotein cholesterol. This review will discuss the prevalence of hypertension in NIDDM, the role of hypertension to increase the risk for macrovascular complications in NIDDM and finally trial evidence for the beneficial effect of blood pressure lowering in patients with NIDDM. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-insulin-dependent diabetes; Coronary heart disease; Hypertension; Drug treatment
1. Introduction The risk for all manifestations of atherosclerotic vascular disease, coronary heart disease (CHD), cerebrovascular disease and peripheral vascular disease (PVD) is substantially increased in diabetic patients [1]. The most important manifestation of macrovascular disease in patients with non-insulindependent diabetes mellitus (NIDDM) is CHD and CHD mortality and morbidity rates are two to four times higher in diabetic patients than in nondiabetic subjects. * Tel.: +358 17 172151; fax: + 358 17 173993.
This review concentrates only on NIDDM but hypertension in patients with insulin-dependent diabetes mellitus is also an important risk factor for macrovascular complications. In NIDDM hypertension can be classified as ‘essential’ hypertension whereas in insulin-dependent diabetes mellitus elevated blood pressure is usually of renal origin. Albumin excretion into the urine increases the occurrence of hypertension and when kidney function impairs practically every insulin-dependent diabetic patient has elevated blood pressure. NIDDM is preceded by a precursor phase of asymptomatic hyperglycemia of variable duration, impaired glucose tolerance (IGT), a category be-
0168-8227/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0168-8227(98)00020-5
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Fig. 1. The prevalence of hypertension (drug treatment or systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 95 mmHg) in newly-diagnosed patients with non-insulin-dependent diabetes mellitus (NIDDM) [7] and in previously diagnosed patients with NIDDM [8] from eastern Finland.
tween normal and diabetic glucose tolerance. Also in IGT the occurrence of hypertension is substantially elevated. NIDDM and IGT share multiple potential risk factors for macrovascular disease: (a) hypertension; (b) obesity; (c) central obesity; (d) hyperinsulinemia; and (e) serum lipid and lipoprotein abnormalities, characterized mainly by elevated serum total triglycerides and low highdensity lipoprotein (HDL) cholesterol [2 – 5]. This review will discuss first the prevalence of elevated blood pressure in NIDDM and secondly, the role of hypertension to increase the risk for macrovascular complications in patients with NIDDM. Finally trial evidence for the beneficial effect of blood pressure lowering in patients with NIDDM will be discussed.
2. Elevated blood pressure as a risk factor for macrovascular complications Patients with NIDDM and subjects with IGT have higher mean values for systolic and diastolic blood pressure and higher prevalence of essential hypertension than nondiabetic subjects [1,6]. Therefore, hyperglycemia can not be the major determining factor for hypertension in NIDDM.
In the two studies from the Kuopio region, eastern Finland, the prevalence of hypertension among newly-detected patients with NIDDM was substantially elevated (Fig. 1) and almost as high as in previously diagnosed NIDDM patients particularly among women [7,8]. The cause for high occurrence of hypertension in patients with NIDDM is unknown but it is associated with insulin resistance and hyperinsulinemia [9] and other components of insulin resistance syndrome, abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol and microalbuminuria. The relationship of blood pressure to cardiovascular disease morbidity and mortality has been reported to be similar in diabetic patients and in nondiabetic subjects [1]. Fig. 2 shows the mortality and morbidity risk ratio (hypertensives versus normotensives) in nondiabetic and diabetic subjects from several studies. In the Whitehall study hypertension increased the risk for cardiovascular mortality by 1.8-fold in nondiabetic and by 2.1fold in diabetic subjects [10]. The UK Prospective Diabetes Study included 3648 newly-diagnosed NIDDM patients who had hypertension. Hypertension increased the risk for cardiovascular mortality among them by 2.4-fold and cardiovascular
M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
S29
Fig. 2. Risk ratios (hypertensive versus nonhypertensive) for cardiovascular mortality and morbidity in nondiabetic and diabetic subjects in the Whitehall Study [10], in the Hypertension in Diabetes Study (HDS) [11], in the DuPont employees [12] and in the Gothenburg Study [13].
in nondiabetic and diabetic subjects. In the DuPont employees study [12] and in the Gothenburg Study [13] cardiovascular morbidity was about 2-fold higher among hypertensive subjects both in nondiabetic and diabetic subjects. Stamler et al. [14] assessed predictors of cardiovascular mortality among men with (5163 men) and without (342815 men) diabetes in the Multiple Risk Factor Intervention Trial. As shown in Fig. 3 systolic blood pressure was positively related to the risk of cardiovascular disease (CVD) death with a significant trend in nondiabetic and diabetic subjects (P B0.001). At every level of systolic blood pressure, CVD death was much greater for diabetic than nondiabetic men but with higher systolic blood pressure levels CVD mortality rate increased more steeply among diabetic men than among nondiabetic men. Relative risk for diabetic compared with nondiabetic men at varying systolic blood pressure levels ranged from 1.89 to 4.40, with lower relative risk at higher systolic blood pressure levels. Hypertension is the single most important risk factor for stroke in nondiabetic subjects [15] as well as in diabetic patients [16]. Also our study
confirmed the finding that hypertension is an important risk factor for stroke in NIDDM patients [17]. High blood pressure level is a significant risk factor for amputation in NIDDM [18]. Selby and Zhang [19] found in their large case-control study including 10068 diabetic patients (primarily non-insulin-dependent) with average 13.2-year follow-up that baseline systolic blood pressure was an independent predictor of amputation (P= 0.004). Moreover, it has been suggested that hypertension is independently associated with the progression of PVD [20]. The risk of cardiovascular mortality has been found to be associated with an increased urinary albumin and protein excretion rate independently of classic cardiovascular risk factors in patients with NIDDM [21,22]. The mechanisms behind this association are poorly understood. Increased urinary albumin excretion rate is often associated with adverse changes in cardiovascular risk factors [23,24]. Interestingly, a simultaneous occur rence of hyperinsulinemia and microalbuminuria identifies a group of subjects with a highly increased risk for CHD [24].
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M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
Fig. 3. Age-adjusted cardiovascular mortality rates by systolic blood pressure for men with and without diabetes in the Multiple Risk Factor Intervention Trial [14].
The simultaneous presence of proteinuria with hypertension potentiates the risk for mortality and morbidity. The WHO Multinational Study including 4714 diabetic patients aged 35 – 55 years demonstrated that patients with NIDDM and hypertension and proteinuria had a 5-fold mortality risk among men and an 8-fold mortality risk among women compared with those without hypertension and proteinuria [25]. In this study of 1056 middle-aged NIDDM patients in whom total urinary protein concentration was available from the morning spot urine specimen, fatal and nonfatal CHD and stroke events were higher in NIDDM subjects with clinical proteinuria than in those without proteinuria [26]. This association remained statistically significant even after adjustment for the presence of hypertension.
3. Does drug treatment for hypertension reduce the risk for macrovascular complications in patients with NIDDM? Several clinical trials have demonstrated that nondiabetic middle-aged and elderly hyperten-
sive patients benefit from drug treatment [27– 30]. However, data are limited on effects of diuretic and other antihypertensive drug treatment on morbidity and mortality in diabetic subjects. No trials have been published on the effect of antihypertensive drugs on morbidity and mortality in NIDDM subjects. However, two studies are available which have included a substantial number of diabetic patients to perform subgroup analyses of the main trial. The Hypertension Detection and Follow-up Program was a population-based trial. Its aim was to assess efficacy of chlorthalidone in preventing all-cause mortality of an intensive stepped care compared with community referred care among nondiabetic and diabetic individuals with diastolic blood pressure greater than or equal to 90 mmHg [28]. Altogether 1079 (9.9%) of 10940 hypertensive participants aged 30–69 years and randomized for the study had diabetes. For the subgroup with mild hypertension (diastolic blood pressure 90–104 mmHg and not receiving antihypertensive drug at baseline) (5680 subjects, of whom 466 (8.0%) had diabetes) all-cause mortality reduced by 20.5% for diabetic subjects and 22.2% for nondiabetic subjects in the inten-
M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
S31
Fig. 4. Morbidity and mortality reduction for cardiovascular events in diabetic and nondiabetic subjects by treatment group in the Systolic Hypertension in the Elderly Program [29].
sively treated group compared to the community referred care. The Systolic Hypertension in the Elderly Program (SHEP) investigated the effect of lowdose, diuretic-based antihypertensive treatment in a double-blind, randomized fashion on major CVD event rates in older, NIDDM patients with isolated hypertension compared with nondiabetic patients [31]. A total of 4149 nondiabetic subjects and 583 NIDDM patients aged 60 years and older at baseline and having systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure less than 90 mmHg were randomized to receive either a low dose of chlorthalidone (12.5 – 25.0 mg/d) with a step-up to atenolol or reserpine or placebo. Fig. 4 shows the relative risk for CVD events in nondiabetic and NIDDM subjects during the 5-year follow-up. Major CVD events, nonfatal and fatal stroke, nonfatal myocardial infarction or fatal CHD and major CHD events reduced in both groups although the reduction was not always significant in the NIDDM group. However, with respect to major CHD events the risk reduction was significant only for NIDDM patients. Thus, on the basis of the SHEP trial a low-dose diureticbased treatment was effective for preventing CVD both in nondiabetic and NIDDM subjects having isolated systolic hypertension.
4. Conclusions The prevalence of hypertension among NIDDM patients is high. According to several studies more than 50% of NIDDM patients have either a drug treatment for hypertension or elevated blood pressure. Furthermore, several studies have indicated that hypertension or elevated blood pressure is at least as important risk factor for CVD in nondiabetic subjects as in NIDDM patients. Therefore, there is a great potential to prevent CVD by treatment of hypertension in NIDDM patients. Indeed, two subgroup analyses from large trials have indicated that NIDDM patients benefit of diureticbased antihypertensive treatment at least as much as nondiabetic subjects. However, these studies have not been primarily designed to investigate the effect of antihypertensive agents in patients with NIDDM. Therefore, trials including only diabetic patients are urgently needed. Because b-blocking agents have been proven to be effective in the secondary prevention of CHD events in nondiabetic subjects the trial including these antihypertensive agents should be carried out also in hypertensive patients with NIDDM. Angiotensin converting enzyme (ACE) inhibitors are neutral or even improve insulin sensitivity among hypertensive subjects and furthermore these drugs are effective in reducing
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M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
albuminuria and proteinuria in diabetic patients. However, no trial evidence is available yet to indicate that ACE inhibitors can prevent CVD events in hypertensive NIDDM patients.
[12]
[13]
Acknowledgements [14]
Our research projects referred to in this review have been financially supported by grants from the Academy of Finland. [15]
References [1] K. Pyo¨ra¨la¨, M. Laakso, M. Uusitupa, Diabetes and atherosclerosis:an epidemiologic view, Diabetes Metab. Rev. 3 (1987) 463 – 524. [2] R.B. Goldberg, Lipid disorders in diabetes, Diabetes Care 4 (1981) 561 – 572. [3] M. Laakso, E. Voutilainen, H. Sarlund, A. Aro, K. Pyo¨ra¨la¨, I. Penttila¨, Serum lipids and lipoproteins in middle-aged non-insulin dependent diabetics, Atherosclerosis 56 (1985) 271 –281. [4] M. Laakso, E. Barrett-Connor, Asymptomatic hyperglycemia is associated with lipid and lipoprotein changes favoring atherosclerosis, Arteriosclerosis 9 (1989) 665– 672. [5] M. Laakso, S. Lehto, I. Penttila¨, K. Pyo¨ra¨la¨, Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes, Circulation 88 (1993) 1421–1430. [6] E. Barrett-Connor, M.H. Criqui, M.R. Klauber, M. Holdbrook, Diabetes and hypertension in a community of older adults, Am. J. Epidemiol. 113 (1981) 276–284. [7] M. Uusitupa, O. Siitonen, K. Pyo¨ra¨la¨, A. Aro, K. Hersio, I. Penttila¨, E. Voutilainen, The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed type 2 (non-insulin-dependent) diabetes, Diabetologia 28 (1985) 653–659. [8] M. Laakso, T. Ro¨nnemaa, K. Pyo¨ra¨la¨, V. Kallio, P. Puukka, I. Penttila¨, Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and nondiabetic subjects in Finland, Diabetes Care 11 (1988) 449 – 462. [9] A.L. Swislocki, B.B. Hoffman, G.M. Reaven, Insulin resistance, glucose intolerance and hyperinsulinemia in patients with with hypertension, Am. J. Hypertens. 2 (1989) 419 – 423. [10] J.H. Fuller, M.J. Shipley, G. Rose, R.J. Jarrett, H. Keen, Coronary-heart disease and impaired glucose tolerance: the Whitehall study, Lancet i (1980) 1373–1376. [11] The Hypertension in Diabetes Study Group, Hypertension in Diabetes Study (HDS): II. Increased risk of car-
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diovascular complications in hypertensive type 2 diabetic patients, J. Hypertens. 11 (1993) 319 – 325. S. Pell, A. D’Alonzo, Factors associated with long-term survival of diabetics, J. Am. Med. Assoc. 214 (1970) 1833 – 1840. A. Rosengren, L. Welin, A. Tsipogianni, L. Wilhelmsen, Impact of cardiovascular risk factors on coronary heart disease among middle aged diabetic men: a general population study, Br. Med. J. 299 (1989) 1127 – 1131. J. Stamler, O. Vaccaro, J. Neaton, D. Wentworth, For the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial, Diabetes Care 16 (1993) (1993) 434 – 444. J. Stokes, W.B. Kannel, P.A. Wolf, L.A. Cupples, R.B. D-Agostino, The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study, Circulation 75 (1987) 65 – 73. S. Lavy, E. Melamed, E. Cahane, A. Carmon, Hypertension and diabetes as risk factors in stroke patients, Stroke 4 (1973) 751 – 759. S. Lehto, T. Ro¨nnemaa, K. Pyo¨ra¨la¨, M. Laakso, Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes, Stroke 27 (1996) 63 – 68. J.S. Lee, M. Lu, V.S. Lee, D. Russell, C. Bahr, E.T. Lee, Lower-extremity amputation. Incidence, risk factors and mortality in the Oklahoma Indian Diabetes Study, Diabetes 42 (1993) 876 – 882. J.V. Selby, D. Zhang, Risk factors for lower extremity amputation in persons with diabetes, Diabetes Care 18 (1995) 509 – 516. P.J. Palumbo, W.M. O’Fallon, P.J. Osmundson, B.R. Zimmerman, A.L. Langworthy, F.J. Kazmier, Progression of peripheral occlusive arterial disease in diabetes mellitus. What factors are predictive, Arch. Intern. Med. 151 (1991) 717 – 721. M.A. Gall, K. Borch-Johnsen, P. Hougaard, F.S. Nielsen, H.-H. Parving, Albuminuria and poor glycemic control predict mortality in NIDDM, Diabetes 44 (1995) 1303 – 1309. M.B. Mattock, N.J. Morrish, G. Vilberti, H. Keen, A.P. Fitzgerald, G. Jackson, Prospective study of microalbuminuria as predictor of mortality in NIDDM, Diabetes 41 (1992) 736 – 741. L. Niskanen, M. Uusitupa, H. Sarlund, O. Siitonen, E. Voutilainen, I. Penttila¨, Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed Type 2 (non-insulindependent) diabetic patients, Diabetologia 33 (1990) 237 – 243. J. Kuusisto, L. Mykka¨nen, K. Pyo¨ra¨la¨, M. Laakso, Hyperinsulinemic microalbuminuria. A new risk indicator for coronary heart disease, Circulation 91 (1995) 831 – 837.
M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33 [25] S.-L. Wang, J. Head, L. Stevens, J.H. Fuller. World Health Organization Multinational Study Group: Excess mortality and its relation to hypertension and proteinuria in diabetic patients, Diabetes Care 19 (1996) 305–312. [26] H. Miettinen, S.M. Haffner, S. Lehto, T. Ro¨nnemaa, K. Pyo¨ra¨la¨, M. Laakso, Proteinuria predicts stroke and other atherosclerotic vascular disease events in non-diabetic and non-insulin-dependent diabetic subjects, Stroke 27 (1996) 2033 – 2039. [27] P. Collins, R. Peto, S. MacMahon, P. Hebert, N.H. Fiebach, K.A. Eberlein, et al., Blood pressure, stroke and coronary heart disease, Lancet 335 (1990) 827–838. [28] Hypertension. Detection and Follow-up Program Cooperative Group. Implications of the Hypertension Detection and Follow-up Program, Prog. Cardiovasc. Dis. 29
(1986) (suppl 1) 3 – 10. [29] Systolic Hypertension in the Elderly Program Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension, J. Am. Med. Assoc. 265 (1991) 3255 – 3264. [30] MRC Working Party, Medical Research Council trial of treatment of hypertension in older adults: principal results, Br. Med. J. 304 (1992) 405 – 412. [31] J.D. Curb, S.L. Pressel, J.A. Cutler, et al., For the Systolic Hypertension in the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated hypertension, J. Am. Med. Assoc. 276 (1996) 1886 – 1892.
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Hypertension and macrovascular disease—the killing fields of NIDDM Markku Laakso * Department of Medicine, Uni6ersity of Kuopio, 70210 Kuopio, Finland
Abstract Diabetes mellitus and particularly non-insulin-dependent diabetes mellitus (NIDDM) increases the risk for all manifestations of: (a) atherosclerotic vascular disease; (b) coronary heart disease (CHD); (c) cerebrovascular disease; and (d) peripheral vascular disease. NIDDM is known to be associated with several adverse cardiovascular risk factors, including: (i) hypertension; (ii) obesity; (iii) central obesity; (iv) hyperinsulinemia; and (v) serum lipid and lipoprotein abnormalities, characterized mainly by elevated serum total triglycerides and low high-density lipoprotein cholesterol. This review will discuss the prevalence of hypertension in NIDDM, the role of hypertension to increase the risk for macrovascular complications in NIDDM and finally trial evidence for the beneficial effect of blood pressure lowering in patients with NIDDM. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-insulin-dependent diabetes; Coronary heart disease; Hypertension; Drug treatment
1. Introduction The risk for all manifestations of atherosclerotic vascular disease, coronary heart disease (CHD), cerebrovascular disease and peripheral vascular disease (PVD) is substantially increased in diabetic patients [1]. The most important manifestation of macrovascular disease in patients with non-insulindependent diabetes mellitus (NIDDM) is CHD and CHD mortality and morbidity rates are two to four times higher in diabetic patients than in nondiabetic subjects. * Tel.: +358 17 172151; fax: + 358 17 173993.
This review concentrates only on NIDDM but hypertension in patients with insulin-dependent diabetes mellitus is also an important risk factor for macrovascular complications. In NIDDM hypertension can be classified as ‘essential’ hypertension whereas in insulin-dependent diabetes mellitus elevated blood pressure is usually of renal origin. Albumin excretion into the urine increases the occurrence of hypertension and when kidney function impairs practically every insulin-dependent diabetic patient has elevated blood pressure. NIDDM is preceded by a precursor phase of asymptomatic hyperglycemia of variable duration, impaired glucose tolerance (IGT), a category be-
0168-8227/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0168-8227(98)00020-5
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M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
Fig. 1. The prevalence of hypertension (drug treatment or systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 95 mmHg) in newly-diagnosed patients with non-insulin-dependent diabetes mellitus (NIDDM) [7] and in previously diagnosed patients with NIDDM [8] from eastern Finland.
tween normal and diabetic glucose tolerance. Also in IGT the occurrence of hypertension is substantially elevated. NIDDM and IGT share multiple potential risk factors for macrovascular disease: (a) hypertension; (b) obesity; (c) central obesity; (d) hyperinsulinemia; and (e) serum lipid and lipoprotein abnormalities, characterized mainly by elevated serum total triglycerides and low highdensity lipoprotein (HDL) cholesterol [2 – 5]. This review will discuss first the prevalence of elevated blood pressure in NIDDM and secondly, the role of hypertension to increase the risk for macrovascular complications in patients with NIDDM. Finally trial evidence for the beneficial effect of blood pressure lowering in patients with NIDDM will be discussed.
2. Elevated blood pressure as a risk factor for macrovascular complications Patients with NIDDM and subjects with IGT have higher mean values for systolic and diastolic blood pressure and higher prevalence of essential hypertension than nondiabetic subjects [1,6]. Therefore, hyperglycemia can not be the major determining factor for hypertension in NIDDM.
In the two studies from the Kuopio region, eastern Finland, the prevalence of hypertension among newly-detected patients with NIDDM was substantially elevated (Fig. 1) and almost as high as in previously diagnosed NIDDM patients particularly among women [7,8]. The cause for high occurrence of hypertension in patients with NIDDM is unknown but it is associated with insulin resistance and hyperinsulinemia [9] and other components of insulin resistance syndrome, abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol and microalbuminuria. The relationship of blood pressure to cardiovascular disease morbidity and mortality has been reported to be similar in diabetic patients and in nondiabetic subjects [1]. Fig. 2 shows the mortality and morbidity risk ratio (hypertensives versus normotensives) in nondiabetic and diabetic subjects from several studies. In the Whitehall study hypertension increased the risk for cardiovascular mortality by 1.8-fold in nondiabetic and by 2.1fold in diabetic subjects [10]. The UK Prospective Diabetes Study included 3648 newly-diagnosed NIDDM patients who had hypertension. Hypertension increased the risk for cardiovascular mortality among them by 2.4-fold and cardiovascular
M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
S29
Fig. 2. Risk ratios (hypertensive versus nonhypertensive) for cardiovascular mortality and morbidity in nondiabetic and diabetic subjects in the Whitehall Study [10], in the Hypertension in Diabetes Study (HDS) [11], in the DuPont employees [12] and in the Gothenburg Study [13].
in nondiabetic and diabetic subjects. In the DuPont employees study [12] and in the Gothenburg Study [13] cardiovascular morbidity was about 2-fold higher among hypertensive subjects both in nondiabetic and diabetic subjects. Stamler et al. [14] assessed predictors of cardiovascular mortality among men with (5163 men) and without (342815 men) diabetes in the Multiple Risk Factor Intervention Trial. As shown in Fig. 3 systolic blood pressure was positively related to the risk of cardiovascular disease (CVD) death with a significant trend in nondiabetic and diabetic subjects (P B0.001). At every level of systolic blood pressure, CVD death was much greater for diabetic than nondiabetic men but with higher systolic blood pressure levels CVD mortality rate increased more steeply among diabetic men than among nondiabetic men. Relative risk for diabetic compared with nondiabetic men at varying systolic blood pressure levels ranged from 1.89 to 4.40, with lower relative risk at higher systolic blood pressure levels. Hypertension is the single most important risk factor for stroke in nondiabetic subjects [15] as well as in diabetic patients [16]. Also our study
confirmed the finding that hypertension is an important risk factor for stroke in NIDDM patients [17]. High blood pressure level is a significant risk factor for amputation in NIDDM [18]. Selby and Zhang [19] found in their large case-control study including 10068 diabetic patients (primarily non-insulin-dependent) with average 13.2-year follow-up that baseline systolic blood pressure was an independent predictor of amputation (P= 0.004). Moreover, it has been suggested that hypertension is independently associated with the progression of PVD [20]. The risk of cardiovascular mortality has been found to be associated with an increased urinary albumin and protein excretion rate independently of classic cardiovascular risk factors in patients with NIDDM [21,22]. The mechanisms behind this association are poorly understood. Increased urinary albumin excretion rate is often associated with adverse changes in cardiovascular risk factors [23,24]. Interestingly, a simultaneous occur rence of hyperinsulinemia and microalbuminuria identifies a group of subjects with a highly increased risk for CHD [24].
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M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
Fig. 3. Age-adjusted cardiovascular mortality rates by systolic blood pressure for men with and without diabetes in the Multiple Risk Factor Intervention Trial [14].
The simultaneous presence of proteinuria with hypertension potentiates the risk for mortality and morbidity. The WHO Multinational Study including 4714 diabetic patients aged 35 – 55 years demonstrated that patients with NIDDM and hypertension and proteinuria had a 5-fold mortality risk among men and an 8-fold mortality risk among women compared with those without hypertension and proteinuria [25]. In this study of 1056 middle-aged NIDDM patients in whom total urinary protein concentration was available from the morning spot urine specimen, fatal and nonfatal CHD and stroke events were higher in NIDDM subjects with clinical proteinuria than in those without proteinuria [26]. This association remained statistically significant even after adjustment for the presence of hypertension.
3. Does drug treatment for hypertension reduce the risk for macrovascular complications in patients with NIDDM? Several clinical trials have demonstrated that nondiabetic middle-aged and elderly hyperten-
sive patients benefit from drug treatment [27– 30]. However, data are limited on effects of diuretic and other antihypertensive drug treatment on morbidity and mortality in diabetic subjects. No trials have been published on the effect of antihypertensive drugs on morbidity and mortality in NIDDM subjects. However, two studies are available which have included a substantial number of diabetic patients to perform subgroup analyses of the main trial. The Hypertension Detection and Follow-up Program was a population-based trial. Its aim was to assess efficacy of chlorthalidone in preventing all-cause mortality of an intensive stepped care compared with community referred care among nondiabetic and diabetic individuals with diastolic blood pressure greater than or equal to 90 mmHg [28]. Altogether 1079 (9.9%) of 10940 hypertensive participants aged 30–69 years and randomized for the study had diabetes. For the subgroup with mild hypertension (diastolic blood pressure 90–104 mmHg and not receiving antihypertensive drug at baseline) (5680 subjects, of whom 466 (8.0%) had diabetes) all-cause mortality reduced by 20.5% for diabetic subjects and 22.2% for nondiabetic subjects in the inten-
M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
S31
Fig. 4. Morbidity and mortality reduction for cardiovascular events in diabetic and nondiabetic subjects by treatment group in the Systolic Hypertension in the Elderly Program [29].
sively treated group compared to the community referred care. The Systolic Hypertension in the Elderly Program (SHEP) investigated the effect of lowdose, diuretic-based antihypertensive treatment in a double-blind, randomized fashion on major CVD event rates in older, NIDDM patients with isolated hypertension compared with nondiabetic patients [31]. A total of 4149 nondiabetic subjects and 583 NIDDM patients aged 60 years and older at baseline and having systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure less than 90 mmHg were randomized to receive either a low dose of chlorthalidone (12.5 – 25.0 mg/d) with a step-up to atenolol or reserpine or placebo. Fig. 4 shows the relative risk for CVD events in nondiabetic and NIDDM subjects during the 5-year follow-up. Major CVD events, nonfatal and fatal stroke, nonfatal myocardial infarction or fatal CHD and major CHD events reduced in both groups although the reduction was not always significant in the NIDDM group. However, with respect to major CHD events the risk reduction was significant only for NIDDM patients. Thus, on the basis of the SHEP trial a low-dose diureticbased treatment was effective for preventing CVD both in nondiabetic and NIDDM subjects having isolated systolic hypertension.
4. Conclusions The prevalence of hypertension among NIDDM patients is high. According to several studies more than 50% of NIDDM patients have either a drug treatment for hypertension or elevated blood pressure. Furthermore, several studies have indicated that hypertension or elevated blood pressure is at least as important risk factor for CVD in nondiabetic subjects as in NIDDM patients. Therefore, there is a great potential to prevent CVD by treatment of hypertension in NIDDM patients. Indeed, two subgroup analyses from large trials have indicated that NIDDM patients benefit of diureticbased antihypertensive treatment at least as much as nondiabetic subjects. However, these studies have not been primarily designed to investigate the effect of antihypertensive agents in patients with NIDDM. Therefore, trials including only diabetic patients are urgently needed. Because b-blocking agents have been proven to be effective in the secondary prevention of CHD events in nondiabetic subjects the trial including these antihypertensive agents should be carried out also in hypertensive patients with NIDDM. Angiotensin converting enzyme (ACE) inhibitors are neutral or even improve insulin sensitivity among hypertensive subjects and furthermore these drugs are effective in reducing
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M. Laakso / Diabetes Research and Clinical Practice 39 Suppl. (1998) S27– S33
albuminuria and proteinuria in diabetic patients. However, no trial evidence is available yet to indicate that ACE inhibitors can prevent CVD events in hypertensive NIDDM patients.
[12]
[13]
Acknowledgements [14]
Our research projects referred to in this review have been financially supported by grants from the Academy of Finland. [15]
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