These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Diabetic Hypertensive Patients Is this a group in need of particular care and attention? Hans-Henrik Parving, MD, DMSC Morbidity and mortality in diabetes are caused mainly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks of microangiopathy, which may lead to end-stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. Systemic hypertension is an early and frequent phenomenon. Nocturnal hypertension is also more frequent in people with diabetes compared with the nondiabetic population. Capillary hypertension has been demonstrated in type 1 diabetic patients. Poor metabolic control may induce elevation in blood pressure, but data are conflicting. The prevalence of white-coat hypertension in the diabetic population is comparable with that in the nondiabetic population. Prospective observational studies in type 1 and type 2 patients have revealed that abnormally increased urinary albumin excretion and other potentially modifiable risk factors—such as hypertension, smoking, poor metabolic control, and social class—predict increased all-cause mortality and cardiovascular mortality. Arterial hypertension is a risk factor in the initiation and progression of diabetic micro- and macroangiopathy. Diabetes, hypertension, and smoking are the three most important risk factors for fatal and nonfatal stroke. A randomized, double-blind, parallel study has revealed that the 5-year major cardiovascular disease rate was lowered by 34% for antihypertensive treatment compared with placebo. Furthermore, the study found a trend for lower all-cause mortality for low-dose antihypertensive-treated diabetic patients. Effective blood pressure reduction with ACE inhibitors and/or non-ACE inhibitors, frequently in combination with diuretics, reduces albuminuria, delays the progression of nephropathy, postpones end-stage renal failure, and improves survival in diabetic nephropathy. Diabetes Care 22 (Suppl. 2):B76–B79, 1999 Morbidity and mortality in diabetes are caused mainly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks of microangiopathy, which may lead to end-stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. It should be stressed that diabetic nephropathy is strongly associated with other severe complications, such as proliferative retinopathy, autonomic neuropathy, peripheral neuropathy, macroangiopathy, and hypertension (1). The prevalence of hypertension is at least twice as high in the diabetic population as in the background population, and furthermore, arterial blood pressure (BP) increases with increasing levels of albumin excretion rate (1,2). In this article, I focus on the strategies to reduce the burden of hypertension in the diabetic patients with and without nephropathy. MORTALITY—We evaluated the impact of microalbuminuria (albumin excretion between 30 and 300 mg/24 h) and macroalbuminuria (albumin excretion rate >300 mg/24 h) on mortality in 328 Caucasian patients with type 2 diabetes followed for 5 years (3). Our study revealed that 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria died during the 5 years of observation. Significant predictors of cardiovascular mortality included preexisting coronary heart disease, macroalbuminuria, poor metabolic control (elevated HbA1c levels), and elevated systolic arterial BP. More recently, we studied the prognostic significance of microalbuminuria and overt diabetic nephropathy and other putative risk factors for cardiovascular and all-cause mortality in type 1 diabetic patients. A total of 939 patients were followed prospectively for 10 years. Fifteen percent of the normoalbuminuric patients, 20% of the microalbuminuric patients, and 44% of patients with overt nephropathy at baseline died during the 10 years of follow-up (Fig. 1). Our study revealed that abnormally increased urinary albumin excretion and other potentially modifiable risk factors—such as hypertension, smoking, poor metabolic control, and social class—predict increased all-cause mortality and cardiovascular mortality (4).
PREVALENCE OF ARTERIAL HYPERTENSION— In 1994, we compared the prevalence of arterial hypertension in type 1 and type 2 diabetic patients according to BP criteria from the World Health Organization (>160/95 mmHg) and the Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) (>140/90 mmHg) (Table 1) (5). Our study revealed that the new JNC-V criteria approved by the American Diabetes Association led to a considerable increase in the prevalence of arterial hypertension in a population of type 1 and type 2 diabetic patients, particularly due to isolated systolic hypertension. The original BP data was generated in 1985, which probably explains the rather low frequency of BP-lowering therapy in patients with abnormally elevated urinary albumin excretion.
Several studies in type 1 and type 2 diabetic patients with incipient and overt diabetic nephropathy have demonstrated a blunted nocturnal decline in arterial BP (nondipping), a condition that might enhance the strain on the microvasculature and cardiovascular system (6,7). The high prevalence of autonomic neuropathy may also contribute to the increased cardiovascular morbidity and mortality (e.g., sudden death, arrhythmia) characteristically found in these patients. Furthermore, it should be recalled that diabetic patients have an enhanced BP rise during exercise as compared with the nondiabetic population (8). Some but not all studies suggest that poor metabolic control may induce a rise in arterial BP level (9,10). In addition, it should be stressed that autoregulation of blood flow (constancy of blood flow in spite of wide variation in systemic BP) is frequently impaired or even abolished in many tissues and organs, including the brain and the kidney (11–13). The clinical importance of this phenomenon is hypoperfusion during low BP and hyperperfusion (capillary hypertension) during high system BP. Actually, Tooke and colleagues (14,15) have demonstrated elevated capillary hydraulic pressure in the nail fold of type 1 diabetic patients but not in type 2 diabetic patients. Early data have suggested a high prevalence of white-coat hypertension (~50%) in type 2 diabetic patients (16). To study this phenomenon further, we determined the prevalence of white-coat hypertension in type 2 diabetic patients with normoalbuminuria, microalbuminuria, or diabetic nephropathy (17). The prevalence of white-coat hypertension (clinic hypertension with normal arterial BP values at home) was determined by comparison of clinic BP (Hawksley Random Sphygmomanometer) and the ambulatory daytime (7:00 a.m. to 11:00 p.m.) BP, measured with the Takeda TM 2420 (Tokyo, Japan). By applying established criteria, white-coat hypertension was confirmed if daytime BP was <135/85 mmHg. The prevalence of white-coat hypertension was significantly higher in normoalbuminuric patients (n = 30, BP 155/86 ± 3/2 [SEM] mmHg) than in microalbuminuric patients (n = 51, 156/89 ± 2/1 mmHg) and in type 1 diabetic patients with diabetic nephropathy (n = 47, 171/90 ± 3/2 mmHg) (17): 23% versus 8 and 9%, P< 0.05, with no difference between the last two groups. The office BP was slightly higher in the diabetic nephropathy group as compared with the other two groups. In conclusion, the prevalence of white-coat hypertension in normoalbuminuric type 2 diabetic patients resembles that observed in nondiabetic subjects with essential hypertension, whereas the prevalence is significantly lower in type 2 diabetic patients with incipient or overt diabetic nephropathy, suggesting a difference between primary and secondary hypertension. ANTIHYPERTENSIVE TREATMENT— Arterial hypertension is a risk factor in the initiation and the progression of diabetic micro- and macroangiopathy (1,2). Diabetes, hypertension, and smoking are the three most important risk factors for fatal and nonfatal stroke. The risk for stroke mortality and morbidity associated with diabetes is approximately twice that of the nondiabetic patient. Diabetes is an independent risk factor for coronary heart disease, and the risk is double when hypertension is also present (2). The goal of antihypertensive treatment should be not only to reduce morbidity and mortality from cardiovascular and renal diseases but to do so without adverse effects on the functional well-being of the patients. In addition, other cardiovascular risk factors, such as obesity, smoking, alcohol abuse, hyperlipidemia, and lack of exercise, should be treated. Nonpharmacological treatment is particularly important in obese patients. Approximately 85% of type 2 diabetic patients are obese. Weight loss, sodium restriction (~80–100 mmol/day), and regular exercise are recommended. Obese hypertensive patients are characterized by sodium and water retention, which probably explains why hypertension in the patients is extremely sodium sensitive. In 1991, Warram et al. (18) claimed that intervention with diuretics to reduce hyper-tension is associated with excess mortality in diabetic patients with and without proteinuria. Furthermore, they stated that until there are clinical trials showing a beneficial effect of diuretic treatment in diabetic patients, there is urgent need to reconsider its continued use in this population. These conclusions arrived from the original diabetic retinopathy study, a multicenter trial evaluating the beneficial impact of laser treatment (19,20). Warram et al. (18) assumed that diuretics were used only as an antihypertensive drug and thus classified all users of diuretics as hypertensives. This crucial assumption is not supported in another major diabetic retinopathy study performed in the U.S. by Klein et al. (21), who found that 32% of diabetic patients taking diuretics had heart disease. In other words, the Warram et al. study (18) is a classic example of confounding by indication, as we have experienced in recent years dealing with the discussion of calcium antagonists and cardiovascular protection. The conclusion made by Warram et al. (18) can be discarded because several studies in diabetic patients with and without diabetic nephropathy have demonstrated a clear beneficial effect of diuretics on morbidity and mortality, as will be discussed below. In 1996, the Systolic Hypertension in the Elderly Programme assessed in a secondary analysis the effect of low-dose diuretic-based antihypertensive treatment on the major cardiovascular disease rate in older type 2 diabetic patients with isolated systolic hypertension compared with nondiabetic patients (22). The 5-year major cardiovascular disease rate was lowered by 34% for active treatment compared with placebo, both for diabetic patients and for nondiabetic patients. Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic versus nondiabetic patients (101/1,000 vs. 51/1,000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients. Furthermore, the study found a favorable trend for all-cause mortality for low-dose antihypertensive-treated diabetic and nondiabetic patients. There was little or no evidence of adverse effects of treatment negating the important positive results in the randomized control trial. Recently, we reviewed the impact of calcium antagonists on kidney function in overt nephropathy (23). Most of the 11 studies available demonstrated that ACE inhibitors have a more beneficial effect on albuminuria than do calcium antagonists. Of major importance, however, is the effect of these two classes on the rate of decline in glomerular filtration rate. The same beneficial effect was observed whether calcium antagonists or ACE inhibitors were used. Unfortunately, only five studies lasted 1 year or more. Bakris and colleagues (24,25) reported a more beneficial effect with calcium antagonists compared with atenolol on the progression of diabetic renal disease in an open randomized 5-year prospective study. Furthermore, we performed a 1-year double-blind, double-dummy, randomized, controlled study comparing nisoldipine (20–40 mg daily) with lisinopril (10–20 mg daily) in 49 hypertensive type 1 diabetic patients with diabetic nephropathy (26). In summary, lisinopril reduced albuminuria but also glomerular filtration rate to a greater extent than nisoldipine did in hypertensive type 1 diabetic patients with nephropathy during the 1st year of treatment. Longer follow-up is required to clarify whether these drugs have different renal protective effects. Studies evaluating the combined effect of these two classes of drugs are urgently warranted.
Effective BP reduction with ACE inhibitors and/or non-ACE inhibitors, frequently in combination with diuretics, reduces albuminuria, delays the progression of nephropathy, postpones end-stage renal failure, and improves survival in diabetic nephropathy (23–25,27–34) (Fig. 2). References 2. Consensus Statement: Treatment of hypertension in diabetes. Diabetes Care 16:1394– 1401, 1993 3. Gall M-A, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H-H: Albuminuria and poor glycemic control predicts mortality in NIDDM. Diabetes 44:1303–1309, 1995 4. Rossing P, Hougaard P, Borch-Johnsen K, Parving H-H: Predictors of mortality in insulin dependent diabetes: 10 year follow-up study. BMJ 313:779–784, 1996 5. Tarnow L, Rossing P, Gall M-A, Nielsen FS, Parving H-H: Prevalence of arterial hypertension in diabetic patients before and after the JNC-V. Diabetes Care 17:1247–1251, 1994 6. Hansen KW, Christensen CK, Andersen PH, Mau Pedersen M, Christiansen JS, Mogensen CE: Ambulatory blood pressure in microalbuminuric type 1 diabetic patients. Kidney Int 41:847–854, 1992 7. Nielsen FS, Rossing P, Bang LE, Svendsen TL, Gall M-A, Smidt UM, Parving H-H: On the mechanisms of blunted nocturnal decline in arterial blood pressure in NIDDM patients with diabetic nephropathy. Diabetes 44:783–789, 1995 8. Karlefors T: Exercise test in male diabetics. Acta Med Scand 180 (Suppl. 449):3–43, 1966 9. Mathiesen ER, Gall M-A, Hommel E, Skøtt P, Parving H-H: Effects of short-term strict metabolic control on kidney function and extracellular fluid volume in incipient diabetic nephropathy. Diabet Med 6:595–600, 1989 10. Miller JA, Floras JS, Zinman B, Skorecki KL, Logan AG: Effect of hyperglycaemia on arterial pressure, plasma renin activity and renal function in early diabetes. Clin Sci 90:189–195, 1996 11. Kastrup J, Nørgaard T, Parving H-H, Henriksen O, Lassen NA: Impaired autoregulation of blood flow in subcutaneous tissue of long-term type 1 (insulin-dependent) diabetic patients with microangiopathy: an index of arteriolar dysfunction. Diabetologia 28:711–717, 1985 12. Kastrup J, Rørsgård S, Parving H-H, Lassen NA: Impaired autoregulation of cerebral blood flow in long-term type 1 (insulin-dependent) diabetic patients with nephropathy and retinopathy. Clin Physiol 6:549–559, 1986 13. Parving H-H, Kastrup J, Smidt UM, Andersen AR, Feldt-Rasmussen B, Christiansen JS: Impaired autoregulation of glomerular filtration rate in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia 27:547–552, 1984 14. Sandeman DD, Shore AC, Tooke JE: Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control. N Engl J Med 327:760–764, 1992 15. Shore AC, Jaap AJ, Tooke JE: Capillary pressure in patients with NIDDM. Diabetes 43:1198–1202, 1994 16. Puig JG, Ruilope LM, Ortega R: Antihypertensive treatment efficacy in type II diabetes mellitus: dissociation between causal and 24-hour ambulatory blood pressure. Hypertension 26:1093–1099, 1995 17. Nielsen FS, Gaede P, Vedel P, Pedersen OB, Parving H-H: White coat hypertension in NIDDM patients with and without incipient and overt diabetic nephropathy. Diabetes Care 20:859–863, 1997 18. Warram JH, Laffel L, Valsania P, Christlieb AR, Krolewski AS: Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Intern Med 51:1350–1356, 1991 19. Diabetic Retinopathy Study Research Group: Report 7: a modification of the Airlie House classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 21:210–226, 1981 20. Diabetic Retinopathy Study Research Group: Report number 6: design, methods, and baseline results. Invest Ophthalmol Vis Sci 21:3–188, 1981 21. Klein R, Moss SE, Klein BEK, DeMets DL: Relation of ocular and systemic factors to survival in diabetes. Arch Intern Med 149:266–272, 1989 22. Curb JD, Pressel SL, Cutler JA, Savage PJ, Appelgate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 276:1886–1892, 1996 23. Parving H-H, Tarnow L, Rossing P: Renal protection in diabetes: an emerging role for calcium antagonists. J Hypertens 14:S21–S25, 1996 24. Bakris GL, Copley JB, Vicknair N, Sadler R, Leugans S: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 50:1641–1650, 1996 25. Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler
R: Effect of calcium channel or 26. Rossing P, Tarnow L, Boelskifte S, Jensen BR, Nielsen FS, Parving H-H: Differences between nisoldipine and lisinopril on glomerular filtration rates and albuminuria in hypertensive IDDM patients with diabetic nephropathy during the first year of treatment. Diabetes 46:481–487, 1997 27. Björck S, Nyberg G, Mulec H, Granerus G, Herlitz H, Aurell M: Beneficial effect of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. Br Med J 293:471–474, 1986 28. Lewis E, Hunsicker L, Bain R, Rhode R: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329:1456–1462, 1993 29. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J 285:685–688, 1982 30. Nielsen FS, Rossing P, Gall M-A, Skøtt P, Smidt UM, Parving H-H: Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 43:1108–1113, 1994 31. Nielsen FS, Rossing P, Gall M-A, Skøtt P, Smidt UM, Parving H-H: Long-term effect of lisinopril and atenolol on kidney function in hypertensive non-insulin-dependent diabetic subjects with diabetic nephropathy. Diabetes 46:1182–1188, 1997 32. Parving H-H, Andersen AR, Smidt UM, Svendsen PA: Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet i:1175–1179, 1983 33. Parving H-H, Hommel E: Prognosis in diabetic nephropathy. BMJ 299:230–233, 1989 34. Parving H-H, Jacobsen P, Rossing K, Smidt UM, Hommel E, Rossing P: Benefits of long-term antihypertensive treatment on prognosis in diabetic nephropathy. Kidney Int 49:1778–1782, 1996 35. Knowles HCJ: Long term juvenile diabetes treated with unmeasured diet. Trans Assoc Am Physicians 84:95–101, 1971 36. Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T: Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25:496–501, 1983 37. Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type 1 diabetes. Am J Med 78:785–794, 1985 From the Steno Diabetes Center, Gentofte, Denmark. Address correspondence and reprint requests to Hans-Henrik Parving, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Received for publication 27 May 1998 and accepted in revised form 3 September 1998. Abbreviations: BP, blood pressure; JNC-V, Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.
Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
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