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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1999  |  Volume : 10  |  Issue : 3  |  Page : 325-332
Treatment of Hypertension in Diabetes


Department of Medicine, University of Melbourne, Heidelberg, Australia

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   Abstract 

Patients with type I and II diabetes mellitus represent a population at high risk of the cardiovascular, cerebrovascular and renal effects of hypertension. Antihypertensive therapy should be considered for those with blood pressures above 130/85 mmHg with the aim to reduce levels below 125/75 especially for those with microalbummuria or diabetic nephropathy. Hypertension tends to occur on a background of multiple other risk factors. Life­style changes such as increased exercise and reduced salt intake, when combined with medication should improve the blood pressure response. On the currently available data, an Angiotensin Converting Enzyme (ACE) inhibitor, initially as mono-therapy, is the first choice antihypertensive agent in the absence of contraindications. Often dual or triple therapy is required to achieve target blood pressure levels.

Keywords: Hypertension, Diabetes, Therapy, Renal disease.

How to cite this article:
Cooper ME, Jerums G, Chattington PD. Treatment of Hypertension in Diabetes. Saudi J Kidney Dis Transpl 1999;10:325-32

How to cite this URL:
Cooper ME, Jerums G, Chattington PD. Treatment of Hypertension in Diabetes. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2020 Aug 13];10:325-32. Available from: http://www.sjkdt.org/text.asp?1999/10/3/325/37240

   Introduction Top


Hypertension is twice as prevalent in people with diabetes as in the general population. Both hypertension and diabetes are inde­pendent risk factors for microvascular and macro vascular disease. [1] In type I diabetes, hypertension is closely associated with evolving diabetic nephropathy and with a positive family history of hypertension. In Type II diabetes, hypertension may indicate evolving diabetic nephropathy but it may also be part of the metabolic syndrome. [2] In addition, raised blood pressure in this popu­lation is often isolated systolic hypertension, a pattern seen in elderly subjects. [3]

Definition of hypertension

The diagnostic criteria for hypertension in diabetes have changed over the last 20 years from blood pressure (BP) level of 160/95 mmHg (1983 WHO) to 140/90 mmHg (1993, Joint National Committee (JNC)-V), [4] and more recently to 130/85 mmHg (1997, JNC­VI). [5] These new criteria imply that many patients previously classified as normotensive should be re-classified as hypertensive. For example, using JNC-V criteria (BP > 140/90 mmHg) the proportion of type I diabetic subjects with hypertension attending a Danish diabetes clinic was 42%,52% and 79% in normo-, mirco- and macroalbuminuric subjects, respectively. [6] In type II diabetes, the correspond­ding proportions were 71%, 90% and 93%. [6] These prevalence rates are likely to be even higher once the JNC-VI definition of hypertension in diabetes (>130/85 mmHg) has been taken into account. Furthermore, the JNC-VI report also recommends a therapeutic goal of <125/75 mmHg in the presence of renal disease. [5]

Impact of hypertension in diabetes

In both Type I and Type II diabetes, hypertension leads to a two to three fold increase in major cardiovascular events. In type II diabetes, stroke and coronary heart disease (CHD) account for the majority of deaths with hypertension being associated with a four to five fold increase in mortality compared with normotensive type II diabetic patients. [1] On average, 75-80% of adult diabetic subjects die from CHD, cerebrovascular and/or peripheral vascular disease. Hypertension is a major contributor to large vessel disease, especially in type II diabetes and the level of urinary albumin, excretion has been shown to reflect the degree of macrovascular risk. [7] Macroalbuminuria in type I diabetes with its high rate of hypertension is associated with up to a 30 fold increase in mortality mostly from CHD. [8]

The role of ambulatory blood pressure monitoring (ABPM)

In diabetic subjects, ABPM may help to identify a high-risk group of patients. Progression from normo- to microalbu­minuria is associated with a concomitant rise in BP when assessed longitudinally by ABPM. [9] Previous work has shown that the nocturnal fall in BP is less in normotensive, normo-albuminuric patients with type I diabetes than in age matched controls, thereby increasing the 24-hour BP load. [10] Nocturnal BP and heart rate are higher in hypertensive, normoalbuminuric patients with type II diabetes and the nocturnal systolic dip in blood pressure is often absent. In patients with micro­albuminuria and type I diabetes the nocturnal dip in systolic blood pressure has been reported to correlate inversely with urinary albumin excretion. [11]

In addition, reduced BP variation was asso­ciated with increased prevalence of end­organ damage. [11]

Antihypertensive drugs and cardioprotec­tion in diabetes

The choice of antihypertensive therapy in the diabetic population needs to be considered in the context of not only providing renopro­tection but also the potential effects of these agents on atherosclerotic events. Indeed, diabetic patients with persistent microalbu­minuria are at increased risk for all-cause mortality, especially from cardiovascular disease. [7] Therefore, monitoring of other cardiovascular risk factors in these patients is critical. Several studies have suggested that ACE inhibitors may be superior to other classes of agents in conferring additional cardioprotection in hypertensive patients with either type I or type II diabetes. In the GISSI-3 trial, lisinopril treatment was associated with improved 30 day survival in diabetic patients after an acute myocardial infarct. [12] In the ABCD trial, in which cardiovascular endpoints were assessed, the hypertensive arm of the study was prematurely halted due to a possible superiority of the ACE inhibitor over the calcium channel antagonist in terms of cardio­vascular events. [13] In the FACET study involving 380 hypertensive type II diabetic subjects it was reported that the ACE inhibitor, fosinopril, was associated with less cardiovas­cular events than amlodipine. [14] In the CAPPP trial, an advantage of the ACE inhibitor over conventional therapy (diuretics, beta blockers) was observed in the diabetic subgroup. [15]

However, there are a number of other studies, which have either failed to show superiority of ACE inhibition or have demonstrated significant benefits on cardio­vascular events with other antihypertensive agents. In the recent HOT study, which involved felodipine based antihypertensive treatment, aggressive blood pressure reduction in the diabetic sub-group was associated with reduced cardiovascular mortality. [16] However, in that study the group with the lowest adverse effects of blood pressure had the highest prevalence of concomitant therapies including ACE inhibitors. Therefore, it remains to be determined if the improved cardiovascular outcome in the diabetic population with the lowest blood pressure levels was due to effective blood pressure reduction or to a specific vasprotective effect of ACE inhibition. In the United Kingdom Prospective Diabetes Study (UKPDS), both captopril and atenolol were associated with reduced cardiovascular events without evidence that one agent conferred a specific additional benefit. [17] However, in that study a significant proportion of subjects in each group were receiving additional antihypertensive agents making it difficult to determine if the lack of difference between the two treatment groups was real or related to confounding effects of other agents. In the recently published SYSTEUR diabetic subgroup analysis, nitrendipine therapy was particularly effective in preventing vascular events3 but this study was performed against placebo rather than against an agent, which interrupts the renin­angiotensin system. It is likely that over the next few years results from other studies will become available, which include even larger numbers of diabetic patients. [18] In addition, several multicenter studies are currently examining the effects of angiotensin II (ATI) receptor antagonists on both renal and cardiovascular endpoints in type II diabetic patients. [19]

Non-pharmacological treatment of hypertension

Because interaction of cardiovascular risk factors leads to more than a simply additive increase in vascular risk, it is important to encourage non-pharmacological measures of risk reduction before and during drug therapy. These include weight reduction if the body mass index exceeds 25, with emphasis on a low energy, low saturated fat, and high complex carbohydrate diet in combination with regular exercise. Alcohol intake should be assessed and excess should be discouraged, while cessation of smoking should be encouraged. Sodium restriction should be considered especially if ACE inhibitors or angiotensin II receptor antagonists are being used without diuretics. Salt restriction reduces hyperfiltration, renal enlargement and albumin excretion in experimental diabetes. [20] In the Melbourne Diabetic Nephropathy Study over a 12 month period both perindopril and nifedipine stabilized albuminuria and the response to ACE inhibition was highly dependent on salt intake. [21]

Diabetes, hypertension and renal disease The importance of antihypertensive therapy in diabetic patients has generally focused on the patient with early or overt renal disease. [22] Experimental studies have clearly shown that hypertension is a major accelerating factor in both the functional and structural features of diabetic nephpathy. [23] Epidemiological studies have confirmed a close association between systemic hypertension and the development of overt nephropathy. [24] Landmark studies were performed over 15 years ago by Mogensen and Parving indicating the importance of blood pressure reduction in retarding the decline in renal function in proteinuric type I diabetic patients. [25],[26] Since then, a large number of studies have been completed exploring the role of antibypertensive treatment regimens in early and advanced diabetic nephropathy. These studies have involved the use of hypotensive drugs in type I and type II diabetes, in the presence or absence of conventionally defined systemic hypertension and in various phases of diabetic renal disease as well as in normoalbuminuric subjects as part of a preventive apporach. [22]

Overt diabetic nephropathy

ACE inhibitors appear to be particularly useful in diabetic patients with overt proteinuria with evidence that these agents not only reduce proteinuria, but decrease the number of patients who will develop end-stage renal failure. [27] However, although ACE inhibition is clearly very useful in this population, in the Collaborative study there was clearly less benefit detected in those type I diabetic subjects with serum creatinine < 0.15 mmol/L or normal blood pressure. These findings are consistent with a meta-analysis, which suggested that the superiority of ACE inhibition over other antihypertensive agents is not as evident at maximum hypotensive doses. [28] A link between reduced rates of progression and improvement in prognosis in nephropathic type I diabetic subjects has been noted by Parving's group using both ACE inhibitors and conventional agents, consistent with the view that the major focus is this population must be on aggressive blood pressure reduction.

Although ACE inhibitors may be anti­proteinuric, many type I diabetic subjects will still have inadequately controlled blood pressure. This lack of strict blood pressure control may be a major factor in the continued rate of decline in renal function in the captopril treated group, albeit at a slower rate, in the Collaborative study. [27] Additional agents may need to be considered including the use of diuretics, the addition of other antihypertensive drugs such as calcium channel blockers [30] or newer pharmacological agents such as the dual ACE/neutral endopeptidase inhibitors, which are at present being investigated in heart failure and hypertension. [31]

In type II diabetic subjects with macroproteinuria, antihypertensive treatment has been shown to be renoprotective although the role of ACE inhibitors has not been as clearly defined as in type I diabetic subjects. [32] There are now several multi-center large scale studies in progress, which are evaluating the role of All receptors antagonists in this clinical context.[19] A number of recent studies have confirmed that ACE inhibitors are superior to other antihypertensive agents including the dihydro-pyridine calcium channel blockers (CCB) in reducing albuminuria in hypertensive type II diabetic subjects with macroportienuria. [32] Parving's group has reported a disparity in effects on albuminuria and renal function with different antihypertensive agents/ Whereas lisinopril was more effective than atenolol in reducing albuminuria, both agents were similar in efficacy in terms of rate of decline in glomerular filtration rate. Bakris et al have reported differences between the sub-classes of CCB and have suggested that dihydropyridine CCBs (such as nifedipine) despite effectively reducing arterial pressure do not confer the same degree of renoprotection as non-dihydro­ pyridine CCBs. [34]

Microalbuminuria

In normotensive, microalbuminuric type I diabetic subjects, ACE inhibition has been clearly shown by the Microalbuminuria Captopril Study Group in a two-year study to retard the rise in albuminuria. [35] In a recent placebo controlled study over eight years, captopril prevented the development of macroproteinuria and was associated with stabilization of renal function. [36] This study by Mathiesen and colleagues provides the first long-term evidence that appropriate timing of the commencement of ACE inhibitor therapy in this normotensive population postpones and possibly in some patients prevents the development of overt nephropathy. Since ACE inhibitors appear to be renoprotective in up to 40% of microalbuminuric type I diabetic subjects at risk of nephropathy, it has been suggested that ACE inhibition may be an appropriate preventive treatment in normoalbuminuric type I diabetic subjects. However, in the EUCLID study, no evidence of a beneficial role for the ACE inhibitor, lisinopril, in normoalbuminuric type I diabetic subjects was observed. [37] This may partly relate to the relatively short duration of only two-years in the EUCLID study.

The use of antihypertensive therapy in type II diabetic subjects with hypertension and microalbuminuria has been evaluated by an increasing number of investigators over the last decade. [32] In the largest of these studies, which involved over 300 subjects, the ACE inhibitor, lisinopril, reduced albuminuria over 12 months whereas nifedipine failed to significantly influence urinary albumin excretion. [38] In normotensive microalbu­minuric type II diabetic subjects several placebo controlled studies have reported the efficacy of ACE inhibition in either reducing or preventing a rise in albuminuria over at least four years. [22]

Angiotensin II receptor antagonists

This relatively new therapeutic class of drugs competitively blocks the binding of angiotensin to angiotensin II receptors and, therefore blocks the effects of angiotensin more selectively than ACE inhibition. [39] These agents reduce angiotensin II-induced vasoconstriction, sodium reabsorption and aldosterone release, but do not influence bradykinin degradation. These agents do not cause cough and may provide a useful alternative to ACE inhibitors for patients intolerant of this particular side effect. Animal studies suggest that the renoprotective effects of All receptor antagonists and ACE inhibitors are similar in diabetes, [40] but results from long-term clinical studies are awaited.

Choice of antihypertensive agent in the metabolic syndrome

In Type II diabetes, hypertension is frequently associated with central obesity, insulin resistance, hyperuricemia, hyper­triglyceridemia, low HDL cholesterol levels and microablbuminuria. It has been suggested that insulin resistance is the underlying cause of this syndrome, although it is difficult to separate cause, effect and association in a disorder as heterogeneous as Type II diabetes. The choice of antihypertensive agent needs to take into account the effect of drugs on lipid parameters and the clinical context. [41] Centrally acting agents, alpha-blockers, vasodilators, ACE inhibitors, angiotensin II receptor antagonists and CCB have little effect on the lipid profile or glycemic status. [41] However, ACE inhibitors can induce hyperkalemia especially in those with type II diabetes and hyporeninemic hypoaldosteronism and may precipitate renal failure in the context of undiagnosed bilateral renal artery stenosis.

Retinopathy

Angiotensin II has angiogenic properties, and therefore it is possible that this hormone will play a role in mediating neovas­cularization in the diabetic retina. Although this possibility has not been extensively investigated in the EUCLID study which evaluated the role of lisinopril in a population of predominantly normotensive, normoalbu­minuric type I diabetic subjects, ACE inhibition was associated with at least a 50% reduction in retinopathy including proliferative retinopathy. [43] This issue requires further investigation, since this study provides preliminary evidence for a retino-protective role for these agents.

 
   References Top

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11.Lindsay RS, Stewart MJ, Nairn IM, Baird JD, Padfield PL. Reduced diurnal variation of blood pressure in non-insulin dependent diabetic patients with microalbuminuria. JHum Hypertens 1995;9:223-7.  Back to cited text no. 11    
12.Zuanetti G, Latini R, Maggioni AP, Franzosi M, Santoro L, Tognoni G. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96:4239-45.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
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14.Tatti P, Pahor M, Byington RP, et al Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Rando­mized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597-603.  Back to cited text no. 14    
15.Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet 1999;353:61 1-6.  Back to cited text no. 15    
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17.Efficacy of atenolol and captopril in risk of macrovascular and microvascular complications in type 2 diabetes UKPDS 39. UK Prospective Diabetes 28. Study Group. Br Med J 1998;3 17;713-20.  Back to cited text no. 17    
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21.Jerums G, Allen TJ, Tsalamandris C, Cooper ME. Angiotensin Converting Enzyme inhibition and Calcium Channel Blockade in incipient diabetic nephropathy. The Melbourne Diabetic Nephropathy Study Group. Kidney Int 1992;41: 904-11.  Back to cited text no. 21    
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37.Randomized placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normo­albuminuriaor microalbuminuria. The EUCLID study group. Lancet 1997;349: 1787-92.  Back to cited text no. 37    
38.Agardh CD, Garcia Puig J, Charbonnel B, Angelkort B, Barnett AH. Greater reduction of urinary albumin excretion in hypertensive type II diabetic patients with incipient nephropathy by lisinopril than by nifedipine. J Hum Hypertens 1996;10:185­-92.  Back to cited text no. 38    
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41.Stein PP, Black HR. Drug treatment of hypertension in patients with diabetes mellitus. Diabetes Care 1991; 14:425-48.  Back to cited text no. 41  [PUBMED]  
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43.Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type I diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998;351:28-31.  Back to cited text no. 43    

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Correspondence Address:
Mark Emmanuel Cooper
Department of Medicine, Austin and Repatriation Medical Center, W. Heidelberg, Victoria 3081
Australia
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