The prevalence of diabetes mellitus, particularly non-insulin-dependent (type II) diabetes mellitus (NIDDM), is increasing worldwide, presumably in relation to progressively increasing life expectancy and the ever increasing incidence of obesity. The incidence of hypertension in diabetic patients increases with age and with duration of disease and, overall, approximately 50% of diabetic patients will also be hypertensive. The importance of antihypertensive treatment and intensive blood pressure control has recently been highlighted by the findings of the UK Prospective Diabetes (UKPD) Study which reinforce the recommendations of the sixth Joint National Committee (JNC VI) report that those patients with a combination of diabetes mellitus and blood pressure values above 140/90 mm Hg should receive intensive antihypertensive drug treatment because they fall into the highest category of cardiovascular risk (1,2).
The adverse consequences of diabetes mellitus and hypertension typically manifest through adverse effects on the kidney; initially, this is detected as microalbuminuria, followed by overt proteinuria and a progressive decline in renal function, particularly if hypertension is untreated or poorly controlled. The adverse prognostic significance of diabetic nephropathy as a predictor or marker of increased cardiovascular morbidity and mortality is also well recognized. Thus, the short- to medium-term goal of intensive blood pressure control is reduction in proteinuria and preservation of renal function, but the long-term goal is a reduction in adverse cardiovascular outcomes.
Although diabetic nephropathy is numerically the most important type of renal disease requiring treatment, it is important to recognize that hypertension is a frequent accompaniment to other types of kidney disease (Table 1). There is again clear emphasis on protecting the kidney and preserving renal function through optimal antihypertensive treatment and intensive blood pressure control.
RENAL DISEASE AND BLOOD PRESSURE CONTROL
It has been recognized for many years that blood pressure reduction retards the decline in glomerular filtration rate in patients with diabetic nephropathy (3). More recently, the results of clinical trials, particularly with angiotensin-converting enzyme (ACE) inhibitor drugs, have indicated that blood pressure reduction by means of an ACE inhibitor regimen not only can significantly reduce proteinuria and the rate of decline of glomerular filtration rate in hypertensive diabetics with nephropathy but also can delay the requirement for renal replacement therapy and reduce overall mortality. The seminal study of Lewis et al. (4) was based on treatment of type I diabetes mellitus with the ACE inhibitor captopril, but results wholly consistent with these benefits have also been obtained with other antihypertensive treatment regimens and other ACE inhibitor drugs.
Although the central role of ACE inhibitor drugs is widely recognized in the management of patients with combinations of hypertension, diabetes mellitus and renal impairment or renal disease, several additional considerations arise in routine clinical practice.
The rates for compliance with drug treatment are as poor in diabetic patients as they are in other patient groups and, for this reason, a once-daily ACE inhibitor drug is preferred. In this respect, and despite the outcome evidence, captopril and its requirement for twice or three times daily dosing is probably not the drug of choice.
Intensive blood pressure control
Irrespective of the dose frequency, it is obviously necessary to obtain good blood pressure control and, while this will frequently require combination drug treatment, an agent capable of providing a consistent and long-lasting antihypertensive effect would seem to be the most suitable first choice. In terms of the 'quality' of its blood pressure control, the results of a recent study indicate that spirapril is at least as effective as enalapril in both the magnitude and consistency of its antihypertensive effect (5).
No significant drug accumulation
In the context of patients with impaired renal function, the obvious clinical concern is that reduced renal clearance might lead to excessive accumulation of drug (or active metabolite) which, in turn, might place patients at increased risk of adverse effects and possible drug toxicity. For this reason, an agent which is eliminated wholly or partly by non-renal mechanisms (i.e., via the liver) would appear to be a preferable choice.
Safety and tolerability
A drug which does not itself cause any deterioration in renal function is obviously required; furthermore, there should be no increase in adverse effects or loss of symptomatic tolerability in patients with functional renal impairment.
SPIRAPRIL IN PATIENTS WITH RENAL IMPAIRMENT
Spirapril is an ACE inhibitor which has dual elimination pathways, with approximately 50% hepatic metabolism and 50% renal elimination (6). The effect of varying degrees of renal impairment on the pharmacokinetics of spirapril have been studied in detail in patients with creatinine clearance values ranging from 11 to 126 ml/min (7). Although there were statistically significant increases in the maximum drug concentrations (Cmax) and of the area under the plasma drug concentration-time curves (AUC) in relation to declining glomerular filtration rates, there were no significant increases in the minimum plasma drug concentrations (Cmin) after both single doses of spirapril (6 mg) and under steady-state conditions after 4 weeks of treatment with spirapril 6 mg daily. Thus, there was no evidence of significant drug accumulation even in patients with creatinine clearance values of less than 20 ml/min (Fig. 1).
Importantly, however, this clinical pharmacological study also investigated the extent of the ACE inhibition and blood pressure reduction with single dose and steady-state spirapril treatment. Under steady-state conditions, there was a significantly greater degree of ACE inhibition both at the time of the maximum and minimum drug concentrations in the patients with the most severe degrees of renal impairment; however, renal function was unaffected, there was no evidence of increased adverse effects and there were no significant differences in the achieved level of blood pressure control.
ANTIHYPERTENSIVE EFFICACY OF SPIRAPRIL
In a comparative study of spirapril and enalapril, both agents produced significant blood pressure reductions relative to placebo (5)(Fig. 2). Overall, the reduction in blood pressure was 18/17 mm Hg with spirapril and 19/14 mm Hg with enalapril; the reduction in diastolic blood pressure was significantly greater with spirapril than with enalapril (Table 2). Furthermore, antihypertensive efficacy in terms of trough: peak ratio was consistently greater than 80% (83 and 84%) with the two cohorts of patients who received spirapril 6 mg (Table 3). In contrast, with enalapril 10 mg the trough : peak ratio was slightly lower at 71% and only with 20 mg enalapril did the trough : peak ratio exceed 80%. Thus, the duration and consistency of the antihypertensive effect (throughout 24 h) is confirmed by the consistently high trough : peak ratio with spirapril. Additionally, this study identifies another small but important practical advantage for spirapril insofar as no dose titration was required and no dose adjustments were necessary to produce the optimal antihypertensive effect.
Spirapril itself has not been studied on a large scale in patients with diabetic nephropathy but the available information is entirely consistent with the results from studies with other ACE inhibitors. For example, in a small-scale comparison of spirapril and isradipine it was shown that there was a clear and significant reduction in proteinuria with spirapril and no change in glomerular filtration rate (Table 4). In contrast, isradipine was associated with a significant increase in proteinuria and a continuing trend for glomerular filtration rate to deteriorate (8).
COMBINATION TREATMENT WITH SPIRAPRIL
It is well recognized that combination drug treatment will be required in more than 50% of patients with essential hypertension (8). Correspondingly, 'tight' blood pressure control in the UKPD Study of hypertensive type II diabetic patients required two or more drugs in more than 60% of patients (1). Thus, combinations involving ACE inhibitors and diuretics have been widely used in the treatment of hypertensive diabetics. More recently, for reasons of antihypertensive efficacy allied to a lack of adverse metabolic effects, the use of ACE inhibition in combination with calcium channel blockade has become widespread. Although the preliminary results of the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) are controversial in terms of the cardiovascular outcomes associated with the different monotherapies, it is interesting to note that the best outcomes were seen in those patients receiving both an ACE inhibitor (fosinopril) and a dihydropyridine calcium channel blocker (amlodipine) (9).
Spirapril has been studied in combination with isradipine to assess the effectiveness of the combination on blood pressure reduction [and also on regression of left ventricular hypertrophy (10,11), and on renal indices]. According to the ambulatory blood pressure measurements in one of these studies (10), the combination achieved the lowest blood pressure values, particularly for systolic blood pressure which was significantly lower than with either monotherapy. The average values (approximate) for the achieved blood pressure with combination treatment were 132/88 mm Hg for daytime blood pressure and 130/80 mm Hg for night-time blood pressure. Neither of the monotherapies reduced systolic blood pressure below 140 mm Hg.
In conclusion, the recommended treatment of hypertension and renal disease, and of diabetic nephropathy in particular, depends upon intensive blood pressure control via an ACE inhibitor-based drug treatment regimen. Since many of these patients will also have functional renal impairment and a compromised ability to eliminate drugs, it is important for both practical and theoretical reasons that no significant drug accumulation occurs. In this respect, the evidence available with spirapril indicates that there is no significant drug accumulation with 6 mg once daily but there is consistent ACE inhibition and blood pressure reduction. The available evidence also suggests that spirapril shares the nephroprotective properties which have been demonstrated through treatment with other ACE inhibitor drugs. Thus, an antihypertensive regimen based upon spirapril is an appropriate treatment for patients with renal diseases including those with hypertension and diabetic nephropathy.
1. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ
2. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI). The Sixth Report of the Joint National Committee on Prevention, Detection and Evaluation and Treatment of High Blood Pressure. Arch Int Med
3. Mogensen CE. Long term antihypertensive treatment inhibiting progression of diabetic nephropathy
4. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
. N Engl J Med
5. Guitard C, Lohmann FW, Alfiero R, Ruina M, Alvisi V. Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension. Cardiovasc Drugs Ther
6. Grass P, Gerbeau C, Kutz K. Spirapril: pharmacokinetic properties and drug interactions. Blood Pressure
1994;3 (suppl 2):7-13.
7. Meredith PA, Grass P, Guitard C, et al. Pharmacokinetics of spirapril in renal impairment. Blood Pressure
199;3 (suppl 2):14-19.
8. Norgaard K, Jensen T, Christensen P, Feldt-Rasmusen. A comparison of spirapril and isradipine in patients with diabetic nephropathy
and hypertension. Blood Pressure
9. Tatti R, Pahor M, Byington RP, et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomised trial (FACET) in patients with hypertension and NIDDM. Diabetes Care
10. Manolis AJ, Beldekos D, Handanis S, et al. Comparison of spirapril, isradipine, or combination in hypertensive patients with left ventricular hypertrophy. Effects on LVH regression and arrhythmogenic propensity. Am J Hypertens
11. Maccariello ER, Geneldu de Abreu Fagundes V, Francischetti EA. The effects of isradipine and spirapril as monotherapy and combined therapy on blood pressure, renal hemodynamics, natriuresis and urinary kallikrein in hypertensive nephropathy. Am J Hypertens
A Spirapril symposium held in Vienna, Austria, August 25, 1998
The symposium and the publication of this supplement were supported by an educational grant from ASTA Medica AG, Frankfurt am Main, Germany.