Lisinopril

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Abstract
Lisinopril, like other ACE inhibitors, lowers blood pressure and preserves renal function in hypertensive patients with non-insulin-dependent or insulin-dependent diabetes mellitus (NIDDM or IDDM) and early or overt nephropathy, without adversely affecting glycaemic control or lipid profiles. On available evidence, renoprotective effects appear to be greater with lisinopril than with comparator calcium channel blockers, diuretics and β-blockers, despite similar antihypertensive efficacy. As shown by the EUCLID (EUrodiab Controlled trial of Lisinopril in Insulin-dependent Diabetes) trial, lisinopril is also renoprotective in nonnotensive patients with IDDM and microalbuminuria. The effect in nonnotensive patients with normoalbuminuria was smaller than in those with microalbuminuria, and no conclusions can yet be made about its use in patients with normoalbuminuria. In complications other than nephropathy, lisinopril has shown some benefit. Progression to retinopathy was slowed during 2 years’ lisinopril therapy in the EUCLID study. Although not yet fully published, these results provide the most convincing evidence to date for an effect of an ACE inhibitor in retinopathy. The drug may also improve neurological function, but this finding is preliminary. Lastly, post hoc analysis of the GISSI-3 trial indicates that lisinopril reduces 6-week mortality rates in diabetic patients when begun as early treatment after an acute myocardial infarction. The tolerability profile of lisinopril is typical of ACE inhibitors and appears to be similar in diabetic and nondiabetic individuals. Hypoglycaemia has occurred at a similar frequency with lisinopril and placebo, as shown in the EUCLID trial. In addition, the GISSI-3 study indicates that the incidence of persistent hypotension and renal dysfunction is increased with lisinopril in general, but the presence of diabetes does not appear to confer additional risk of these events in diabetic patients with acute myocardial infarction receiving lisinopril. In summary, lisinopril lowers blood pressure and produces a renoprotective effect in patients with IDDM and NIDDM without detriment to glycaemic control or lipid profiles. Like other ACE inhibitors, lisinopril should thus be viewed as a first-line agent for reducing blood pressure and preventing or attenuating nephropathy in hypertensive diabetic patients with IDDM or NIDDM and microalbuminuria or overt renal disease. The EUCLID study, using lisinopril, provides new data supporting an additional place in managing nonnotensive patients with microalbuminuria and IDDM. These findings, together with some evidence for an effect of lisinopril in delaying progression of retinopathy and in reducing mortality, suggest a broader role for the drug in managing diabetic vascular complications. Lack of insulin causes abnormal glucose metabolism in patients with insulin-dependent diabetes mellitus (IDDM). In patients with non-insulin-dependent disease (NIDDM), hyperglycaemia (leading to poor glycaemic control), hyper-insulinaemia, hypertension, dyslipidaemia and possibly other conditions are believed to be linked to insulin resistance as part of the cluster of conditions known as ‘syndrome X’. The link between poor glycaemic control and vascular injury is currently a topic of much interest. Hypertension is more common in patients with diabetes than in nondiabetic individuals and is associated with the development of microalbuminuria [small increases in urinary albumin excretion rate (AER)]. Microalbuminuria presages overt nephropathy and renal failure, is linked to retinopathy and neuropathy, and is a risk factor for cardiovascular morbidity and mortality. A proposed pathogenic factor for microalbuminuria is a widespread abnormality of the vascular endothelium. Abnormal glucose metabolism is one of the likely causes of the endothelial cell dysfunction thought to contribute to microalbumin-uria and diabetic vascular complications. The renin-angiotensin-aldosterone system appears to play a role in causing endothelial cell dysfunction, most plausibly via the undesirable vasoconstrictive and trophic actions of angiotensin II (AII). Local tissue ACE may promote vascular injury by degrading bradykinin and suppressing kinin-nitric oxide—dependent vasodilatory pathways, although this is not proven as yet. ACE inhibitors reduce blood pressure and proteinuria and delay the progression of nephropathy in hypertensive patients with IDDM and overt nephropathy. These drugs also reduce albuminuria in normotensive patients with IDDM and microalbuminuria and in patients with NIDDM and established nephropathy. Results from the EUCLID (EUrodiab Controlled trial of Lisinopril in Insulin-dependent Diabetes) trial using lisinopril (see Clinical Efficacy summary) support limited data obtained with captopril and enalapril suggesting benefit in retinopathy. Mechanisms for these effects of ACE inhibitors are not known, but it is probable that vasodilation caused by reducing AII levels increases skeletal blood flow and improves transport of glucose and insulin to muscle. Postglomerular vasodilation reduces intraglomerular pressure and renal afterload, possibly decreasing the risk of protein-induced renal damage. Prevention of the trophic effects of AII and potentiation of bradykinin and nitrosovasodilatory pathways may be involved at a biochemical level. ACE inhibitors also modestly increase insulin sensitivity, but the relevance of this is unclear. Interestingly, the ACE inhibitor quinapril improved endothelial dysfunction in normotensive patients with coronary heart disease but not heart failure or severe dyslipidaemia. This has implications for ameliorating endothelial dysfunction and correcting metabolic abnormalities seen with hypertension and diabetes. Lisinopril lowers blood pressure and exerts renoprotective effects in patients with diabetes (see Clinical Efficacy summary) without affecting glycaemic control or other metabolic parameters (see Tolerability summary). Like other ACE inhibitors, lisinopril inhibits the activity of ACE and hence reduces AII activity and increases bradykinin levels. In patients with hypertension, arterial distensibility is improved and blood pressure is reduced, as are systemic vascular resistance, left ventricular end-diastolic and end-systolic pressures, cardiac index and left ventricular mass. Cardiac output or glomerular filtration rate (GFR) are usually unchanged, renal plasma flow and filtration fraction tend to increase and renal vascular resistance tends to decrease in patients with hypertension treated with lisinopril. Ejection fraction is increased in patients with anterior myocardial infarction receiving prolonged lisinopril therapy. The drug possesses additional cardio-and vasculoprotective effects, some demonstrable in humans, and may attenuate sympathetic nervous system function. While evidence for an effect of lisinopril on insulin sensitivity in nondiabetic patients with hypertension is ambiguous, it is somewhat stronger in patients with diabetes. Lisinopril increased total and nonoxidative glucose disposal in hyper-tensive and normotensive nonobese patients with NIDDM to a similar extent to the calcium channel blocker lacidipine. However, as for ACE inhibitors in general, the clinical importance of these findings is undetermined. Lisinopril may attenuate ammonia-induced renal tubular injury associated with proteinuria. Some evidence for improved neurological function in rats treated with lisinopril is supported by limited data in humans (see Clinical Effi-cacy summary). Pharmacokinetic details for lisinopril specifically in patients with diabetes are not available. Plasma lisinopril concentrations peak within 6 hours and are detectable for up to 96 hours after a dose in healthy volunteers. Lisinopril is not bound to plasma proteins and its volume of distribution is 124L. The effective half-life of elimination for lisinopril is about 13 hours, which is followed by a longer terminal elimination phase with a half-life of about 30 hours. Because lisinopril is eliminated via renal mechanisms, its clearance is decreased in patients with renal dysfunction. Although the drug is not metabolised hepatically, there is some evidence for reduced clearance in patients with hepatic cirrhosis. Lisinopril (usually 10 to 20 mg/day) effectively lowers blood pressure and improves parameters of renal function in hypertensive patients with concomitant IDDM or NIDDM and overt nephropathy and, more significantly, early renal disease. Renoprotection appears to be at least partly independent of the antihyper-tensive activity of the drug, as shown by its greater effect than calcium channel blockers or β-blockers on AER, despite similar blood pressure reductions. As well, the 2-year EUCLID study indicates that treatment with lisinopril reduces AER significantly in normotensive patients with microalbuminuria and IDDM and to a lesser, nonsignificant extent in normoalbuminuric patients. AER in lisinopril recipients decreased by 18.8% overall relative to placebo, but the drug was clearly most effective in the presence of microalbuminuria (−49.7%). Significant reductions of about 40 to 60% in AER and 40 to 50% in fractional albumin clearance rates have been observed in normotensive or hypertensive patients with IDDM or NIDDM and early or overt nephropathy receiving lisinopril, usually 10 to 20 mg/day. Benefits have been achieved in nonsmokers and, to a lesser degree, in smokers. The influence of lisinopril on other parameters such as GFR, renal plasma flow and filtration fraction varies depending on baseline patient characteristics. ACE gene insertion/deletion (I/D) polymorphism may influence the effect of ACE inhibitor therapy. Diabetic patients with the I/I type may be most likely and those with the D/D form least likely to benefit from lisinopril, as indicated by the EUCLID study. As regards other microvascular complications, interesting new evidence from EUCLID has demonstrated a delay in progression of retinopathy during lisinopril therapy in normotensive patients with IDDM and mainly nonproliferative disease. Retinopathy progressed in 12 vs 26% of lisinopril versus placebo recipients, yielding a relative risk reduction of 0.41. Limited data suggesting that the drug may improve neurological function require confirmation in controlled trials. Lisinopril has also reduced mortality rates in patients with diabetes. Post hoc analysis of results from GISSI-3 indicates that early treatment with lisinopril 5 to 10 mg/day improves survival in diabetic patients with an acute myocardial infarction. Six-week mortality was reduced by 44.1 and 24.5%, respectively, in patients with IDDM (n=254) or NIDDM (n=1130) who received lisinopril, compared with no-lisinopril groups. Left ventricular mass has also been reduced in patients with hypertension and NIDDM with or without nephropathy who were treated with lisinopril for 1 year. Generally, lisinopril appears to be as well tolerated in patients with diabetes as in other types of patients, although adverse events have often not been reported in great detail in clinical trials. Of 3328 patients with NIDDM in a postmarketing study, 2.2% reported adverse events (mainly cough in 0.7% and dizziness in 0.3%) over a 3-month period. Cough was the only event experienced more often by lisinopril than by placebo recipients in the EUCLID trial (4.5 vs 3%). Hypotension and renal dysfunction develop infrequently during lisinopril therapy. Results of GISSI-3 show that, while lisinopril-treated patients with diabetes experience a higher incidence of hypotension and renal dysfunction than do groups not receiving the drug, the presence of diabetes as such does not appear to increase the risk of these events. With the exception of hyperkalaemia (which occurred in 11% of patients with diabetes in 1 trial but was not documented in any others), lisinopril has no detrimental effects on serum levels of electrolytes, lipids, plasma albumin, uric acid or creatinine. The number of hypoglycaemic events was similar for lisinopril and placebo (13 vs 12) in patients with IDDM in the EUCLID study. Although comparative data in patients with diabetes are limited, lisinopril appears to be at least as well tolerated as calcium channel blockers and better tolerated than atenolol. In patients with diabetes receiving lisinopril or other ACE inhibitors, there is theoretical potential for hypoglycaemia to develop when these drugs are coadministered with hypoglycaemic agents. Renal failure is more frequent with ACE inhibitors such as lisinopril when combined with diuretics, than with ACE inhibitors alone. Indomethacin can attenuate and hydrochlorothiazide and acetylcysteine can potentiate the antihypertensive effects of lisinopril. The incidence of hyperkalaemia with lisinopril is increased by using potassium-sparing diuretics, potassium-containing salt substitutes or high-potassium diets. As happens with others of its class, lisinopril reduces lithium excretion and may potentiate lithium toxicity. There are no formal dosage recommendations for lisinopril in patients with diabetes, although clinical trials have generally employed dosages used in hypertension (10 to 20mg once daily). General recommendations for patients with hypertension can therefore be used as a guide, with adjustments made for impairment of renal function. Lisinopril is given orally and may be administered without regard to timing of meals. In the UK the starting dosage of lisinopril is 2.5mg once daily, titrated to response. The usual maintenance dosage is 10 to 20mg once daily. In the US, the usual starting dosage in patients not receiving diuretics is 10mg once daily orally. The usual maintenance dosage is 10 to 40mg once daily. Caution is needed when using lisinopril in patients with or at risk of hyperkalaemia or renal artery stenosis, or those with volume or salt depletion. In patients with renal dysfunction, appropriate starting dosages are 5 to 10 mg/day for patients with creatinine clearance (CLCR) values of 31 to 70 ml/min, 2.5 to 5mg for CLCR 10 to 30 ml/min and 2.5mg for CICR <10 ml/min.