Non-insulin-dependent diabetes mellitus (NIDDM) is reaching epidemic proportions worldwide. In the United States its prevalence is increasing as the population becomes older, less active, and more obese. According to current estimates, approximately 15 million Americans, one in every 17 individuals, have diabetes (1). It is clear that with increase in prevalence of the disease and its complications, the economic burden of treating diabetes and its complications is enormous (2,3).
NIDDM is associated with increased long term morbidity and an increased risk of mortality (4). Microvascular complications lead to more than 50,000 lower extremity amputations each year, about 13,000 new cases of end-stage renal disease (ESRD), and about 15,000 to 39,000 new cases of blindness (5). Cardiovascular disease is only of the macrovascular complications and the leading cause of death in these people, especially women.
Fifty percent of adults with diabetes also have preexisting hypertension, and patients with NIDDM who do not already have hypertension are more than twice as likely to become hypertensive than nondiabetic persons (6). In a subgroup of diabetic subjects arterial blood pressure starts to rise once urinary albumin excretion has consistently increased. This increase in albuminuria is a surrogate marker of glomerular injury as well as renal disease progression. In turn, hypertension accelerates the rate of increase in urinary albumin excretion and precipitates the progression of diabetic nephropathy in both patients with type I diabetes as well as NIDDM. Thus, when diabetes and hypertension coexist, as is usually the case, they place patients at an even greater risk than with either disorder alone for ESRD, coronary artery disease and cerebrovascular and peripheral vascular disease (7).
PATHOPHYSIOLOGY OF HYPERTENSION AND DIABETES
Diabetic patients who are destined to develop nephropathy invariably develop hypertension. However, many pathophysiologic changes are associated with the development of hypertension in diabetes. Two notable pathophysiologic changes that occur in such patients include an increase in total exchangeable body sodium of about 10% and an increased vascular reactivity to various vasoconstrictors (8). A subgroup of these patients may be "salt-sensitive," as defined by a heightened vasoconstrictive response for a given salt-load (increase in systolic blood pressure of >10 mm Hg) compared to "salt-resistant" individuals. This altered vascular reactivity may be responsible for some of the abnormal renal hemodynamic responses observed in the diabetic state. Salt-sensitive patients have been well described to have poor outcomes relative to cardiovascular end points, including progression of renal disease (9).
Although a number of morphologic and hemodynamic changes are seen in the kidneys of patients with diabetes, four fundamental changes occur early in its natural history. These include an increase in intraglomerular capillary pressure as well as ΔP, increased shunting of albumin through glomerular membrane pores, along with a loss of glomerular membrane charge, and an increase in mesangial matrix proteins (10). Some of these changes have been hypothesized to relate to increases in intraglomerular capillary pressure.
Increases in intraglomerular pressure lead to shear stress and contribute to activation of certain growth factors, i.e., vascular epidermal growth factor (VEGF), platelet-derived growth factor (PDGF), transformation growth factor-β (TGF-β), and others located in endothelial and possibly mesangial cells (11). In turn, these growth factors, coupled with high glucose levels and an associated increase in glycated albumin, alter mesangial matrix production. In addition, in vitro studies demonstrate that endothelial and smooth-muscle cells, when exposed to shear stress, not only increase production of various vasoconstrictor growth factors but also increase production of mesangial matrix proteins such as laminin, fibronectin, collagen type IV, and others (10-14). Release of these growth factors subsequently causes alterations in the cell membrane wall and contributes to architectural changes that ultimately contribute to the genesis of microalbuminuria (15). An additional growth factor produced by endothelial cells, vascular permeability factor, may also contribute to development of microalbuminuria (14). Antihypertensive treatment with either an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II (Ang II) receptor antagonist, or a nondihydropyridine calcium-channel antagonist (CCA) can attenuate the development of albuminuria and increases in mesangial matrix proteins (15-18). Studies in animal models of diabetes and long-term clinical studies have also shown that these classes of agents have unique renal properties beyond blood pressure reduction alone (15-18).
Another factor that contributes to morphologic changes in the kidneys of diabetic patients is cholesterol and its subfractions. Hyperlipidemia is an important risk factor for the development of atherosclerosis and glomerulosclerosis (19-24). The lipid profile of NIDDM patients is characterized by elevated serum triglycerides and very low-density lipoprotein (VLDL) levels and by reduced high-density lipoprotein (HDL) cholesterol levels. Serum low-density lipoprotein (LDL) levels may also be elevated in some patients (19,20). Several alterations in the biochemical and physical properties of LDL particles are, however, more characteristic (small, dense, and triglyceride-rich LDL subfractions), resulting in reduced receptor-specific uptake of these lipoproteins. Nonenzymatic glycosylation of LDL and augmented oxidation are common in diabetic patients, making lipoproteins susceptible to uptake by macrophage scavenger receptors and thus leading to foam-cell formation and further glomerular damage (20). LDL cholesterol is also known to increase mesangial matrix protein production in animal models of renal insufficiency (24). The combination of hyperlipoproteinemia and hypertension appears to act synergistically to yield a more rapid decline in renal function (22,23,25).
This article focuses on the treatment of blood pressure rather than on lipids. It discusses the effect of blood pressure reduction on progression of renal disease. Before this dicussion, however, we present the concept that the level to which blood pressure is reduced is perhaps the most important goal in retarding the progression of diabetic nephropathy.
LEVEL OF BLOOD PRESSURE CONTROL
Over the past few decades a number of antihypertensive agents have been used to lower arterial pressure in diabetic subjects. Studies with thiazide diuretics and β-blockers have clearly demonstrated that lowering blood pressure to levels around 140/90 mm Hg slows the progression of diabetic renal disease (25-29). An analysis of diabetic patients at high risk for progression to ESRD suggests that the level to which blood pressure is reduced may be as critical as the agents selected to achieve this goal with regard to lowering overall renal and cardiovascular mortality (29-33). These high-risk groups are outlined in Table 1. Although the natural history of nephropathy between those with NIDDM and IDDM may differ, the rate of progression to renal failure in diabetic nephropathy is a continuous function of both systolic and diastolic blood pressure down to about 120 mm Hg systolic and 70 mm Hg diastolic blood pressure (30).
Although reductions in blood pressure to levels of <130/85 mm Hg clearly slow progression of renal disease in diabetic patients, small changes in arterial pressure reduction may provide additional protection against progression of renal disease (29,30-33). This is evidenced by results from a post hoc analysis of the Captopril Trial, in which small but significant differences in mean arterial pressure between groups may account for a significantly greater slowing of the progression of renal disease (34). Additional evidence to support this point comes from a recently published 6-year follow-up study in patients with NIDDM-associated nephropathy. In this study, a 4-mm Hg higher systolic pressure in the group receiving β-blockers yielded a worse renal outcome compared to either the ACE inhibitor or the nondihydropyridine calcium-channel blocker group (35).
Differences in arterial pressure reduction may also provide some insights for interpreting the results of various clinical trials with regard to renal disease progression in patients with NIDDM nephropathy. These differences in pressure are borne out on cardiovascular end points as well as in other longer-term, larger studies, such as the MRC study (36). Taken together, these data support the recent recommendations of the High Blood Pressure Education Group Consensus Report that blood pressure levels need to be reduced to levels of ≤130/85 mm Hg to maximize renal preservation (37). These studies, coupled with the finding that diuretics and β-blockers worsen lipid and glucose profiles and have no specific effects on morphologic progression of diabetic nephropathy, led to the speculation that appropriately controlling the blood pressure with these classes of antihypertensive medications may contribute to their less than optimal protection of renal function. In addition, although β-blockers may reduce mortality, it has been proposed that their failure to achieve the predicted reduction in cardiovascular events may relate to their worsening of lipids and glucose (D. Hall, personal communication).
Because progression of renal disease associated with diabetes is a long-term problem, clinical studies of less than 3 years duration cannot provide meaningful results. This is true even when one evaluates surrogate markers of renal disease progression, such as albuminuria. Therefore, we have restricted our comments on renal function outcome to randomized prospective studies that are greater than or equal to 3 years in duration.
Non-ACE inhibitor/CCA based treatment
All for major antihypertensive classes of medications have been used in the treatment of hypertension in patients with diabetes. However, only the diuretics and β-blockers have been evaluated in randomized, prospective double-blind trials as to their effects on slowing progression of NIDDM-associated diabetic nephropathy. Results from all these trials show no independent renal benefit to the hypertensive diabetic patient other than that associated with blood pressure.
Thiazide diuretics (≥25 mg/day, hydrochlorothiazide) can reduce the expanded plasma volume of patients with diabetes but are associated with adverse metabolic effects, such as dyslipidemia, decreased insulin sensitivity, and hypokalemia (38). However, thiazide diuretics have been shown in a 4-year, randomized, double-blind, placebo-controlled trial to slow progression of NIDDM-associated nephropathy almost to the same degree as ACE inhibitors (27), thus suggesting that, in the absence of significant metabolic changes induced by these agents, they slow progression of renal disease.
β-Blockers have been shown to reduce albuminuria and to preserve glomerular filtration rate in diabetic hypertensive patients, as long as the blood pressure is reduced to average levels of <150/95 mm Hg. Their effects, however, appear to be entirely related to the degree of arterial pressure reduction, without any independent effects on preservation of renal function (25-28,39,40). Moreover, their adverse lipid profile and their attenuation of hypoglycemia perception, as well as their worsening of glycemic control secondary to decreased insulin secretion and worsening of insulin resistance, militate against a benefit independent of blood pressure reduction. These factors are mentioned above and may cause further problems for diabetic patients (38).
Although α-adrenergic antagonists (e.g., prazosin, terazosin, doxazosin) have neutral metabolic effects, they have never been evaluated in a clinical trial with regard to efficacy in slowing renal disease progression. A recent animal study in diabetic rats, however, has shown favorable metabolic effects of doxazosin in blunting the rise of proteinuria and potentiating the hypoglycemic actions of insulin (41). However, these agents did not significantly prevent mesangial matrix expansion unless glucose was controlled.
The new class of antihypertensive medications, the selective Ang II receptor antagonists (AT1), show a great deal of of promise regarding their effects on progression of diabetic nephropathy. Although there are no available clinical data on progression of diabetic nephropathy, there are three ongoing multicenter, randomized, doubleblind clinical trials that evaluate the effect of AT1 receptor antagonists on progression of NIDDM-associated nephropathy (18). The results of these trials will not be known for at least another few years. In animal models of diabetes, however, AT1 receptor antagonists have effects on renal hemodynamics and morphology similar to those of ACE inhibitors (42).
Ang II has a variety of intrarenal effects, including regulation of renal blood flow and glomerular filtration rate (through constriction of the postglomerular arteriole) and tubule reabsorption of sodium (independent of glomerular filtration rate) (43). Therefore, the major hemodynamic effects of ACE inhibitors are attenuation of vasoconstriction and decrease in ΔP. The net result is a decrease in the glomerular capillary hydrostatic pressure and a tendency towards acute lowering of the glomerular filtration rate (39,43).
Many long-term studies have also shown that these agents reduce microalbuminuria and blunt the rise in albuminuria (25,26,44-47). The mechanism of this effect is a reduction in the shunting of protein through pores in the glomerular capillary membrane and partial restoration of a negative charge to the membrane (15,17). Other mechanisms may also contribute to reductions in albuminuria, including, ACE inhibitor-associated attenuation in the increase of matrix proteins such as laminin and fibronectin. These effects have been shown to be independent of the blood pressure reduction caused by these agents (48).
The effects of ACE inhibitors compared to other antihypertensive therapy in diabetic nephropathy have been investigatived in a number of human studies (40,49). Some studies in patients with NIDDM-associated nephropathy also show a greater benefit in progression of renal disease with ACE inhibitors over conventional therapy (35). In the largest and most comprehensive study to date, the Collaborative Study Group found that ACE inhibition slowed the progression of renal disease to a greater extent than placebo treatment. In this study of 409 patients with type I diabetes, the group receiving captopril showed a significant reduction in the combined end points of progression to ESRD and death (44). In addition, in the captopril group serum creatinine was doubled at a significantly slower rate compared to the placebo group. Overall, the greatest benefit was seen in patients with more advanced disease at baseline (serum creatinine >1.5 mg/dl) with nephrotic range proteinuria, possibly because this group showed a greater propensity to progress to ESRD (34). Although this may be due to the more advanced stage of renal disease, it is also due to a significant lower arterial pressure in the ACE inhibitor group.
Animal and human studies have shown that CCAs have a variable effect on the progression of diabetic nephropathy. Specifically, the nondihydropyridine CCAs (verapamil, diltiazem), like the ACE inhibitors, reduce mesangial matrix expansion and decrease proteinuria (10,16,35,37,40,50). However, the dihydropyridine CCAs have never been shown in animal models of diabetes and/or renal insufficiency or in clinical studies to consistently reduce urinary protein excretion or to prevent glomerulosclerosis (10,17,49,51-56).
Recent animal studies in diabetic beagle dogs demonstrate similar effects on slowing matrix expansion by either lisinopril or diltiazem (16). Other studies have evaluated the development of glomerulosclerosis in the rat. They confirm this observation and show similar results for diltiazem (57). This has never been shown, however, for any dihydropyridine (nifedipine-like) CCAs (17). This observation has clinical implications because four recent meta-analyses demonstrate a relatively greater impact on slowing progression of renal disease with nondihydropyridine compared to dihydropyridine CCAs (40,49,58,59). These observations, however, are based predominantly on short-term studies. Unfortunately, there are no long-term (>3 years) studies utilizing nondihydropyridine CCAs in patients with IDDM-associated nephropathy to observe the effects on time to dialysis or death.
Studies in animal models of diabetic nephropathy with dihydropyridine CCAs have also examined intrarenal hemodynamic changes with the use of various antihypertensive agents. These studies uniformly demonstrate a failure to reduce intraglomerular pressure and to prevent development of glomerulosclerosis or albuminuria (17,53,56). It should also be noted that dihydropyridine CCAs have failed to demonstrate any reduction in cardiovascular mortality from ischemic heart disease or progression of renal disease in heart failure, despite improvement in cardiac function (60,61).
More recently, three long-term studies with nondihydropyridine CCAs support these short-term findings on proteinuria and renal disease progression (61-63). In the first trial in heart failure patients, amlodipine was shown to increase renal disease progression compared to placebo (61). In the second 4-year study from the Melbourne Diabetes Study Group, a failure of nifedipine to reduce proteinuria and progression of renal disease was noted (62). This observation was in contradistinction to this group's earlier finding of a positive effect of nifedipine. In the third and perhaps most damaging trial for nifedipine, a recent 6.5-year post hoc analysis of over 500 patients with nondiabetic renal disease showed a more rapid progression of renal disease in those who received nifedipine vs. those who received benazapril, despite similar levels of blood pressure reduction (63).
Nondihydropyridine CCAs, on the other hand, have clearly been shown to reduce proteinuria in animal and human studies of diabetic nephropathy (10,16,17,35,37,40). In a recent study, 52 patients with NIDDM-associated nephropathy and hypertension were treated with either an ACE inhibitor (lisinopril), nondihydropyridine calcium-channel blockers (verapamil or diltiazem SR) or a β-blocker (atenolol) and were followed for about 6 years (35). The primary end point of the study was a change in creatinine clearance slope in each group. After 6 years of follow-up, the mean rate of decline in creatinine clearance was greatest in the atenolol group, with no difference between the lisinopril and nondihydropyridine CCA groups. The greatest changes in proteinuria paralleled the slowest rates of decline in renal function. The reduction in blood pressure was similar in all treatment groups. These observations were further exemplified in a 5-year randomized study among African-American patients with NIDDM nephropathy (50). In this study, verapamil was associated with a 62% slower progression of renal disease compared to atenolol, given similar reductions in arterial pressure.
Conversely, studies on NIDDM-associated renal disease progression with dihydropyridine agents, with the exception of one (47), have thus far failed to show any significant reduction in albuminuria or slowed progression in nephropathy (10,17). Moreover, the one study that shows an apparent benefit is plagued by two confounding factors. First, it is the only study to date that shows a significant reduction in glomeruler filtration rate acutely with a dihydropyridine CCA. Second, it was a study in a very early phase of diabetic nephropathy, therefore requiring at least 6-7 years of follow-up to note any significant change in renal function between groups.
The reasons for these disparate effects between the subclasses of calcium-channel blockers on morphologic and hemodynamic changes in the diabetic kidney are beyond the scope of this article. However, the reader is referred to two recent in-depth articles on this topic (10,64). Factors that do account for these differences, however, are summarized above.
Many studies in the past two decades have clearly demonstrated that a decrease in blood pressure slows the progression of diabetic renal disease and that arterial pressure reduction is the ultimate factor that uniformly leads to preservation of renal function. Recent recommendations by the National High Blood Pressure Education Group suggest that patients with diabetic renal disease should have their arterial pressure reduced to levels well below <130/85 mm Hg (37). As clinicians know, it is extremely difficult to achieve such levels in clinical practice. Therefore, because the majority of patients with diabetic nephropathy require more than one medication to reduce arterial pressure, a combination of antihypertensive agents individually shown to reduce arterial pressure and proteinuria and to preserve renal morphology and function would be preferred.
Only a few animal and human studies have examined the effects on diabetic nephropathy of the combination of ACE inhibitors and CCAs. Because preliminary evidence supports the notion that both ACE inhibitors and nondihydropyridine calciun-channel blockers slow progression of diabetic renal disease to a greater extent than conventional blood pressure-lowering agents, it can be predicted that the combination of these two classes of agents would provide better overall renal protection than either agent alone. In addition, fixed-dose combinations of these antihypertensive agents are associated with a lower side-effect profile compared to more conventional agents such as β-blockers, diuretics, and central α-agonists.
Carmines and Navar (65) first demonstrated in isolated perfused kidney pretreated with an ACE inhibitor that the addition of a nondihydropyridine CCA potentiated the afferent and efferent arteriolar dilatation induced by the ACE inhibitor (65). This concept was shown to be of practical value in two clinical studies. The first examined the impact of combination therapy in a 4-year follow-up study of a small number of patients with NIDDM-associated nephropathy, randomized to either verapamil plus lisinopril, each in reduced doses, vs. either agent alone (66). This study demonstrated that the combination of verapamil with lisinopril was associated with a slower rate of decline in renal function, a lower degree of proteinuria, and the lowest side-effect profile over either agent alone. The second study also noted potentiation of an antiproteinuric effect in patients with NIDDM-associated nephropathy with comparable blood pressure control when a fixed-dose combination of an ACE inhibitor with an nondyhrodropyridine CCA (trandolapril and verapamil, respectively) vs. its individual components was given over a 1-year period (67).
This clinical observation is further exemplified by a recent report of an animal model of nephropathy in which these agents preserved renal morphology and had an additive antiproteinuric effect over the individual components without a significant reduction in arterial pressure (68). Therefore, all of the aforementioned studies with a nondihydropyridine CCA/ACE inhibitor combination demonstrated almost additive effects on albuminuria reduction and prevention of glomerulosclerosis, independent of blood pressure level. Conversely, results from an animal study that compared the effect of an ACE inhibitor in combination with amlodipine vs. either alone demonstrated protection against the increase in albuminuria and glomerulosclerosis that was observed with amlodipine alone (69).
Thus far, four combinations of ACE inhibitors/calcium-channel blockers have been approved by the FDA, two with a dihydropyridine calcium-channel blocker (benazepril/amlodipine and enalapril/felodipine) and two with a nondihydropyridine calcium-channel blocker (trandolapril/verapamil and enalapril/diltiazem ER). Two recent reviews of combination therapy noted that combinations of ACE inhibitors with CCAs have fewer side effects than either agent alone (70,71). As an example, there are reports of significant reductions in the incidence of pedal edema induced by dihydropyridine CCAs when ACE inhibitors are added. This reduction is largely due to the venodilating capacity of the ACE inhibitors. In addition, there have been reductions in CCA-associated constipation and headache, because the doses of these agents are reduced when they are used in combination with ACE inhibitors.
There is no definitive answer to the question of whether the effects on any factor other than blood pressure reduction of ACE inhibitors and CCAs, each at lower doses, are additive. However, preliminary data from both animal and clinical studies suggest that combinations of nondyhyrdopyridine CCAs with ACE inhibitors produce an additional decrease in proteinuria and have more favorable side-effect profiles than either alone. Although these preliminary findings are provocative, it is evident that carefully controlled, randomized, prospective studies of long duration will be needed to establish the precise effects of a combination of ACE inhibitors and CCAs on the progression of both diabetic nephropathy and chronic renal failure. Such trials should assess a number of variables, including the optimal doses of these drugs and the level to which blood pressure is lowered. At present, one ongoing study is comparing ACE inhibitors in combination with CCAs vs. either intervention alone in patients with nondiabetic renal disease (NEPHROS Study). This study will compare the renal protective effects of ramipril vs. felodipine and the combination of the two.
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Proceedings of satellite symposium of the 8th European Meeting on Hypertension June 13, 1997; Milan, Italy