Diabetes Mellitus and Associated Hypertension, Vascular Disease, and

Nephropathy
An Update
1.
2.

James R. Sowers,
Murray Epstein
+ Author Affiliations

1. From Wayne State University (Detroit, Mich) and Miami (Fla) University Schools of
Medicine and VA Medical Centers.
1.
Correspondence to James R. Sowers, MD, Wayne State University School of Medicine,
UHC-4H, 4201 St Antoine, Detroit, MI 48201.
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Abstract

Abstract Because considerable important information has been published since our previous
review, this update concentrates on new findings with regard to cardiovascular and renal risk
factors contributing to the striking morbidity and mortality of these coexisting diseases. For
example, a large body of investigative data has recently emerged suggesting or delineating a
pathogenic role for hyperglycemic-related glycosylation and oxidation of lipoproteins and
vascular and renal tissues. Great strides have recently been made in the understanding of platelet,
coagulation, lipoprotein, and endothelial abnormalities in the pathogenesis of cardiovascular and
renal disease associated with diabetes mellitus and hypertension. Major progress has been made
in clarifying the pathophysiology of glomerulosclerosis and other processes involved in the
progression of diabetic nephropathy. Furthermore, accumulating data surveyed in this review
address new and promising pharmacological interventions that specifically address these
pathophysiological mechanisms.
Key Words:
diabetes mellitus
cardiovascular disease
diabetic nephropathy
Diabetes mellitus and hypertension are interrelated diseases that strongly predispose an
individual to atherosclerotic cardiovascular disease. 1 2 An estimated 3 million Americans have
both diabetes and hypertension.2 Hypertension is about twice as frequent in individuals with
diabetes as in those without.2 Lifestyle and genetic factors are important factors contributing to
both hypertension and diabetes mellitus. The prevalence of coexisting hypertension and diabetes
appears to be increasing in industrialized nations because populations are aging and both
hypertension and NIDDM incidence increases with age. 1 2 Data obtained from death certificates
show that hypertensive disease has been implicated in 4.4% of deaths coded to diabetes, and
diabetes was involved in 10% of deaths coded to hypertensive disease. 1 2 Indeed, an estimated
35% to 75% of diabetic cardiovascular and renal complications can be attributed to
hypertension.1 2 Hypertension also contributes to diabetic retinopathy, which is the leading cause

of newly diagnosed blindness in the United States. 2 For all these reasons, hypertension and
diabetes should be recognized and treated early and aggressively.
Essential hypertension accounts for the majority of hypertension in individuals with diabetes,
particularly those with NIDDM (type II diabetes), who constitute more than 90% of people with
a dual diagnosis of diabetes and hypertension.1 2 Hypertension often antedates and likely
contributes to the development of nephropathy in many diabetic individuals. 3 4 Diabetic
nephropathy, which occurs after 15 years of diabetes in one third of people with IDDM (type I
diabetes) and 20% of those with NIDDM, is an important contributing factor to the development
of hypertension in the diabetic individual.1 2 The high BP associated with diabetic nephropathy is
usually characterized by sodium and fluid retention and increased peripheral vascular
resistance.1 2 Isolated systolic hypertension is considerably more common in diabetics, and
supine hypertension with orthostatic hypotension is not uncommon in diabetic individuals with
autonomic neuropathy.1 2
Increasing investigation has delineated an important role for several mechanisms acting together
in mediating the pathogenesis of vascular disease in the diabetic hypertensive patient. We will
review some of the more important mechanisms of cardiovascular and renal injury associated
with diabetes mellitus and hypertension.
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Mechanisms Contributing to Systemic Vascular Disease
Platelet Adhesion and Platelet Aggregation
Platelet adhesion and platelet aggregation are often enhanced in both diabetes mellitus and
hypertension (Table 1). The precise etiology of enhanced platelet reactivity in both disorders is
complex, but it appears that abnormalities in platelet intracellular divalent cation metabolism
may play an integral role. Both platelet intracellular calcium ([Ca2+]i) and magnesium ([Mg2+]i)
have seminal roles in platelet activation.5 6 7 8 9 10 11 Platelet aggregation is associated with an
elevation in [Ca2+]i, a necessary first event in the aggregation process. Enhanced platelet
[Ca2+]i responses to LDL cholesterol have been observed in NIDDM patients with and without
hypertension.6 Similarly, parallel hyperaggregation and platelet release reactions have been
observed in NIDDM patients with and without hypertension. 5 6In vitro, increased [Mg2+]i can
exert an inhibitory effect on platelet aggregation.7There is considerable evidence that many
patients with essential hypertension, as well as those with diabetes mellitus, have elevated
platelet [Ca2+]i and decreased [Mg2+]i.7 8 9 Consequently, this altered balance between the relative
intracellular concentrations of these divalent cations may contribute to the enhanced platelet
aggregation in individuals with diabetes and hypertension.
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Table 1.
Abnormalities of Platelet Function in Diabetes Mellitus and Hypertension
In diabetes mellitus the balance between coagulative and fibrinolytic activities in the circulation
is affected in a number of ways 10 11 12 13 14 (Table 2). A procoagulant state in diabetes appears to
be mediated in part by higher-than-normal levels of a number of coagulation factors. For
example, an increase in the endothelium-derived von Willebrand factor occurs in diabetes
mellitus, particularly in association with endothelial cell injury,10 11 12 13 14 microvascular and
macrovascular damage,10 and poor diabetic control.12 13 14 High concentrations of factor VIII are
related to hyperglycemia, accelerate the rate of thrombin formation, and contribute to occlusive
vascular disease in diabetic patients. Levels of fibrinogen, factor VII, and thrombin-antithrombin
complexes have also been reported to be elevated in diabetic patients. 11 Elevated coagulation
levels of these factors, particularly fibrinogen, are important for increasing the survival of the
provisional clot matrix on transformation of fibrinogen to fibrin at the site of injured
endothelium.11 Indeed, increased levels of thrombin-antithrombin complexes have been observed
in diabetic patients in association with enhanced thrombin generation. 11 High PAI-1 levels have
been observed in patients with diabetes mellitus. 10 11 12 13 Furthermore, elevated PAI-1 levels have
been reported in untreated hypertensive individuals 13 and in men with myocardial infarction at
risk for reinfarction. Elevated levels of PAI-1 also appear to be associated with elevated serum
levels of insulin and triglycerides.10 11 13 Indeed, insulin has been shown to stimulate PAI-1
synthesis in hepatocytes.13 Thus, it appears that hyperinsulinemia and associated insulin
resistance, in addition to being integral to syndrome X, are independent risk factors, along with
diabetes and hypertension, for an abnormal balance between coagulation and fibrinolysis.14
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Table 2.
Coagulation and Lipoprotein Abnormalities Seen in Patients With Hypertension and Diabetes
Mellitus
Lipoprotein Abnormalities
Although hypertension and diabetes mellitus are both independent risk factors for ischemic heart
disease, insulin resistance and hyperinsulinemia associated with hypertension and NIDDM also
likely contribute to accelerated atherogenesis15 16 1718 (Table 2). A number of metabolic
abnormalities are often present in patients with diabetes and hypertension (Table 2). Plasma
levels of lipoprotein(a) have been noted to be elevated in diabetic individuals, particularly those
with poor glycemic control.16 By inhibiting fibrinolysis, possibly via fibrin binding attributable to
structural homology with apolipoprotein(a), lipoprotein(a) may delay thrombolysis and thus

contribute to plaque progression. Augmented lipoprotein oxidation has also been observed in
diabetic states.17 18 Ox-LDL is not recognized by the classic LDL receptor but by the macrophage
scavenger receptors.17 18 Foam cell uptake of LDL via the scavenger pathway is enhanced by
oxidative modification of LDL. Once taken up by the foam cell, however, Ox-LDL degradation
is impaired, which leads to further accumulation in the cell. Ox-LDL is toxic to endothelial cells,
altering both structure and function.18 Ox-LDL increases adhesion of circulating monocytes to
damaged endothelium, increasing their migration into the vascular intima.18
Glycosylation, the nonenzymatic linkage of glucose to proteins, has also been found to alter LDL
particles in vivo.18 Importantly, apolipoprotein B, which regulates receptor-mediated uptake of
LDL, can undergo glycosylation, thereby facilitating its atherogenicity in diabetic individuals.
Similar to Ox-LDL, glycated LDL can enhance foam cell formation and is less well recognized
by the native LDL receptor.18 Glycated LDL is also immunogenic, forming antibody-lipoprotein
complexes that stimulate foam cell formation and enhance platelet aggregation. 18Compared with
normal LDL, glycated LDL sequestered in the arterial intima has a greater propensity to become
bound by glucose-mediated cross-links to local matrix proteins. Once this occurs, the LDL
particles may undergo even more extensive glycative and oxidative modification. 18 Finally,
evidence is accumulating that glycation in itself may render the particle more susceptible than
normal to further oxidative damage.18
Endothelial Dysfunction in Diabetes and Hypertension
A number of anatomic and functional abnormalities of the vascular endothelium are associated
with both diabetes mellitus and hypertension19 (Table 3). In insulin-resistant states, endothelial
cell lipoprotein lipase activity is decreased, as is the conversion of cholesterol esterenriched
very-low-density lipoprotein to LDL. The resulting large and abnormal cholesterol ester
enriched very-low-density lipoprotein is injurious to endothelial cells after receptor-mediated
uptake.19Hyperglycemia
appears
to
contribute
to
endothelial
dysfunction
as
19 20 21
20
well.
Hyperglycemia activates protein kinase C in endothelial cells, which in turn may
account for increased production of vasoconstrictor prostaglandins, endothelia and ACE, and
platelet and vascular growth factors, which directly and indirectly enhance vasomotor reactivity
and vascular remodeling and growth.17 18 19 20 Furthermore, hyperglycemia alters endothelial cell
matrix production, which may contribute to basement membrane thickening. Hyperglycemia
increases endothelial cell collagen IV and fibronectin synthesis and increases the activity of
enzymes involved in collagen synthesis.21 Hyperglycemia also delays cell replication and
increases endothelial cell death in part by enhancing oxidation and glycation.18
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Table 3.
Alterations in Vascular Endothelium Associated With Diabetes Mellitus and Hypertension

Additional metabolic and hemodynamic factors may contribute to endothelial dysfunction in

diabetes and hypertension. Hypercholesterolemia and perhaps hypertriglyceridemia impair
endothelium-dependent relaxation.22 Both insulin and IGF have potentially important effects on
endothelial cells. Insulin appears to have a modulating influence on glucose stimulation of
protein kinase C and diacylglycerol in endothelial cells. 23 One hypothesis for endothelial
dysfunction in diabetes relates to elevated protein kinase C activity in diabetic vascular
endothelium, which may enhance vascular tone, permeability, and atherosclerosis. 23 Elevated
diacylglycerol and protein kinase C levels are induced by hyperglycemia; insulin treatment that
achieves euglycemia can prevent the increase in diacylglycerol levels and protein kinase C
activity.23 24 These results suggest that impaired insulin action, as exists in NIDDM and
hypertension, may contribute to the endothelial dysfunction seen in these disorders. However, a
recent report suggests that hypertension is not associated with impaired carbohydrate metabolism
or dyslipidemia, but endothelium-dependent vasodilation is preserved.25 This report provides
additional credence to the concept that the metabolic abnormalities that often accompany
hypertension and diabetes mellitus play a pivotal role in the development of endothelial
dysfunction.
VSMC Abnormalities: Role of Insulin and IGF-1
The concept that decreased insulin action on VSMCs may explain the exaggerated vascular
resistance associated with both NIDDM and IDDM was carefully reviewed in our previous
updates on diabetes mellitus and hypertension.1 2 14 Accordingly, the current material represents
an update of the understanding of this important topic. Research conducted over the past several
years has shown that VSMC tissue, like skeletal muscle and adipocytes, is sensitive to the
metabolic effects of both insulin and IGF-1.14 26 27 28 29 30 In this regard, these studies have
confirmed that insulin and IGF-1 regulate VSMC cation metabolism (Fig 1) and that both
hormones stimulate VSMC glucose uptake and metabolism.14 28 30 Insulin and IGF-1 are
structurally related, share receptors, and have similar postreceptor actions. Unlike insulin, which
must traverse the endothelium before acting on VSMCs in vivo, IGF-1 is synthesized by VSMCs
and is more likely to act in an autocrine and paracrine fashion. Importantly, recent investigations
indicate that IGF-1, like insulin, attenuates vasoconstrictive responses and increases blood flow
in regional vascular beds and lowers BP in healthy individuals. 26 27 IGF-1 is expressed,
synthesized, and secreted by VSMCs and appears to exert its actions on VSMCs in an autocrine
fashion.14 IGF-1, like insulin,29 increases VSMC Na+,K+-ATPase activity, suggesting one
mechanism by which IGF-1 modulates VSMC [Ca2+]i (Fig 1) and attenuates vascular
contractility.14 30

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Figure 1.
Diagram shows mechanisms regulating divalent cation metabolism and contraction in VSMCs
and proposed targets of insulin and IGF-1 action. Pivotal steps in regulation of divalent cation
metabolism are indicated by circled numbers. DAG indicates diacylglycerol; IP3, inositol 1,4,5trisphosphate.
Roles of Insulin and IGF-1 in Atherosclerosis
Insulin and IGF-1 may exert their atherogenic effects through influences on both vascular
endothelial cells and VSMCs.14 30 Both insulin and IGF-1 increase mitogenic signaling pathways
and thymidine incorporation into DNA in vascular endothelial cells and VSMCs. 14 24 30 Insulin
likely mediates most of its VSMC proliferative effects through IGF-1 rather than insulin
receptors.31 Both IGF-1 and IGF-2 enhance proteoglycan synthesis by microvascular and largevessel endothelial cells.21 Insulin also increases the uptake and esterification of lipoprotein
cholesterol by VSMCs and decreases its deesterification and release by these cells. 14 25 Insulin
resistance and hyperinsulinemia may also promote atherosclerosis by retarding the fibrinolytic
process.12 13 14 Insulin stimulates PAI-1 production,12 and there is a strong relation between
plasma insulin levels and fibrinogen and PAI-1 levels.12 13 Both insulin and IGF-1 appear to
function as progression factors or cofactors and promote the proliferative properties of several
cytokines, including tumor necrosis factor.14 24 Thus, elevated circulating levels of insulin, as
exist in type II diabetes in many patients with essential hypertension, may contribute directly or
in conjunction with IGF to the accelerated atherosclerosis associated with these conditions.
Role of Hyperglycemia in the Vascular Abnormalities Associated With Diabetes and
Hypertension
Chronic hyperglycemia may exacerbate the vascular disease associated with diabetes mellitus
and hypertension.30 At high concentrations glucose has a direct, toxic effect (independent of
osmolality) on vascular endothelial cells.19 20 21 This toxic effect may lead to decreased
endothelium-mediated vascular relaxation, increased vasoconstriction, promotion of VSMC
hyperplasia, vascular remodeling, and atherosclerotic events.14 30 High glucose concentrations, as
seen in the diabetic hyperglycemic state, have been shown to induce the overexpression of
fibronectin and collagen IV in cultured human vascular endothelial cells. 32Increased expression
of fibronectin and collagen IV further contributes to endothelial cell dysfunction. Fibronectin is a
glycoprotein with a critical role in cell matrix interactions, 32 and its overexpression may
contribute to both diabetic vascular disease30 and thickening of the glomerular basement
membrane and mesangial hyperplasia.32

Hyperglycemia also accelerates the formation of nonenzymatic advanced glycosylation products,

which accumulate in vascular tissue33 (Table 4). There are a number of sites where
nonenzymatic protein glycosylation can affect key processes in atherogenesis and vascular
remodeling. Indeed, a close association has been noted between the accumulation of increased
levels of AGE and vascular disease.33 Glycosylation of collagen results in increased rigidity and
decreased responsiveness to collagenase (proteinase digestion).33 There is also abnormal covalent
cross-linking and an enhanced ability to bind nonglycosylated proteins, such as LDL, albumin,
and immunoglobulins. Lipoprotein binding to glycosylated collagen may not only prolong its
intimal residence time but also enhance its susceptibility to oxidation within the arterial intima.33
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Table 4.
Potential Vascular Effects of Nonenzymatic Protein Glycosylation in Diabetes Associated With
Hypertension
A membrane-associated macrophage receptor that specifically recognizes proteins to which AGE
are bound has been identified.33 The binding of these proteins to macrophage receptors induces
the synthesis and secretion of tumor necrosis factor and interleukin-1. 33 These cytokines in turn
stimulate other cells to increase protein synthesis and to proliferate. 33 AGE proteins also increase
platelet-derived growth factor secretion, enhance endothelial cell permeability, and are
chemotactic for blood monocytes.33 Apolipoproteins and LDL are glycosylated, and this process
leads to enhanced cholesterol ester synthesis and accumulation in macrophages and impaired
degradation and release.33 Thus, prolonged hyperglycemia may result in enhanced production of
extracellular matrix and in proliferation of VSMCs as a result of an increase in the number of
highly cross-linked proteins with AGE, with resulting vascular hypertrophy and remodeling. The
fact that chronic hyperglycemia is associated with decreased elasticity of vascular arterial wall
connective tissue and elevated pulse pressures may be related in part to AGE.30 33
Several other mechanisms associated with chronic hyperglycemia may also contribute to the
hypertension frequently accompanying diabetes mellitus. For example, elevated glucose levels
have been reported to increase VSMC [Ca 2+]i,34which could result in increased vascular
tone.2 14 30 Glucose can be extracted by renal proximal tubule cells by an active process in which
sodium and glucose cotransporters are involved. Hyperglycemia results in hyperfiltration of
glucose, which in turn stimulates the proximal tubular sodium-glucose cotransporter.35This
process is insulin independent and rapidly operative, as elevated proximal tubular cell sodium
concentration and increased Na+,K+-ATPase activity occur within days of inducing
hyperglycemia.35 The resultant sodium retention caused by hyperglycemia can help explain the
increased total exchangeable sodium seen in diabetic hypertensive patients.1 14
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Metabolic Abnormalities and Renal Glomerular Disease: Analogy to Vascular

Atherosclerosis
Pathophysiological changes of diabetic nephropathy are histologically different from those of
other types of renal disease.1 36 37 In humans, mesangial expansion leads to the earliest lesions
seen in IDDM.38 In experimental studies the earliest pathological change is an increase in the
thickness of the glomerular basement membrane; usually the volume of the glomerulus is
increased compared with that of nondiabetic subjects. Subsequently, the amount of matrix in the
mesangium increases, and in some patients this mesangial expansion can progress to increasingly
more severe diffuse or nodular glomerulosclerosis.36 Basement membranes are specialized
regions of extracellular matrix composed of type IV collagen, laminin, entactin/nidogen, and
proteoglycans, which together form a complex meshlike structure. 37 Sievelike permselectivity is
one important function of basement membrane that may be gradually lost in diabetes mellitus,
with associated progressively increasing proteinuria.37 Nonenzymatic glycosylation of long-lived
proteins, such as the basement membrane components type IV collagen and laminin, and crosslink formation of these components appear to lead to modification of basement membrane
ultrastructure and loss of permselectivity.37AGE can also have important influences on renal
mesangium. AGE binding to mesangial cells can lead to a significant increase in fibronectin and
several other mesangial structural proteins.37 AGE binding to mesangial AGE receptors can lead
to an increase in basement membrane collagen as well. 37 Thus, hyperglycemia clearly contributes
to the development of diabetic nephropathy.36
Mesangial cells share many properties with VSMCs. They are known to contract in response to
vasoactive agents such as angiotensin II, vasopressive platelet-activating factor, and endothelin1.1 19 39 40 41 Contraction of mesangial cells is important because the mesangium binds together
capillary loops; contraction of the mesangium thus can alter capillary flow, pressures, or both.
The mesangial cell synthesizes several growth factors that may act in an autocrine/paracrine
fashion. These include IGF-1, platelet-derived growth factor, platelet-activating factor,
endothelin, prostanoids, and interleukin-1. Thus, the mesangial cell has supportive, filtrative, and
synthetic functions. The glomerular endothelial cell is separated from the mesangial cell of the
kidney only by its basement membrane; passage of substances between these two cells is easily
accomplished. Substances elaborated by the endothelium affect mesangial cell growth
contraction and protein synthesis. For example, endothelin-1 increases growth and extracellular
matrix production by mesangial cells. Endothelium-derived relaxing factor and vasodilator
prostaglandins inhibit mesangial cell growth and contraction.39 Furthermore, increased local
production of growth factors by stimulated endothelial and inflammatory cells can result in
mesangial expansion. For example, endothelial damage can result in platelet activation, with
release of platelet-derived growth factor and other growth factors that can also enhance
mesangial cell proliferation and matrix overproduction.19 39
Mesangial cell abnormalities typically appear after 5 to 15 years of clinical diabetes in
individuals with type I disease.36 37 38 The most common abnormality observed by light
microscopy is diffuse intercapillary sclerosis due to expansion of the mesangium. Nodular

intercapillary sclerosis is seen in approximately 25% of patients with diabetic

nephropathy.36 37 38 The pathophysiological alterations that occur with focal and diffuse
glomerulosclerosis are similar to those that occur in vascular glomerulosclerosis, with mesangial
cell changes paralleling those in VSMCs, including proliferation, hypertrophy, foam cell
accumulation, appearance of extracellular matrix material, deposits of amorphous debris, and
evolving sclerosis. The observed mesangial expansion is primarily related to mesangial cell
hypertrophy and an accumulation of mesangial cell matrix. A number of hormones have been
demonstrated to alter mesangial cell growth in vitro, but only angiotensin II and vasopressin
have been clearly demonstrated to promote hypertrophy,19 36 37 38 which is more prominent in
glomerulosclerosis than is proliferation. This may help explain why ACE inhibitors have been
shown to slow the progression of glomerulosclerosis in both type I and type II diabetic
patients.4243
Diabetic nephropathy has become the leading cause of end-stage renal disease in the United
States.2 36 37 38 Hypertension is acknowledged to be a major risk factor in the progression of
diabetic renal disease.2 Diabetic nephropathy, defined as the appearance of proteinuria, elevated
arterial BP, and diminished GFR, will develop in as many as 40% of IDDM patients. 2 36 37 38 In
patients with the onset of diabetes at an early age, renal disease is an important contributor to
mortality, accounting for up to 31% of all deaths. 2 36 37 38 Renal disease also complicates NIDDM
in adults and contributes significantly to morbidity and mortality in this group. 2 36 A smaller
percentage of patients with NIDDM develop renal disease, and the incidence of end-stage renal
disease is strongly related to the duration of diabetes. However, more than 50% of diabetic endstage renal disease is associated with NIDDM because this form of diabetes constitutes more
than 90% of diabetic patients.2 36
In both types of diabetes mellitus the appearance of clinically detectable proteinuria (>200
g/min of urinary albumin excretion) signals the onset of the relentless progression of diabetic
nephropathy, which is typically followed by deterioration to end-stage renal
disease.2 36 37 38 Currently, it is believed that diabetic nephropathy develops as a result of the
interplay of the metabolic abnormalities inherent to diabetes (eg, hyperglycemia) and
hemodynamic abnormalities of the renal microcirculation that result in progressive structural and
functional glomerular abnormalities.36 37 38
Previous SectionNext Section
Treatment of Hypertension in Patients with Diabetes Mellitus
General Goals of Therapy
No large, population-based, randomized trials of hypertension treatment in diabetic patients have
been conducted. Nevertheless, as proposed by a recent consensus statement,2 the goal of treating
hypertension in diabetic patients should be to prevent death and disability associated with high
BP. In addition, other reversible risk factors for cardiovascular disease need to be addressed. For
example, target-organ involvement should be considered when a treatment plan is being
formulated. The major focus of clinical and investigative efforts has been on retarding the

progression of diabetic nephropathy (see below) and to a lesser extent reducing cardiovascular
morbidity and mortality. The diagnosis of hypertension should be based on multiple BP
measurements obtained in a standardized fashion on at least three occasions. Supine, sitting, and
standing BPs should be measured in all diabetic patients. Automated ambulatory BP monitoring
may be especially helpful in the diabetic patient for evaluating BP control over a 24-hour period
to document the absence of the usual nocturnal fall in BP in diabetes (especially with autonomic
dysfunction or nephropathy). Ambulatory BP monitoring may also be useful in documenting
episodic hypertension, orthostatic hypotension, or resistant hypertension, which are relatively
common in diabetic individuals with accompanying hypertension.2
What Is the BP Goal in Diabetics With Hypertension?
Although the optimal BP level during antihypertensive treatment in patients with diabetic
nephropathy has not been defined, a review of the relationship between the rate of fall in GFR
and the BP level during antihypertensive treatments suggests that we should strive for lower goal
BP than recommended by current guidelines.244 First, the benefit of reducing BP has been
demonstrated most clearly when treatment is instituted before GFR is markedly reduced. 44 This
emphasizes the concept that efforts to reduce BP should begin before serum creatinine is
elevated. Second, the best results apparently have been achieved by reducing BP below
conventionally accepted levels.2 44 Indeed, the smallest decline in renal function is found in
patients with BP levels around 130/85 mm Hg, a level that is readily attainable during treatment
in incipient diabetic nephropathy before the decline in GFR has started. This is also the goal of
BP attainment recommended in a recent consensus2 44 (Fig 2).
Figure 2.
Chart shows suggested approach to hypertension therapy in diabetic individuals. Treatment goal
is to maintain BP at less than 130/85 mm Hg. Diabetic renal disease, autonomic dysfunction, and
adverse effects on glucose and lipid metabolism must be considered before the course of
therapeutic intervention is chosen. (Adapted from Reference 22 with modification.)
Nonpharmacological Therapy in Diabetic Hypertensive Patients
Lifestyle modifications may serve as definitive therapy for mild hypertension in diabetic patients
or as an adjunct to pharmacological therapy to lower the number and dose of antihypertensive
drugs.2 The diet recommended by the American Diabetes Association, which is low in calories
and fat, high in carbohydrate and soluble fiber, and moderately low in protein, has been reported
to lower BP in diabetic patients.2 Moderate salt restriction reduces systolic BP, which is often
inordinately elevated in diabetic patients.2 Weight reduction is important, particularly in type II
diabetics, and improves glucose tolerance as well as reducing BP.2 8 For example, for each 10-lb
weight reduction, systolic and diastolic pressures can be expected to decrease by 10 and 5 mm
Hg, respectively.2 8Moderate but regular aerobic exercise improves glycemic and lipemic control
and helps with weight reduction.
Results of the Diabetes Control and Complications Trial (DCCT), 45 a 7-year study of more than
1440 patients, demonstrated that intensive insulin therapy reduced the occurrence of

microalbuminuria by 39% and that of albuminuria by 54%. In addition, intensified therapy

patients had lower rates of serious retinopathy requiring photocoagulation, lower rates of
decreased visual acuity, and fewer cases of nephropathy. Similar results were reported from a
study designed to test the hypothesis that optimized glycemic control in type I diabetic recipients
of renal allografts will prevent or delay diabetic renal lesions in the allograft. 46 This study was a
prospective, controlled, and randomized trial of glycemic control in an inception cohort (ie, all
patients were at stage 0 for diabetic renal lesions in the graft when randomized to the trial) of
type I diabetic renal allograft recipients. The experimental group had maximized glycemic
control, and the standard group received standard clinical diabetic care. Patients underwent
baseline (before transplant) and 5-year posttransplant allograft biopsies. More than a twofold
increase in the volume fraction of mesangial matrix per glomerulus occurred, as well as a
threefold increase in arteriolar hyalinosis, greater widening of the glomerular basement
membrane, and increase of volume fraction of the total mesangium in the patients receiving
standard treatment compared with those with maximized glycemic control. This trial indicates a
causal relationship between hyperglycemia and an important lesion of diabetic nephropathy,
mesangial matrix expansion, in renal allografts transplanted into diabetic recipients. In summary,
newly available data suggest that aggressive control of blood sugar in the very early stages of
this disease process can provide significant protection against its development.
Prospective clinical trials in type I diabetic patients with overt nephropathy47 48showed that even
with moderate protein restriction, renal function is stabilized in diabetic nephropathy. Although
both studies were limited to diabetic patients with overt nephropathy, it has been suggested that
dietary protein restriction will produce even better results if implemented during the early stages
of diabetic nephropathy. In recognition of these data, the American Diabetes Association has
recommended that dietary protein be restricted to 0.8 g/kg body wt per day in all patients with
diabetes other than children and pregnant or lactating women. It is still unclear to what extent
dietary protein intake needs to be restricted to obtain maximal effects on delaying the
progression of renal disease, but without producing metabolic side effects or malnutrition. For
most diabetic patients, restricting dietary protein to 0.8 g/kg body wt per day would constitute a
significant but practical reduction of their usual protein intake and would be likely to have a
beneficial effect. Patients are also more likely to adhere to moderately protein-restricted diets
than to more drastic restrictions.
BP Control and Progression of Diabetic Nephropathy
Hypertension invariably complicates the course of patients with diabetic nephropathy. Of the
35% to 40% of either IDDM or NIDDM patients who ultimately develop nephropathy, all at
some time in their natural history will be hypertensive. 2Numerous clinical trials of both IDDM
and NIDDM hypertensive patients with nephropathy have assessed diverse forms of BPlowering therapy on the progression of renal disease. 1 2 44 These trials have all demonstrated that
aggressive reduction of an elevated BP to levels below 140/90 mm Hg will retard the progression
of diabetic renal disease. Furthermore, recent data suggest that some antihypertensive drugs may
confer unique beneficial effects in attenuating the progression of this disease independent of their
BP-lowering effects.42 43 44

Pharmacological Treatment of Hypertension in the Diabetic Patient

Pharmacological therapy should be initiated when lifestyle modifications are unsuccessful in
controlling hypertension in the diabetic individual2 (Fig 2). The National Institutes of Health
Consensus Panel recommended four classes of drugs that are effective as first-line single-agent
therapy.2 Each drug class has potential advantages and disadvantages. Recent data from several
large-scale hypertension treatment trials suggest that some classes may be preferred in the
diabetic patient with nephropathy, and these considerations will be addressed. The five major
classes of antihypertensive drugs currently being used in the United States for the diabetic
hypertensive patient are discussed below.
ACE Inhibitors
ACE inhibitors have no adverse effects on lipid levels or glycemic control. 2Experimental studies
have provided a theoretic framework for anticipating that ACE inhibition may preferentially
retard the progression of diabetic renal disease. Studies over the past decade have demonstrated
that the sustained increase in glomerular capillary pressure evoked in response to loss of renal
mass produces a destructive sclerosing reaction.49 Administration of ACE inhibitors decreases
glomerular capillary pressure, with a resultant reduction of glomerulosclerosis, suggesting that
ACE inhibitor therapy may protect the injured kidney from hemodynamically mediated
glomerular damage.49
The results of the first major attempt to compare patients randomized to an ACE inhibitor or
alternative therapy were reported in 1992 from a study of 40 patients with IDDM and diabetic
nephropathy randomized to treatment with either enalapril or metoprolol, generally combined
with furosemide.50 Treatment with enalapril compared with metoprolol resulted in a highly
statistically significant reduction in the rate of decline of GFR and in the level of proteinuria.
Overall, there was no statistical difference in the BP reduction or BP achieved with the two
treatments. Recently, the Diabetes Collaborative Study Group reported the results of a trial
designed to determine whether the ACE inhibitor captopril is more effective in slowing the
progression of diabetic nephropathy than are agents that act primarily by reducing BP.42 This was
a randomized, controlled trial comparing captopril with placebo in patients with IDDM in whom
urinary protein excretion was greater than or equal to 500 mg/d and serum creatinine
concentration was less than or equal to 2.5 mg/dL. The BP goal was to achieve BP control during
a median follow-up of 3 years. The primary end point was a doubling of the baseline serum
creatinine concentration. Serum creatinine concentrations doubled in 25 patients in the captopril
group compared with 43 patients in the conventional therapy group. The reduction in the risk of a
doubling of serum creatinine concentration was 48% in the captopril group as a whole. Captopril
therapy was associated with a 50% reduction in the risk of the combined end points of death,
dialysis, and transplantation that was independent of the small disparity in BP between the
groups. In a recent subgroup analysis of the data, remission of nephrotic-range proteinuria was
observed in 7 of 42 patients assigned to captopril (16.7%; mean follow-up, 3.40.8 years) but in
only 1 of 66 patients assigned to placebo. The findings were interpreted as suggesting that both

BP control and reduced proteinuria contribute to the reduced rate of GFR loss in the remission
group.
Whereas most available clinical trials have assessed the effects of ACE inhibition in patients with
IDDM, recent clinical trials in NIDDM patients have been reported. A long-term 5-year study
evaluating the effects of ACE inhibition on proteinuria and on the rate of decline in renal
function in NIDDM patients with microalbuminuria was recently conducted in Israel. 43 In a
randomized, double-blind, placebo-controlled trial of 94 patients ACE inhibition during the early
stages of diabetic nephropathy resulted in long-term stabilization of plasma creatinine levels and
of the degree of urinary loss of albumin. Lebovitz et al51 recently reported the results of a 3-year
prospective, double-blind, placebo-controlled trial in NIDDM patients and demonstrated that an
antihypertensive regimen that included the ACE inhibitor enalapril preserves renal function to a
greater extent than does therapy with antihypertensive agents excluding ACE inhibitors. The rate
of loss of GFR was significantly greater in patients with overt proteinuria at baseline (urinary
albumin excretion >300 mg/24 h) compared with patients with baseline subclinical proteinuria
(urinary albumin excretion 300 mg/24 h). Antihypertensive treatment with enalapril preserved
GFR better in the patients with subclinical proteinuria at baseline than the other antihypertensive
treatments that excluded the ACE inhibitor. Furthermore, only 7% of the enalapril-treated group
progressed to clinical albuminuria compared with 21% of control patients. On the basis of these
findings these investigators suggested that ACE inhibitors should be used as initial treatment for
hypertensive NIDDM patients with or without microalbuminuria and not held in reserve until
clinical albuminuria or proteinuria develops.
An important meta-regression analysis of the relative effects of different antihypertensive agents
on proteinuria and renal function in patients with diabetes was recently reported. 52 This analysis
assessed 100 controlled and uncontrolled studies that provided data on renal function,
proteinuria, or both before and after treatment with an antihypertensive agent. Multiple linear
regression analysis indicated that ACE inhibitors decreased proteinuria independent of changes
in BP, treatment duration, and type of diabetes or stage of nephropathy. It was concluded that
ACE inhibitors had a unique ability to decrease proteinuria independent of the reduction in
proteinuria caused by changes in systemic BP.
Despite these promising results, several caveats are in order. Lowering of BP per se may be the
major factor contributing to the salutary renal effects of ACE inhibitors as well as other
antihypertensive agents in patients with diabetes and hypertension. 53 ACE inhibitors are not free
of side effects. An infrequent but important risk of ACE inhibitors is an acceleration of renal
insufficiency, particularly in patients with bilateral renal artery stenosis and possibly more
commonly in patients with diabetes. Under conditions in which filtration pressure depends on
angiotensin II, the converting enzyme inhibitors may cause a precipitous fall in GFR. This
complication is most likely to occur in the presence of bilateral renal artery stenosis due to
atheromatous plaques or severe congestive cardiac failure. ACE inhibitors may provoke
hyperkalemia, particularly in those individuals with decrements in GFR or hyporeninemic
hypoaldosteronism.2 Finally, care must be exercised in initiating ACE inhibitor therapy in
patients receiving diuretics because BP may drop and renal function decline profoundly.2

Calcium Antagonists
The published studies regarding calcium antagonists and diabetic renal disease have been widely
divergent in their design and findings.53 54 The Melbourne Diabetic Nephropathy Study Group
has reported the 24-month results of their prospective, randomized study comparing the effects
of the ACE inhibitor perindopril with those of the calcium antagonist nifedipine on BP and
microalbuminuria in 43 diabetic patients with persistent microalbuminuria. 55 After 12 months of
therapy the investigators observed that both drug regimens were equally efficacious in reducing
BP and albumin excretion in hypertensive patients. However, the 2-year follow-up data
demonstrated that proteinuria had returned to baseline in the nifedipine-treated group but
remained decreased in the perindopril-treated group. 55 Thus, more long-term prospective studies
need to be conducted to determine the benefits of both dihydropyridine and nondihydropyridine
calcium antagonists in patients with hypertension and associated diabetic nephropathy.
In addition, it has been suggested that the combination of a calcium antagonist with a converting
enzyme inhibitor should result in a greater reduction in urinary protein excretion and slowed
morphological progression of nephropathy.56 One study compared the renal hemodynamic and
antiproteinuric effects of a nondihydropyridine calcium antagonist and an ACE inhibitor alone
and in combination in NIDDM patients with documented nephrotic range proteinuria,
hypertension, and renal insufficiency.56 Patients treated with the combination of a calcium
antagonist and ACE inhibitor manifested the greatest reduction in albuminuria. In addition, the
decline in GFR was the lowest in this group. Although such an approach is extremely attractive,
additional studies will be required to extend these initial observations.
Thiazide Diuretics
Thiazide diuretics in small doses are used frequently and successfully to treat hypertension in
individual diabetic patients2 (Fig 2). These drugs have been shown to reduce cardiovascular
morbidity and mortality in large population-based randomized trials (Systolic Hypertension in
the Elderly Program [SHEP]). If the dose is low (ie, 25 mg or less hydrochlorothiazide or
chlorthalidone daily), adverse effects on carbohydrate metabolism, hypokalemia, and
hypomagnesemia are uncommon. Because the diabetic hypertensive patient is generally volume
expanded, diuretics are often necessary for adequate control of BP. The disadvantages of
thiazides are that they cause short-term dyslipidemia, altered carbohydrate metabolism,
hypokalemia, hypomagnesemia, and hyperuricemia in some patients, but these adverse effects
are minimized at the low doses recommended. 2 Diuretics are also very useful antihypertensive
agents when used in conjunction with ACE inhibitors; this combination is often synergistic in
lowering BP and minimizes the metabolic side effects of diuretics.
-Blockers
Several concerns limit the usefulness of -blockers in treating people with diabetes: (1) These
agents may have adverse effects on glucose and lipid metabolism. (2) Most troublesome for the
insulin-treated diabetic subject is the observation that -blockers can interfere with awareness of
hypoglycemia in patients with diabetes and perhaps also prolong the recovery from
hypoglycemia.2The catecholamine-mediated symptoms of hypoglycemia-induced symptoms can

be blunted if not abolished. The reflex tachycardia that serves to warn the patient of
hypoglycemia may be blocked, putting the patient at greater risk of progressing to central
nervous system symptoms. (3) -Blockers can reduce peripheral blood flow and worsen
claudication and vasospasm in patients who already have a compromised peripheral vascular
system. (4) Finally, when -blockers are added to diuretics, an aggravation of the hyperglycemic
effect of the latter may occur.2Results from a recent investigation suggest that obese elderly
patients treated with -blockers and diuretics were at greater risk of developing NIDDM
compared with obese elderly normotensive individuals. 57 Thus, except under special
circumstances (eg, in the presence of angina pectoris and after myocardial infarction), -blockers
should no longer be used as first-line antihypertensive medications in these patients.
1-Blockers
1-Blockers have been recommended for the treatment of diabetic hypertension on the basis of
their efficacy, lack of adverse effects on glucose or insulin metabolism, and neutral or perhaps
beneficial effect on the lipid profile. 2 These agents infrequently produce or exacerbate sexual
dysfunction and may permit improvement of sexual function when substituted for a central
sympatholytic agent.2 Currently, there is no reported clinical evidence that peripheral -blockers
aggravate diabetic orthostatic hypotension, as is said to be the case with centrally acting
sympatholytics.2
There are both advantages and disadvantages to the use of central sympatholytic antihypertensive
agents (eg, clonidine, guanabenz, methyldopa, guanfacine) in the diabetic patient. Advantages
include their lipid-neutral2 and minimal-to-absent hyperglycemic effects.2 However, centrally
acting sympatholytic medications may worsen or unmask both orthostatic hypotension and
sexual dysfunction in diabetic patients.2 In summary, although central sympatholytic agents have
few if any metabolic side effects, some of their putative other adverse effects render them less
than ideal antihypertensive agents for the management of diabetic patients.
Summary of Pharmacological Therapy
The available data at present indicate that overall, ACE inhibitors produce more beneficial
effects on diabetic nephropathy (reductions in proteinuria) than other antihypertensive agents
studied. It has recently been reported that predictions in proteinuria are related to reduced rates of
decline in renal function.58 It should be pointed out, however, that not all ACE inhibitors have
been studied in diabetic nephropathy. Considering their efficacy in lowering BP, low incidence of
side effects, and renal protective properties, ACE inhibitors appear to be a logical first-choice
class of drugs for use in hypertensive diabetic patients with albuminuria (>30 mg/24 h) when
economically feasible and not contraindicated. ACE inhibitors may also be beneficial in
normotensive patients with albuminuria, but the evidence is less clear. When ACE inhibitors are
contraindicated or ineffective, other antihypertensive agents should be used.
Concerns Regarding Sexual Dysfunction
Clinically relevant side effects associated with antihypertensive pharmacological therapy appear
to be more frequently observed in diabetic individuals than nondiabetic people with
hypertension.2 59 Diabetic hypertensive people often manifest a side-effect profile very similar to
that seen in elderly patients treated with antihypertensive drugs. For example, as with the elderly,

many diabetic individuals have reduced baroreceptor sensitivity and the tendency toward
orthostatic hypotension in response to antihypertensive drug therapy.2 59 Diabetes mellitus,
hypertension, and advancing age are independently associated with an increased prevalence of
sexual dysfunction in both women and men 2 59 (Fig 3). Hypertension, neuropathy, vascular
insufficiency, and physiological problems all have been implicated in impotence, impaired
ejaculation, and decreased libido in men and decreased vaginal lubrication, orgasmic
dysfunction, and decreased libido in women2 59 (Fig 3). The absence of standards for
evaluation of sexual dysfunction in women has led to underreporting and inadequate
comprehension of the extent of this problem in women with diabetes and hypertension.
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Figure 3.
Chart shows interrelation of factors in sexual dysfunction in hypertensive diabetic patients (see
Reference 22 ).
Any antihypertensive medication can contribute to sexual dysfunction, perhaps some more than
others, and this should be a consideration in evaluating people with both hypertension and
diabetes who have this problem.2 59 For example, several carefully conducted trials have
indicated that men taking thiazide diuretics have a relatively high prevalence of sexual
dysfunction, including a decrease in libido, difficulty in gaining and maintaining an erection, and
difficulty with ejaculation.2 59 Thus, patients with both diabetes and hypertension should be
evaluated for sexual dysfunction; appropriate therapy, including changes in medication or
referral for sex counseling, should become routine in their clinical care.
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Future Considerations
Increasing investigation should also focus on identifying appropriate antihypertensive agents that
not only lower BP but also reduce cardiovascular risk and retard the rate of progression of
diabetic renal disease. In light of the recent report of the Diabetes Collaborative Study Group
demonstrating that ACE inhibition retards the progression of diabetic nephropathy in IDDM
patients, it would be important to ascertain whether this intervention is also applicable to patients
with NIDDM. In light of conflicting evidence that calcium antagonists may also confer renal
protection in diabetic nephropathy, prospective long-term studies will be needed to further
delineate and corroborate these actions. Furthermore, in light of the attractive theoretic
framework commending their use, clinical trials should be initiated to assess the long-term

effects of interventions including 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors,

aminoguanidine, acarbose, and aldose reductase inhibitors on the natural course of decline of
GFR and, if possible, on the progression of anatomic abnormalities. Finally, in light of divergent
results on the effects of protein restriction, additional studies are warranted to delineate the
precise role of this intervention in both IDDM and NIDDM patients.
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Selected Abbreviations and Acronyms
ACE
= angiotensin-converting enzyme
AGE
= advanced glycosylation end product(s)
BP
= blood pressure
GFR
= glomerular filtration rate
IDDM
= insulin-dependent diabetes mellitus
IGF
= insulin-like growth factor(s)
LDL
= low-density lipoprotein
NIDDM
= noninsulin-dependent diabetes mellitus
Ox-LDL
= oxidized low-density lipoprotein
PAI
= plasminogen activator inhibitor
VSMC
= vascular smooth muscle cell
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Acknowledgments