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Hypertension in a critical determinant of the development and progression of both the macrovascular and microvascular complications of diabetes. Importantly, hypertension is common in the setting of insulin resistance; 70% of patients with type 2 diabetes have a blood pressure greater than or equal to 140/90 mmHg. Multiple clinical trials have demonstrated a close correlation between blood pressure and cardiovascular events and mortality, development and progression of nephropathy, and progression of retinopathy and development of blindness. For example, in the United Kingdom Prospective Diabetes Study (UKPDS), every 10 mmHg decrease in mean systolic pressure was associated with reduced risk by 12% for any diabetic complication, 15% for diabetes-related deaths, 11% for myocardial infarction, 13% for macrovascular complications, and a no risk threshold was found for any end-point studies [1]. In addition, hypertension exacerbates diabetic cardiomyopathy, enhancing the progression to heart failure, which occurs commonly in patients with diabetes. Because of these pathophysiological relationships to renal and cardiovascular disease, hypertension increases mortality in diabetes by 4 –5 fold.

TREATMENT GOALS

Based on results of clinical trials, the American Diabetes Association (ADA) and the National Kidney Foundation (NKF) and the Joint National Committee 7 (JNC7), recommend a goal blood pressure of 130/80 mmHg or less [2]. For patients with isolated systolic hypertension, which the ADA defines as a systolic blood pressure greater than or equal to 180 mmHg with a normal diastolic blood pressure, the treatment goal is to reduce systolic pressure to below to 160 mmHg. The NFK and Joint National Committee VI (JNCVI) also recommended that in patients with evidence of renal disease, microalbuminuria or proteinuria, blood pressure goals should be targeted at 125/75 mmHg or less [3]. The average number of antihypertensive agents needed to reach these treatment goals is 3.4 [4]. Therefore, increased understanding of the mechanisms contributing to hypertension in insulin resistance and the pathophysiology of diabetic vascular complications, as well as awareness of the results of antihypertensive trials in patients with diabetes is important to develop a logical, evidence-based treatment strategy.

PATHOPHYSIOLOGY OF HYPERTENSION IN INSULIN RESISTANCE

An elevated blood pressure occurs twice as commonly in the insulin resistant state compared to the insulin sensitive state. Multiple studies over the past two decades have tried to elucidate the mechanisms of this association. Early studies suggested that hypertension in diabetes was associated with volume expansion, and insulin is known to enhance proximal tubular sodium reabsorption [5]. There is also evidence that insulin stimulates the sympathetic nervous system [6]. Whether hyperinsulinemia is a culprit remains controversial. Chronic infusion of insulin into rodents, but not dogs, is associated with elevations in blood pressure [7]. Recent data in man suggests that chronic infusion of insulin (> 6h) is associated with endothelial dysfunction [8]. In UKPDS tight glucose control with either insulin or sulfonylurea had no difference in outcomes, although a subgroup of obese subjects with diabetes had decreased cardiovascular events with metformin, which generally lowers circulating insulin. In insulin resistant animals and humans, there is increased activity of the mitogen activated protein kinase (MAPK) pathway, which promotes vascular and cardiac injury and which is activated by both insulin and AngII [9]. Indeed early in insulin resistance, even before multiple components of the Metabolic Syndrome appear, there is evidence of endothelial dysfunction, even in the coronary circulation [10]. In addition, to hyperinsulinemia, insulin resistance is associated with vascular inflammation resulting from adipose tissue production of adipokines [11]. Increasing evidence suggests that adipose tissue, particularly visceral, is a production depot for cytokines including tumor necrosis factor a (TNFa), leptin, PAI-1, interleukin-6 (IL-6) which stimulates liver production of c-reactive protein (CRP), and angiotensinogen, the precursor of AngII. Circulating levels of these cytokines are generally increased in obese subjects and in patients with diabetes [12]. Indeed, hs CRP levels are increased in obese subjects and are predictive not only of CAD, but of later development of diabetes, as well [13]. Taken together, multiple factors, particularly volume expansion and endothelial injury contribute to increased blood pressure in insulin resistance, which then promotes further vascular damage as well as injury in cardiac, renal, and brain tissue, as well (Figure 1).

Figure 1.

TREATMENT

More recent clinical trials evaluating antihypertensive agents incorporated large numbers of patients with diabetes or focused on diabetic nephropathy outcomes (Table 1). In general, approaches that inhibit the renin-angiotensin system (RAS) consistently had better renal outcomes, as well as better cardiovascular (including stroke) outcomes compared to a standard regimen, dihydropyridines or beta-blockers [14]. This was alos true in high risk patients such as those with documented coronary artery disease or with hypertension and left ventricular hypertrophy (LVH) In contrast, one of the largest trials in hypertension ever completed, the Antihypertensive and Lipid-lowering treatment to Prevent Heart Attack Trial (ALLHAT), recruited over 12,000 patients with type 2 diabetes aged 55 years or older with hypertension and diabetes with no other risk factors for coronary artery disease CAD [15]. The incidence of fatal and nonfatal myocardial infarction was no different in patients treated with chlorthalidone, lisinopril or amlodipine, suggesting that blood pressure lowering, rather the mechanism by which blood pressure was lowered, was important. However, nondiabetics randomized to the diuretic arm had nearly double the incidence of new-onset diabetes compared to the angiotensin converting enzyme (ACE) arm or calcium channel blocker arm Similar to ALLHAT, the hypertension substudy of the UKPDS demonstrated that more aggressive lowering of blood pressure (150/90 vs. 140/82 mmHg) improved results in all categories of endpoints. There was no difference in outcomes between patients who were randomized to captopril or atenolol [16]. Patients with diabetes with or without other CAD risk factors were recruited to this study. These conflicting results have lead to confusion regarding first-line therapy for the treatment of hypertension in the setting of insulin resistance and diabetes.

One important consideration is whether other CAD or renal risk is present as outlined in Table 1:

Diabetic Nephropathy - The RAS has been implicated in the pathogenesis of glomerular disease in diabetes. Angiotensin II (AngII) is not only a major arterial vasoconstrictor, but it promotes hypertrophy of glomerular mesangial cells and mesangial production of the profibrotic cytokine, transforming glucose factor b (TGFb) as well as plasminogen activator inhibitor-1 (PAI-1) which prevents activation of plasmin and matrix metalloproteinase (MMPs) that degrade extracellular matrix (ECM, [29-31]). The resulting accumulation of ECM leads to glomerulosclerosis, which ultimately wipes out filtering capacity of the glomerulus [32]. In addition, AngII promotes apoptosis of glomerular podocytes, which play an important role in protein sieving [33, 34]. Loss of podocytes, largely through apoptosis in diabetes, contributes to proteinuria, as well as to focal glomerulosclerosis in areas of podocyte loss [35]. In general, inhibition of the RAS with either ACE inhibitors or with angiotensin AT1 receptor blockers (ARBs) attenuates proteinuria beyond effects of blood pressure lowering alone [21, 36]. In the Captopril trial, patients with type 1 diabetes and 500 mg or more proteinuria per day had less doubling serum creatinine, dialysis, transplantation and death when administered captopril vs. a standard regimen not including ACE inhibitor [17]. Similar trials with ACE inhibitors in patients with type 2 diabetes had less consistent effects [37]. However, two recent ARB trials, Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study and the Irbesartan Diabetic Nephropathy Trial (IDNT) demonstrated not only decreased proteinuria, but less doubling of serum creatinine, dialysis and transplantation in type 2 diabetes with 500 mg/day or greater proteinuria in patients on losartan compared to usual care regimen, RENAAL [18], or irbesartan compared to amlodipine or placebo, IDNT [19]. Based on these results the ADA recommended ACE inhibitors as first-line therapy for patients with type 1 diabetes and nephropathy and ARBs as first-line therapy for patients with type 2 diabetes and nephropathy [38].

Hypertension and LVH - AngII has been demonstrated to promote myocyte hypertrophy and cardiac interstitial fibrosis [9]. This octapeptide stimulates multiple pathways that increase extracellular matrix production and accumulation including cardiac fibroblast replication, expression of TGF-b, PAI-1, osteopontin, and ECM proteins, formation of focal adhesions and activation of the mitogen activated protein kinase pathways. Cardiac fibrosis is increased in diabetic cardiomyopathy, which has been shown in man to be exacerbated by hypertension. Functional changes begin with diastolic dysfunction progressing to heart failure; the RAS has been shown to be activated at all of these stages of decreased cardiac function [39]. In the LIFE trial which randomized diabetics and nondiabetics to either losartan or atenolol, subjects given losartan had less LVH, improved ejection fraction and less stroke [21]. The LIFE trial included 1195 patients with diabetes and, these subjects also had reduced all cause mortality, as well as less stoke [40].

Heart failure and postmyocardial infarction. Multiple heart failure and post MI trials have shown that addition of ACE inhibitors and an aldosterone blocker decrease mortality and recurrent MI [24, 41]. Recent trials with ARBs suggest they are likely to be as useful as ACE inhibitors for heart failure, and there may be additive effects of ACE inhibitors and ARBs [42]. Inhibition of AngII effects on the myocardium, as discussed above, likely contribute, as well as inhibition of AngII-mediated vascular damage as discussed below. Beta blockers also decrease post-MI mortality, likely through decreasing cardiac nerve activity and arrythmias and possibly other mechanisms [25, 26].

High Atherosclerosis Risk – AngII accelerates multiple mechanisms of vascular injury. These include inflammation, thrombosis, oxidation, cell growth and hypertrophy, in addition to its prominent vasoconstrictive effect [43]. An important question is whether some of these effects are accelerated in the setting of insulin resistance with hyperinsulinemia and activated inflammatory mechanisms. Many AngII effects are mediated by the mitogen activated protein kinase pathway, which is also activated by insulin or insulin-like growth factor 1 (IGF-1). In fact, AngII and insulin/IGF-1 have additive effects to activate MAPK, so that AngII effects may be amplified in the setting of hyperinsulinemia [44]. AngII further stimulates vascular TNFa, PAI-1 and other proinflammatory substances. Because of perivascular fat production of angiotensin, vascular levels of AngII may be elevated to further increase mechanisms of AngII-mediated vascular injury.(del) The MicoHOPE trial demonstrated that ACE inhibitor administration (ramipril) compared to placebo in patients with diabetes and known cardiovascular disease (n=3557) decreased cardiovascular events and mortality, attenuated renal disease development and progression, and decreased stroke [45]. Thus, these results are highly consistent with data demonstrating damaging effects of AngII on the vascular wall.

Hypertension and Diabetes – If diabetes itself is an atherosclerosis risk equivalent, why didn’t inhibition of RAS demonstrate superiority in UKPDS and ALLHAT? In UKPDS, ACE inhibition and beta blockade were used in the aggressive blood pressure treatment arm and had similar event reduction. Beta blockade reduces renin production, but whether it is as effective in attenuating the RAS as ACE inhibition in diabetes remains to be determined. Non-ACE mechanisms have been shown in humans to generate AngII, despite ACE inhibition [46]. It is possible that losartan had better effects than atenolol in the LIFE trial because blockade of the AngII AT1 receptor blocks the final common pathway of AngII which mediated its multiple effects on the vasculature, heart and kidney. In ALLHAT, the diuretic (chlorthalidone) was as effective on cardiovascular events as ACE inhibition (lisinopril) or calcium channel blockade (amlodipine) [28]. It is difficult to explain this discrepancy with results of microHOPE, CAPP and other trials discussed above. One explanation may be that systolic blood pressure reduction was 2–10 mmHg more with the diuretic and amlodipine compared to ACE inhibition which was significant over the 5 years of the study [47]. Another explanation may be that a greater burden of cardiovascular or renal injury was present in microHOPE and in the ARB renal trials, possibly associated with enhanced activity of the tissue RAS and, thus, allowing for the demonstration of greater effects in a shorter time period with RAS inhibition. Further studies with RAS blockade, PEACE and EUROPA, will help to address some to these issues.

A major concern in ALLHAT was that nondiabetic patients on chlorthalidone had 18% increased development of diabetics (FG≥126mg/dl) compared to amlodipine and 43% increased in diabetes compared to lisinopril [47]. Crossing this threshold enhances the probability of developing microvascular complications of nephropathy, retinopathy, and neuropathy and likely accelerates CHD. With an emphasis on prevention, blood glucose and electrolytes (low K⁺ and Mg⁺⁺ contribute to impaired insulin secretions and insulin resistance) should be monitored carefully in patients with the Metabolic Syndrome or prediabetes who are given diuretics.

RECOMMENDATION

Lowering blood pressure to 130/80 mmHg or less is crucial in the patient with diabetes to decrease risk and slow the progression of all vascular complications. The strategy to achieving this goal depends on several factors. The presence of renal disease, demonstrated CAD, LVH or heart failure warrants inhibition of the RAS, which is likely to be done in combination with a diuretic. In the absence of these factors, a diuretic could be used as first line antihypertensive therapy, although worsening of glycemic control and careful monitoring for the development of renal disease or more extensive heart disease is necessary and may be difficult. Thus, even in a diabetic patient with little evidence of vascular and renal complications, the combination of a diuretic and RAS inhibition as first line therapy may be prudent. Indeed, the majority of hypertensive patients require more than one therapeutic agent to reach goal blood pressure. Since there is evidence of volume expansion in diabetes, and insulin resistance, as well as potential activation of the tissue RAS, strategies targeting both of these mechanisms will likely be useful and are complementary. Inhibition of the RAS attenuates the hypokalemia and hypomagnesia caused by diuretics and, thus attenuates the worsening of glycemic control. There is also evidence that inhibition of the RAS can improve insulin sensitivity, albeit modestly [48, 49]. Furthermore, diuretics increase the efficacy of RAS inhibition on blood pressure lowering. The later addition of other agents should be individualized. A b blocker should be present in the post MI state. Calcium channel blockade is useful if further lowering of blood pressure is necessary. Nondihydropyridines have been shown to be additive to RAS inhibition in attenuating progression of renal disease [50]. Alpha-blockade may be useful in light of severe dyslipidemia and insulin resistance [51]. Drugs targeting the aldosterone receptor may be useful in heart failure or renal disease [52]. Clearly multiple choices are available, so therapy must be individualized and target blood pressure goals must be reached.