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Abstract

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

Resistance to antihypertensive drugs is common in hypertensive patients with type 2 diabetes. This is unfortunate because hypertension is one of the most important risk factors for development of cardiovascular events, and the goal blood pressure level is set lower in diabetic subjects than in nondiabetic subjects. Previous outcome trials in diabetic subjects have mainly focused on end points such as microalbuminuria or the incidence of cardiovascular events rather than on reduction of blood pressure; some reports, however, have suggested mechanisms for the drug resistance. These include several clinical conditions known to be associated with difficulty in reducing blood pressure specifically in diabetes mellitus: change in the renin-angiotensin system and chymase, volume overload, central sympathetic hyperactivity, sleep apnea, secondary hypertension, pseudoresistance (white coat hypertension), and poor compliance related to subclinical depression. In this review, the authors focus on the mechanisms of resistance to antihypertensive therapy (particularly for monotherapy with either angiotensin-converting enzyme inhibitors or angiotensin II antagonists) in the treatment of diabetic hypertension.

In the treatment of hypertension, resistance to antihypertensive drugs is common and is one of the most important risk factors for future cardiovascular events. In patients with hypertension and diabetes mellitus, both hypertensive and diabetic target organ damage occurs. The cardiovascular prognosis is worse than in patients with only hypertension, and hence the goal blood pressure (BP) is lower than in hypertensive subjects without diabetes.1 According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)2 and other international guidelines,3–5 angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists (ARBs) are strongly recommended as drugs of first choice in patients who have hypertension and microalbuminuria, macroalbuminuria, nephropathy, or renal insufficiency because these drugs have been shown to be effective in preventing or delaying diabetic complications. In patients who have hypertension and diabetes, not only ACE inhibitors or ARBs but also diuretics, β-blockers, and calcium channel blockers (CCBs) are regarded as first-line treatment.2

Several clinical conditions are known to be associated with difficulty in reducing BP in diabetic hypertensive patients. Most of the outcome trials in diabetic subjects that have examined the effects of different types of antihypertensive drugs used an average of 3 drugs.1 However, these studies have mainly focused on end points such as microalbuminuria or the incidence of cardiovascular events rather than on reduction of BP.6,7 Few reports show the reason why antihypertensive monotherapy is usually not effective in lowering BP to target BP levels in diabetic hypertensive subjects. In this review, we focus on the mechanisms of resistance to monotherapy (particularly for ACE inhibitors and ARBs) in the treatment of diabetic hypertension. As a search strategy, we identified original research articles, reviews, and editorial comments by going through leading journals that publish basic and clinical research in the field of hypertension and by electronically searching the Medline database. We directed special attention to reports published since 1997. We reviewed consensus documents on hypertension coexisting with diabetes as well as guidelines for the management of hypertension.

Improving Outcome in Hypertensive Patients With Diabetes

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

There is no argument concerning the efficacy of inhibiting the renin-angiotensin system (RAS) to improve renal outcomes and cardiovascular prognosis in high-risk individuals.8 The definition of high risk is somewhat arbitrary, however, because diabetes mellitus itself renders a patient high-risk for renal and cardiovascular complications. Should all diabetic hypertensive patients take RAS inhibitors? Two types of antihypertensive drug trials in patients with diabetes mellitus have been conducted: those showing that BP lowering itself is important regardless of therapeutic drug class and those showing that specific types of medication are important. These are reviewed below.

Trials of BP Reduction

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

Lowering BP to the target level is difficult in diabetic hypertensive patients. In data from the US National Health and Nutrition Examination Surveys (NHANES), the percentage of diabetic patients meeting the JNC VI BP goal (<130/85 mm Hg) increased from 28.5% in 1988–1991 to 35.9% in 2001–2002.9 The control rates among diabetic hypertensive patients were higher than the 22% rate reported for a university hypertension clinic, but lower than in the International Verapamil SR-Trandolapril (INVEST) trial, where almost half of the diabetic subjects with coronary heart disease had BPs <130/85 mm Hg.10 Several clinical trials11–14 have consistently shown that diabetic patients needed a large number of medications to achieve target BPs.1 In the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, patients with diabetes were not only more resistant and required a larger number of drugs, but the final BP levels were still higher than those of nondiabetic patients.15

In the Hypertension Optimal Treatment (HOT) trial, there was a 4-mm Hg difference in the achieved diastolic BP between the intensive treatment group and the less intensively treated group (84.6 vs 81 mm Hg).13 Despite this modest difference, there were fewer cardiovascular events in diabetic patients at the lower level of BP, although this was not seen in the overall study population. In the United Kingdom Prospective Diabetes Study (UKPDS), BP lowering itself was critical for preserving renal function and reducing cardiovascular risk.11 Risk reductions in the tight BP control group were 24% in diabetic-related end points, 44% in strokes, and 37% in microvascular end points when compared with the less tightly controlled group. Although ACE inhibitors or ARBs are strongly recommended as first-line agents in diabetic patients with albuminuria or renal impairment, using either of these drugs alone usually fails to achieve goal BP,10,11,15 a circumstance that is true for all antihypertensive drug classes.14,16 Thus, there is a paradox: diabetic hypertension is difficult to treat, but successful BP reduction is the most important element for preventing cardiovascular events.1,8 For this reason, combination therapy with at least 1 type of RAS inhibitor plus diuretics or calcium channel blockers (CCBs) has been recommended.17

Trials of Specific Drugs

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

ACE inhibitors and ARBs have been reported to have a favorable effect on the kidney,1 heart,18 and brain,19 independent of BP control in diabetes.20 In the Captopril Prevention Project (CAPPP) trial, although the results between the captopril and conventional therapy groups in the overall patient population were not different for primary end points, the subpopulation with diabetes showed a 41% lower rate for primary end points than did the captopril group. The BP in the captopril group was slightly but significantly higher than in the conventional therapy group throughout the study for all the subjects, but the BP-lowering effect in the diabetic subpopulation was not described.21 The MICROalbuminuria, cardiovascular, and renal outcomes Heart Outcomes Prevention Evaluation (MICRO-HOPE) study22 examined the effects of ramipril in 3577 diabetic patients. Although the BP change was very slight (ramipril group systolic BP/diastolic BP −1.92/−3.3 mm Hg, placebo group +0.55/−2.3 mm Hg compared with baseline), the primary outcome was lowered 25% by the ACE inhibitor compared with placebo, even after adjustment for the difference in BP. In contrast, no difference was found in reduction of diabetic complications between captopril and atenolol in the UKPDS trial. In the Antihypertensive and Lipid-Lowering Therapy to Reduce Heart Attack Trial (ALLHAT), the use of ACE inhibitors in diabetic patients had no advantages for cardiovascular and renal outcomes when compared with a CCB or diuretic, but the antihypertensive effects of the 3 types of drugs in diabetic patients were weaker than in nondiabetic subjects.14

In diabetic patients with nephropathy or a history of cardiovascular disease, an ACE inhibitor or ARB regimen is beneficial.2–4,6,8 However, most of the trials have used complex drug regimens. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 78% of the patients receiving losartan also received calcium antagonists, 84% got diuretics, 40%α-blockers, and 34%β-blockers.6 In the Irbesartan Diabetic Nephropathy Trial (IDNT), an average of 3.3 and 3.0 nonstudy drugs were used in the placebo group and treatment groups, respectively.23 Despite the similar reduction of BP between the amlodipine and the irbesartan groups, a specific protective effect against the progression of nephropathy was seen more frequently in the irbesartan group. Therefore, in diabetic subjects who have renal or cardiovascular complications, using a RAS inhibitor has valuable effects beyond BP lowering.

Mechanisms of Resistance in Diabetes

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

Several mechanisms can be proposed to explain why hypertension with diabetes mellitus is so hard to control (Table).

Table Table.  Causes of Drug Resistance to Diabetic Hypertension
Inadequate use of antihypertensive drugs (dose, combination)
Pseudoresistance (so-called white coat hypertension)
Poor compliance to antihypertensive drug therapy (including subclinical depression)
Volume overload due to high salt intake
Sympathetic hyperactivity
Sleep apnea

Change of RAS. In diabetes mellitus, the circulating components of the RAS are suppressed, but the renal tissue RAS is activated24; hyperglycemia also increases tissue angiotensin II. In early diabetes, AT1 receptors are upregulated, especially in renal tissue, but AT2 receptors are downregulated,24 suggesting that locally produced, rather than systemic, angiotensin II mediates renal damage.20 Angiotensin II has been shown to directly modulate permeability independent of its effects on glomerular pressure and mesangial cell growth, which is an early marker of diabetic nephropathy.25 Although the newer ACE inhibitors and ARBs have been shown to be effective in blocking the tissue RAS,26 strong RAS inhibition is necessary to achieve effective blockade. An ACE inhibitor or ARB alone may result in incomplete blockade of the RAS when angiotensin II is activated by increased sympathetic nervous system activity such as heart failure or nephropathy.

A study of individuals with type 2 diabetes in Japan demonstrated that the antihypertensive effect of ACE inhibitor therapy was less potent than with a CCB.27 The mechanisms underlying the different levels of effectiveness of antihypertensive drugs in different populations are not well known, but several patient groups have been found to be less sensitive to drugs that block the RAS. These include patients who have low renin hypertension, salt sensitivity (which is a feature of diabetes), African American race, and old age. However, the clinical characteristics of hypertensive patients who are resistant to ARBs and ACE inhibitors are still unclear.

Change of Chymase. The resistance to ACE inhibitors in diabetes can be partly explained by the change of chymase.28 The clinical effectiveness of ACE inhibitors in lowering BP is limited because these agents do not block chymase-mediated AII formation. In diabetes mellitus, chymase is reported to be upregulated in the kidneys29 and can be induced by advanced end glycation products.30 Upregulation of chymase is associated with cardiac fibrosis in the chronic stage of hypertension, and with renal fibrosis. The role of these alterations of chymase in BP regulation in diabetic hypertension is not well understood; however, chymase is possibly associated with drug resistance to ACE inhibitors via an ACE independent pathway to produce AII,28 or with other mechanisms to induce target organ damage of the heart and kidneys described above. Resistance to therapy with ACE inhibitors alone and the effectiveness of dual blockade with the combination therapy of ACE inhibitors and ARBs in patients with diabetes could be explained by this mechanism. Although the ARB-ACE inhibitor combination is also effective in nondiabetic hypertensive subjects, there is no evidence that it works better in diabetic patients than in patients without diabetes. In addition, higher doses of ACE inhibitors or ARBs as monotherapy might be equally effective as the 2-drug combination.31

Pseudoresistance. Pickering originally proposed performing ambulatory BP monitoring for the evaluation of resistant hypertension to exclude unreliably high BP readings in the clinic.32 The rate of white coat hypertension in patients with diabetes has not been well investigated. Some reports indicate that patients with diabetes and white coat hypertension have more extensive target organ damage than do nondiabetic patients with white coat hypertension.33 Therefore, in patients with diabetes mellitus, even if white-coat hypertension or an exaggerated white coat effect is diagnosed, careful follow-up may be needed.

Subclinical Depression in Patients With Diabetes. In patients with diabetes mellitus, the prevalence of depression is reported to be twice as high as in nondiabetic subjects34 and is associated with a high prevalence of diabetic complications.35 Depressed patients engage in less physical exercise, are less likely to take lipid-lowering medications (despite a higher lipid profile), and are not compliant with prescribed medications.35 In a recent meta-analysis of the effects of depression on adherence to therapy, the odds ratio of noncompliance was 3 times greater in depressed than in nondepressed patients. These data suggest that diabetic patients who are depressed are also likely to be noncompliant to both pharmacologic and nonpharmacologic therapies. Lack of lifestyle modification could be another important cause of resistance to antihypertensive therapy.36

Secondary Hypertension. Resistance to antihypertensive medication could be a consequence of renovascular hypertension. Among elderly patients with hypertension, renal artery stenosis may often go undiagnosed. However, even if patients with renal artery stenosis are identified, the clinical significance of performing angioplasty or surgical repair is unclear, because renal parenchymal disease may already be irreversible. ACE inhibitors or ARBs are commonly used regardless of BP levels, and the rationale for avoiding the use of ACE inhibitors in renal artery stenosis may be weaker than previously reported.37 In an autopsy study, renal artery stenosis was more common in hypertensive patients with diabetes mellitus than in those without diabetes.38 Based on these data, renal artery stenosis that might cause renovascular hypertension is likely to be much more common in diabetics with resistant hypertension.

Hyperaldosteronism is one of the commonest causes of resistant hypertension in nondiabetic subjects and may be present in as many as 20% of cases.39 Because primary aldosteronism (PA) is strongly associated with diabetes mellitus and glucose intolerance,40 it is reasonable to think that PA is a significant cause of drug resistance in diabetic hypertension. However, none of 61 patients with hypertension and diabetes met the criteria of PA in 1 small study.41 Further study is needed to clarify the prevalence and significance of PA in patients with diabetes and hypertension.

Volume Overload. Volume overload is the commonest cause of resistant hypertension.36 Higher intake of dietary sodium has been shown to reduce the effectiveness of antihypertensive drugs42 such as RAS inhibitors,43–45 diuretics,46 and β-blockers,47 but not CCBs.48,49 In diabetic patients, hyperglycemia leads to a hyperosmotic state when hyperglycemia is severe enough to produce an osmotic diuresis.50 However, increased plasma volume and total-body exchangeable sodium are reported in diabetic subjects.50 Dry mouth and occult autonomic neuropathy may induce taste disturbances, which may result in increased salt intake in diabetics. Insulin resistance, accompanied by type 2 diabetes, also exert subtle sodium-reabsorbing effects on the kidney. Hypertension early in the course of diabetes and obesity are associated with increased cardiac output and relatively normal systemic vascular resistance.51 These volume and hemodynamic factors may be important causes of drug resistance in diabetics even in the early stage in diabetes without renal complications.

Sympathetic Nervous System. Diabetic patients with or without hypertension have central sympathetic hyperactivity, and the combination of hypertension and diabetes results in a greater sympathetic activity and higher level of plasma insulin than either condition alone.52 In contrast to reported antiadrenergic effects of RAS inhibitors in healthy volunteers53 or in patients with heart failure or renal failure, ARBs can cause sympathetic activation in humans.54 This could be one of the causes of drug resistance to ARBs in hypertension with diabetes mellitus.

Baroreflex sensitivity is impaired in diabetic patients.55 Ruiz and colleagues56 reported that diabetic neuropathy was closely related to the impairment of baroreflex sensitivity. Since diabetic neuropathy can exist in the early stage of diabetes mellitus, asymptomatic diabetic patients should be screened for its presence. In reports of essential hypertension, there is a nearly universal agreement that antihypertensive treatment resets baroreflex control of heart rate to a lower pressure level.57–60 However, results are unclear as to whether baroreflex control of sympathetic neural activity to the peripheral circulation also resets after antihypertensive drug therapy; it has been reported as being enhanced61 or unchanged.62 Fu and associates63 showed that muscle sympathetic nerve activity was increased by chronic antihypertensive treatment with losartan-hydrochlorothiazide, although both sympathetic and vagal baroreflex regulation evaluated with the Valsalva maneuver remained unchanged. The reason for inadequate BP control despite medical therapy can be partly explained by this augmented sympathetic activation and unchanged baroreflex control.63

Sleep Apnea. Sleep apnea syndrome is very common in obese individuals and is often suggested as a cause of drug resistance in hypertension.64 Sleep apnea can activate sympathetic nerve activity and cause hypertension.65 In obstructive sleep apnea, not only are circulating vasoconstrictors such as norepinephrine and endothelin elevated, but so are plasma angiotensin II and aldosterone levels elevated.66 Reichmuth and coworkers67 reported that diabetes mellitus is related to sleep apnea syndrome, based on their cross-sectional analysis of 1387 participants. Polysomnography was used to characterize sleep-disordered breathing. There was a greater prevalence of diabetes in subjects with sleep-disordered breathing: 14.7% of subjects with apnea-hypopnea index >15 versus 2.8%of subjects with an index <5. The odds ratio of having diabetes mellitus with an apnea-hypopnea index >15 versus <5 was 2.30 (95% confidence interval 1.28–4.11; P=.005) after adjustment for age, sex, and body habitus.

Conclusions

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References

Although both ACE inhibitors and ARBs are recommended to protect against the development of target organ damage, these drugs are less potent when used singly in diabetic subjects than in those without diabetes; hence multiple drug therapy is generally needed to reach target BP. Before adding other drugs, however, the physician should attempt to identify specific mechanisms of drug resistance in individual patients. By recognizing and treating these factors, clinicians will increase the likelihood that ACE inhibitors and ARBs will be more effective.

References

  1. Top of page
  2. Abstract
  3. Improving Outcome in Hypertensive Patients With Diabetes
  4. Trials of BP Reduction
  5. Trials of Specific Drugs
  6. Mechanisms of Resistance in Diabetes
  7. Conclusions
  8. References
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  • 56
    Ruiz J, Monbaron D, Parati G, et al. Diabetic neuropathy is a more important determinant of baroreflex sensitivity than carotid elasticity in type 2 diabetes. Hypertension. 2005;46:162167.
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