Metabolic effects of antihypertensive agents.Where IR=insulin resistance, and Total Chol, HDL-C, LDL-C, and TG are total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides, respectively. Unk=unknown. ACEI refers to angiotensin converting enzyme inhibitors, and ARBs refer to angiotensin receptor blockers. 1 Thiazide diuretics (especially chlorthalidone) are alternative first choice agents in nondiabetic patients but should be used carefully in patients with elevated BMI. In those instances where patients become diabetic after initiation of thiazides, an alternative antihypertensive class should be used. For details, see text.
Cardiovascular disease remains the leading cause of death in industrialized nations. Type 2 diabetes confers cardiovascular risk comparable to a previous myocardial infarction, and is the most common cause of chronic kidney disease. Diabetes and hypertension account for 2/3 of cardiovascular risk . Over 75% of adults with diabetes are hypertensive, or being treated with hypertensive medications  In patients with type 1 diabetes, the presence of hypertension signals significant kidney damage whereas in patients with type 2 diabetes, hypertension is usually present at the time of diagnosis . On the other hand, many hypertensive treatments, specifically diuretics, worsen glucose control; the overall implications of this are as yet unclear . Because of the singular risk resulting from the combination of diabetes and hypertension, significant effort has been expended to improve patient outcome. While several recent excellent reviews address different aspects of this issue [1-3], we will evaluate the management of hypertension in diabetes, particularly from the perspective of managing hypertension in metabolic syndrome. We will evaluate the metabolic effects of different agents used for blood pressure control, consider specific patient-related issues, discuss shortcomings of recent trials, and consider possible future directions in genetic analyses.
There are over 65 million hypertensives in the United States . Unfortunately, the pharmacological treatment of these individuals has had less than the predicted benefit on coronary heart disease (CHD) mortality -. For many years, It has been postulated that treatment with some antihypertensives might have metabolic and other untoward effects that negate some of the benefits of blood-pressure lowering , . This may be particularly true for individuals with the metabolic syndrome, a constellation of anthropometric and metabolic abnormalities that includes central obesity, hypertension, elevated levels of fasting glucose and triglycerides, low concentrations of high-density lipoprotein cholesterol (HDL-C), and insulin resistance which is associated with increased cardiovascular disease morbidity and mortality [9-11]. Of the five diagnostic criteria for metabolic syndrome, hypertension and central obesity are most frequently present [12, 13].
Why is this increasingly important in the US? The prevalence of obesity has doubled in the US in the past 20 years ; the number of extremely obese individuals with a BMI >35 kg/m2 is almost 5% of the population. Obese compared with normal weight individuals have a 3.5 fold increased risk of developing hypertension while up to 60% of obese individuals have hypertension [15, 16]. The association between obesity and hypertension may be related to greater insulin resistance, leptin-mediated enhancement of sympathetic activity, sodium and fluid retention, and adipocyte-mediated effects on angiotensin II and atrial natriuretic peptide levels . Patients with hypertension have an increased prevalence of type 2 diabetes mellitus and impaired glucose tolerance [18, 19]. Patients with mild hypertension also have lower HDL-cholesterol concentrations and higher HDL catabolic rates; these findings appear to correlate with insulin resistance . With hypertension, obesity and diabetes mellitus increasing in frequency, it is not surprising that the age-adjusted prevalence of metabolic syndrome in the general US population is 24.0% for men and 24.3% for women .
Lifestyle therapies for patients with metabolic syndrome, including weight reduction, increased physical activity, decreased sodium and alcohol reduction, reduced consumption of saturated and trans fats and cholesterol, and increased consumption of fresh fruits and vegetables are extremely important. Studies have shown that dietary changes can lower blood pressure and improve other metabolic syndrome components [22, 23]. Increased exercise can also lower blood pressure .
Despite the benefits of lifestyle changes, pharmacological treatment of hypertension is frequently needed. However, the choice of an antihypertensive is controversial. Studies suggest that treatment with different antihypertensive drug classes may have varied effects on glucose and lipid metabolism . Changes in insulin sensitivity are associated with adverse effects on glucose control [26, 27]. Increases in blood glucose during antihypertensive treatment have been found to be a predictor of myocardial infarction . Insulin resistance is also associated with endothelial dysfunction, which is also predictive of future cardiovascular events . Lind et al. have reported that these metabolic effects persist with long-term (> 2-3 years) antihypertensive treatment . In this context, it would be important to choose antihypertensives that have the least adverse metabolic effects, particularly in patients with the metabolic syndrome.
In addition, to the choice of antihypertensive agent, the degree of blood pressure lowering is important. The lower the goal, the greater the number of antihypertensive agents needed, the cost of these agents and the potential for side effects. Patient adherence declines with the number of medications required. It is important to balance these drawbacks with improvement in clinical outcomes.
2. Evidence for blood pressure goals
By some standards, the Action to Control Cardiovascular Risks in Diabetes Study (ACCORD) was a disappointment. ACCORD was a large well-designed trial that attempted to study the effects of tight control of blood sugar, hypertension, and lipids in patients with type 2 diabetes mellitus . In the original report, published in the
4,733 participants in ACCORD were randomly assigned to intensive blood pressure therapy, targeting a systolic pressure of <120 mm Hg or standard therapy targeting a systolic pressure of <140 mm Hg . Again, the primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. The annual rate of the primary outcome was 1.87% in the intensive therapy group and 2.09% in the standard therapy group (P=0.20). The annual death rates from any cause were 1.28% and 1.19% in the two groups, respectively (P=0.55). The annual stroke rate, a pre specified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2,362 participants in the intensive therapy group (3.3%) and 30 of the 2,371 participants in the standard therapy group (1.3%) (P <0.01). There were more subjects with a decrease of their estimated glomerular filtration rate to less than 30 ml per minute per 1.73 m2 of body surface area in the intensive therapy group than in the standard therapy group (99 versus 52 events, P <0.01).
The interpretation of the ACCORD blood pressure results is complicated by a number of factors. The event rate observed in the standard therapy group was almost 50% lower than expected. This result may have been a consequence of the frequent use of statins and inclusion criteria that directed participants with dyslipidemia into the ACCORD lipid trial, leaving participants who were at lower risk in the blood pressure trial. Additionally, ACCORD may have been under powered and of too short of duration to discern a benefit . In ACCORD the confidence intervals were wide and do not exclude a 27% benefit for the intensively treated group for the primary end point at 5 years. It is also possible that the effects of intensive blood pressure control in the setting of good lipid and glucuose control may differ for cerebrovascular and coronary events. That is, intensive blood pressure control is more likely to prevent strokes than myocardial infarctions. In a classic meta analysis, Collins and colleagues found that the decrease in stroke from antihypertensive therapy in clinical trials was what would be predicted based on epidemiologic studies . However the decrease in coronary artery disease (CAD) was about one-half of what would be predicted.
The ACCORD blood pressure study population was relatively healthy and thus unlikely to have a high proportion of events. The 5,000 patients pre study mean systolic blood pressure was 140 mm Hg of mercury. Their mean age was 62 years and nearly one-half were women. The mean serum creatinine of this group was 0.9 mg per deciliter and 87% were receiving antihypertensive medication at the time of enrollment. The average glycated hemoglobin level was 8.3% and the mean body mass index was 32 kg/m2. The mean urinary albumin/creatinine ratio was 14.3. Although these middle-aged patients were overweight and had type 2 diabetes, they had no substantial evidence of kidney disease and appeared to have good blood pressure control. At the 12 month visit, nearly 90% of patients were receiving a drug that blocks the renin angiotensin system, while more than 50% received β-blockers, about 40% received a calcium channel blocker, and nearly 60% received statins and platelet inhibitors. One might conclude that at 5 years, people with type 2 diabetes who have good quality cardiovascular care and no evidence of kidney disease do not have a major therapeutic advantage from lowering systolic blood pressure to <120 mm Hg. A longer follow-up time might be necessary to see a benefit of lowering blood pressure to this degree.
The negative outcome in ACCORD in the intensely treated blood pressure arm might also be attributed to the lack of effect on ischemic heart disease events that are included in the composite end point. In the intensive treatment arm, investigators were advised to begin a regimen of an ACE inhibitor or angiotensin receptor blocker (ARB) plus a thiazide-like diuretic, chlorthalidone . The same requirements were not given to the less intensively treated group. This resulted in the intensively treated group receiving roughly twice as much chlorthalidone as the less intensively treated group. That is, diuretics were used 83% and 89% of the time at 12 months and at the last visit, respectively, in the intensively treated group while in the standard care group, the usage was 52% and 56%. This amount of diuretic usage could account for the greater prevalence of hypokalemia seen in the intensive treatment group (P=.01) . Data from the Systolic Hypertension in the Elderly Program (SHEP Trial), suggest that this degree of hypokalemia would essentially eliminate the projected benefit on ischemic heart disease events from the blood pressure reduction achieved in ACCORD .
The United Kingdom Prospective Diabetes Study (UKPDS) was a randomized, prospective, multicenter trial that, in addition to its attention to glycemic control, randomized patients to a "tight" blood pressure control regimen including ACE inhibition (captopril) or β-blocker therapy (atenolol), or "less-tight" blood pressure control that excluded these agents . For tight compared to less-tight control of blood pressure, there were dramatic and significant improvements in risk reduction in any diabetes-related end point (24%), diabetes-related death (32%), stroke (44%), and microvascular disease (37%) . In UKPDS, the goal blood pressure for the tight group was <150/85, and for the less-tight, <180/105. The mean achieved blood pressures were 144/82 and 154/87 mm Hg for the tight and less-tight groups, respectively. Of note, the mean blood pressure, at entry, was 160/94.
The Steno-2 Study reported a post interventional benefit for micro- and macrovascular complications of diabetes that persisted after risk factor intervention, although within-trial differences in risk factors for these complications (e.g., blood pressure) diminished, suggesting a persistent effect of earlier improvement in risk factors—a so-called legacy effect . The diminishment in the difference of risk factors resulted from different phenomena: In the intensively-treated group, systolic blood pressure rose slightly in follow-up, while it remained stable in the conventionally-treated group. On the other hand, diastolic blood pressure remained low in the intensively-treated group, while it continued to fall in the conventional group. Recently, the survivor cohort of UKPDS was evaluated after a 10-year post-interventional follow-up that examined whether a continued benefit of improved blood pressure control could be demonstrated . In contrast to the Steno-2 Study, the benefits of previously-attained improved blood pressure control were not sustained when between-group differences were lost. There were no differences in blood pressure control in patients treated with captopril or atenolol. Again, in contrast to the Steno-2 findings, in both "tight" and "less-tight" groups, blood pressures actually improved in follow-up and were indistinguishable, in the mid-140's/high 70's range. Thus, it may be that it was the improved blood pressure control in the "less-tight" group, as opposed to treatment failure in the "tight" group that decreased treatment differences.
INVEST (INternational VErapamil-SR/Trandolapril STudy) studied patients with multiple risk factors . Of the 22576 participants (who were recruited because they had both coronary disease and hypertension), 6400 (28%) had diabetes. These patients were evaluated for the effects of achieved systolic blood pressure on the risk of cardiovascular events. Patients were categorized into three groups on this basis: tight (<130), usual (130-<140), and uncontrolled (≥140) mm Hg achieved systolic blood pressure. Tight control was not associated with improved cardiovascular outcome compared to usual control. Uncontrolled patients did worse. A similar post hoc analysis of INVEST compared participants with and without peripheral arterial disease (PAD) . 41.4% of PAD patients and 26.6% of those without PAD had diabetes (P<0.001). A J-shaped relationship was observed for patients with PAD: the hazard ratio for the primary outcome (all-cause death, nonfatal myocardial infarction, or nonfatal stroke), when plotted against achieved blood pressure, showed fewest events at blood pressures of 135-145/60-90); this was more pronounced for systolic blood pressure. Patients without PAD did not manifest this J-shaped association with systolic blood pressure. Patients with or without diabetes were not analyzed separately.
What lessons can be drawn about goal blood pressure for patients with metabolic syndrome from the studies cited above? It does not appear that the notion “the lower the better” applies to blood pressure in patients with type 2 diabetes, especially in those who are nonsmokers, have reasonable glycemic control and are taking statins and anti-platelet therapy. In ACCORD, lowering systolic blood pressure from the mid-130s to 120 mm Hg did not further reduce cardiovascular events, with the possible exception of stroke, which should be a pre-specified primary endpoint in future blood pressure clinical trials that aim for such low blood pressures. The price of lowering blood pressure to this degree in ACCORD was generally one additional antihypertensive and it was accompanied by a significantly higher rate of serious adverse events. Thus, it appears that lowering systolic blood pressure to 120 mm Hg is not warranted and recommendations to aim for a systolic blood pressure of <140 mm Hg and a diastolic blood pressure, based on the HOT and UKPDS results presented above, of <80 mm Hg are best supported by current evidence. However, it must be remembered that longer term follow-up of ACCORD may lead to different conclusions.
3. Effect of different classes of antihypertensive on components of the metabolic syndrome
Several studies have suggested an association between thiazide use and the development of glucose intolerance and diabetes. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the group randomized to chlorthalidone had a higher proportion of patients who developed diabetes than those randomized to either amlodipine or lisinopril . In the Systolic Hypertension in the Elderly Program (SHEP), there was not a statistically significant increased rate of diabetes comparing chlorthalidone with placebo after 3 years, but in a later 14.3 year follow-up, 13% of patients given chlorthalidone versus 8.7% of those given placebo ( P < 0.0001) developed diabetes [45, 46]. In a large study of hypertensive men and women, after adjustment for BMI, those taking compared with those not taking thiazide diuretics had an increased risk of developing diabetes . We studied 2624 patients who were initiated on thiazide diuretics . Increasing values of fasting blood glucose (FBG) were associated with increasing baseline BMI and there was a positive association between a new diagnosis of diabetes after thiazide initiation and increasing BMI that ranged from 2.7% in the first quartile of BMI to 6.5 % in the heaviest quartile. Studies have also found an association between blood glucose and thiazide dose [49, 50]. A review of nine studies using a relatively low dose (12.5 mg) of hydrochlorothiazide as monotherapy found that increases in glucose levels were nether clinically nor statistically different from baseline levels . Interestingly, in most of these studies, there was little relationship between blood pressure effects and diuretic dose. An association between hypokalemia and glucose intolerance, even in euglycemic subjects, has been described [48, 52, 53]. In patients on thiazides, hypokalemia has been associated with higher FBG that improved after replacement of potassium .
Thiazide diuretics may impair glucose metabolism by decreasing peripheral insulin sensitivity, resulting in increasing insulin secretion [55-57]. Our results suggest that the probability of developing new diabetes after thiazide initiation is associated with increasing BMI . This association is supported by our previous work (DS). In 139 patients randomized to 50 mg of hydrochlorothiazide for 2 months, there was an increasing change from baseline serum insulin levels as a consequence of increasing body mass index .
Diuretics may also affect lipid metabolism. In general, high dose diuretics have been reported to increase serum total cholesterol by about 4% and serum LDL-cholesterol by 10% . In ALLHAT, the group randomized to chlorthalidone had a higher total cholesterol levels at 2 years by about 3 mg/dL (~1.5%) than those randomized to either amlodipine or lisinopril (P<.001 for both); this difference diminished at 4 years for amlodipine, although not for lisinopril . In SHEP, there was a small but significant increase of total cholesterol (P<.01) and decrease of HDL-cholesterol (P<.01) comparing chlorthalidone to placebo after 3 years. In another study, there was a 10% increase (P<.05) in fasting triglycerides from baseline after 16 weeks of treatment with hydrochlorothiazide compared with those treated with valsartan . In a cross-sectional study from Brazil, hypertensive patients treated with diuretic monotherapy had a more atherogenic lipid profile (increased total- and LDL-cholesterol and apolipoprotein B) than patients on combined diuretic-based medication regimes, suggesting that the nondiuretic therapy had a mitigating effect on the lipid profile . The mechanism of diuretic induced dyslipidemia may be related to increased hepatic production, in part mediated by a reduction in insulin sensitivity .
The impact of the ALLHAT findings on clinical recommendations is controversial . On the one hand, are the metabolic abnormalities associated with chlorthalidone noted above. On the other hand, is the fact that those patients randomized to chlorthalidone had virtually identical clinical outcomes compared with lisinopril and amlodipine in terms of the primary outcome: the occurrence of coronary heart disease and nonfatal myocardial infarction. For secondary outcomes, chlorthalidone was superior to amlodipine in preventing heart failure, and compared with lisinopril, chlorthalidone was superior as a means to lower blood pressure and prevent stroke, as well as to prevent combined cardiovascular disease and perhaps heart failure. At present, we believe that thiazide diuretics (especially chlorthalidone) are alternative first choice agents in nondiabetic patients with metabolic syndrome but should be used carefully in patients with elevated BMI. In those instances where patients become diabetic after initiation of thiazides, we recommend that an alternative antihypertensive class be used rather than treat the metabolic consequences of thiazides with diabetic medications. In diabetics, thiazides diuretics may also be used. However, in those instances where initiation of these agents results in a worsening of glucose control, again, we would recommend the use of alternative agents.
The place of β-blockers in the treatment of hypertension is controversial. This is partly based on the finding that these agents are less effective in reducing the incidence of stroke [60, 61], myocardial infarction and death than are other antihypertensives [61, 62]. These findings are complicated by the diversity of β-blockers that have varying pharmacological properties. The mechanisms of action and pathophysiological effects vary widely among the nonselective, selective, and vasodilating β-blockers. Added to this variation are the effects of agents such as carvedilol that have both non-selective β-blocker and α1-blocking properties.
In several studies of non-selective  or β1 selective [64-66] β-blockers, there was a significant decrease in insulin sensitivity in hypertensive patients. This decrease in insulin sensitivity may have a deleterious effect on glycemic control in patients with hypertension or in those with type 2 diabetes mellitus. In patients with the metabolic syndrome, decreases in insulin sensitivity may be initially compensated for by increases in insulin secretion by pancreatic β-cells. However, after a period of time, the β-cells are no longer able to keep up with the increasing insulin demands and increase in blood glucose, and potentially overt diabetes, may result.
In the Atherosclerosis Risk in Communities Study (ARIC), hypertensives treated with β-blockers had a 28% increased risk of developing type 2 diabetes compared with patients taking no medication . In INVEST, hypertensives randomized to verapamil-based therapy had a 15% lower incidence of new onset diabetes than subjects in the atenolol group . Other studies have found similar results comparing β-blockers to either the angiotensin-converting enzyme (ACE) inhibitors  or angiotensin receptor blockers (ARBs) .
Several actions of β-blockers may affect insulin sensitivity and glycemic control. β-blockers block pancreatic β2 receptors resulting in an inhibition of insulin secretion that results in an impairment of glucose metabolism leading to hyperglycemia . This effect is more pronounced with nonselective β-blockers, but can also be seen with higher doses of selective β-blockers . β-blockers have been associated with weight gain leading to the metabolic syndrome due to the weight gain itself as well as through obesity mediated impairment of insulin sensitivity [72, 73]. Insulin promotes vasodilatation resulting in increased blood flow in skeletal muscles . During treatment with nonselective β-blockers, unopposed α1-activity causes vasoconstriction leading to decreased blood flow to muscles . This may result in decreased insulin-stimulated glucose uptake and insulin resistance. In insulin-resistant states such as type 2 diabetes and obesity, endothelium-dependent insulin-mediated vasodilatation is impaired which may also lead to insulin resistance [74, 76]. In the metabolic syndrome, the interaction of obesity and hyperglycemia with β-blockers may lead to more severe skeletal vasoconstriction resulting in worsening insulin resistance.
Newer β-blockers that cause vasodilatation appear to not have the deleterious effects on insulin sensitivity and glucose metabolism described above. Carvedilol, as noted above, a non-selective β-blocker with α1-blocking properties has been found to improve insulin sensitivity. In 72 hypertensive patients without diabetes, carvedilol compared with metoprolol resulted in a 14% increase in insulin sensitivity while metoprolol led to a decrease . A study comparing carvedilol with atenolol had similar results . In two trials comparing carvedilol with metoprolol, the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial and the Carvedilol or Metoprolol European Trial (COMET), the carvedilol group had decreases in both insulin resistance and HbA1c while the metoprolol group had an increase in HbA1c and no change from baseline in insulin resistance (GEMINI) , and improved rates of survival and cardiovascular hospitalizations (COMET). In GEMINI, although blood pressure was similar between groups, progression to microalbuminuria was less frequent with carvedilol than with metoprolol. This may reflect an antioxidant effect specific to carvedilol . Findings from GEMINI also suggest that the use of vasodilating β-blockers may not result in weight gain . In addition to carvedilol, vasodilating β-blockers available in the US are labetalol and nebivolol.
The effects of β-blockers on lipid metabolism are modest, but also vary according to β-blocker type. Nonselective β-blockers increase serum triglycerides and tend to lower HDL-cholesterol, while cardioselective β1-blockers and β-blockers without intrinsic sympathomimetic activity have qualitatively similar but less pronounced effects. These effects may be, at least in part, mediated by weight gain. In the Losartan Intervention for Endpoint (LIFE) reduction study, HDL- cholesterol decreased more and remained lower during the first 2 years of the study in those treated with the β1-selective blocker atenolol compared with those randomized to losartan . In a study comparing atenolol with metoprolol, treatment increased serum triglycerides by 21% and 29%, respectively, compared with placebo, and decreased HDL-cholesterol by about 7% . In a recent study comparing the effects of carvedilol and metoprolol on serum lipids in diabetic hypertensive patients, both drugs decreased HDL-cholesterol and increased triglycerides . Comparing the two drugs, there was no difference in HDL-cholesterol levels but carvedilol resulted in statistically significant lower levels of total cholesterol, triglycerides and non-HDL cholesterol.
Based on the above, it appears logical in patients with the metabolic syndrome, who require a β-blocker, to treat them with one of the newer vasodilating agents that have neutral or beneficial metabolic effects. That said, at present, there are few studies that directly compare the different types of β-blockers on hard clinical outcomes, especially total mortality. Adding to this uncertainty is the fact that newer β-blockers are far more expensive than older agents such as atenolol and metoprolol.
ACE inhibitors and angiotensin receptor blockers
Over20 years ago, the ACE inhibitor captopril was shown to benefit glucose metabolism and insulin resistance, particularly in comparison to thiazides . ACE inhibitors and ARBs may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin II. Angiotensin II activates the sympathetic nervous system resulting in impairment of insulin secretion and peripheral glucose uptake . Angiotensin II also impairs pancreatic blood flow and enhances insulin resistance, while ACE inhibitors directly improve insulin sensitivity primarily in skeletal muscle .
The magnitude of the beneficial effect of ACE inhibitors on glucose metabolism is demonstrated by clinical trials such as the HOPE (Heart Outcomes Prevention Evaluation) Study, which demonstrated a reduced rate of new onset diabetes mellitus in patients taking the ACE inhibitor ramipril . Angiotensin II has a central role in glucose metabolism, in addition to its effect on the sympathetic nervous system and aldosterone release, that includes activation of insulin-stimulated mitogenic pathways that promote vascular smooth muscle proliferation (MAPK), but suppression of pathways involved in glucose transport (PI-3K) [87-91]. Nitric oxide synthase may play a key role in mediating angiotensin effects , as might oxidative stress [93, 94]. In an animal model of atherosclerosis, (the Watanabe Heritable Hyperlipidemic Rabbit), the combination of the aldosterone antagonist eplerenone with the ACE inhibitor enalapril led to additive protective effects on endothelial function and atherosclerotic changes . In patients with documented atherosclerosis, ramipril lowered highly sensitive C-reactive protein . This “crosstalk” between vascular growth and metabolic pathways may explain many of the defects in the metabolic syndrome. In patients with cardiac allograft vasculopathy, ACE inhibitors appear to be associated with plaque reduction .
While many of the studies reviewed above have grouped ACE inhibitors and ARBs together as generally having similar mechanisms of action, there are differences both among ACE inhibitors and between ACE inhibitors and ARBs. The ACE inhibitors enalapril and perindopril were compared in normotensive patients with coronary artery disease; neither agent lowered blood pressure, but perindopril was superior in terms of anti-oxidant, antithrombotic, and profibrinolytic activities . In mild hypertensive patients, zofenopril (a sulfhydryl-containing ACE inhibitor) lowered LDL-cholesterol, oxidized LDL, peroxide, and increased flow-mediated dilation (a marker of endothelial function) compared to ramipril (a carboxylic-containing ACE inhibitor), and atenolol. Blood pressure was comparable in all three groups .
ARBs do not appear to be active on these pathways. Furthermore, there may be differences among ARBs. Telmisartan, for example, seems to activate insulin-sensitizing PPAR-γ pathways , with benefit in preclinical and clinical studies [101, 102]. Studies in nondiabetic hypertensive patients shown improvement in insulin sensitivity, measured by the homeostasis model assessment (HOMA) technique, when telmisartan was used alone; this effect was blunted when the drug was used in combination with the dihydropyridine calcium channel blocker nisoldipine . This benefit occurred without changes in serum values of the adipose tissue-derived cytokine, adiponectin. Similar results on insulin sensitivity, also assessed by HOMA, were reported in a study of hypertensive type 2 diabetic patients . Other investigators have found that telmisartan is associated with decreased vascular inflammation, reduced visceral fat, and increased adiponectin , while others have reported that telmisartan, compared to candesartan lowered fasting plasma glucose and body weight, and increased adiponectin. Diastolic blood pressure was comparably reduced in both treatment groups compared to control . Losartan, another ARB, has an uricosuric effect that may be of benefit in cardiovascular risk .
A recent development in this treatment approach includes renin inhibitors, that improve blood pressure but have not been studied for their metabolic effects [108, 109], although recent data suggests an improvement (reduction) in atherosclerosis progression with aliskerin .
Calcium Channel Blockers
Calcium channel blockers (CCBs) may impair insulin release, but this effect on glucose metabolism appears to be balanced by their action to increase peripheral glucose uptake [110, 111]. CCBs have been shown to have no significant adverse metabolic effect [112, 113], or a slight negative effect . Some short-term studies have even suggested a slight positive effect on glucose and insulin metabolism . In one study, long-acting CCBs have been reported to have no significant metabolic effect , while an early study comparing short-acting nifedipine to atenolol showed improvement in postprandial glucose (suggesting improved insulin action since concurrent insulin concentrations were unaffected) and triglyceride values, as well increased HDL values, with the former agent .
Dihydropyridine CCBs (i.e., nifedipine) have no antiproteinuric effect, unlike the benzothiazepine diltiazem and the phenylalkylamine verapamil, and do not slow the progression of diabetic nephropathy . This may have particular relevance in these high-risk patients. In a study of 12 550 nondiabetic hypertensives, subjects taking β -blockers, but not those taking thiazides, ACE inhibitors or calcium channel blockers, were at increased risk of developing diabetes . In a study of 16176 coronary patients with hypertension, CCB-based therapy (verapamil SR) was less likely to result in the development of newly diagnosed diabetes mellitus than β-blocker (atenolol) based treatment . In this study, addition of the ACE inhibitor trandolapril to verapamil SR decreased diabetes mellitus risk and the addition of hydrochlorothiazide to atenolol increased risk. In hypertensive patients with chronic kidney disease (stage not defined, but baseline creatinine ~1.6), treated with either telmisartan or amlodipine, creatinine, proteinuria, IL-6, MMP-9, and total cholesterol all declined, while 24 hour urinary creatinine clearance improved with telmisartan but not with amlodipine, despite comparable blood pressure reduction . In another trial, treatment with the ARB valsartan was associated with a greater reduction in new onset diabetes compared with amlodipine .
CCBs appear to have systemic antiinflammatory effects that may be additive with other antihypertensive agents [119-121]; there may also be improvement (reduction) in oxidized LDL-cholesterol levels .
Prazosin, using fasting and postprandial glucose and insulin data, has been found to improve insulin sensitivity in patients with essential hypertension . Pollare, et al. similarly reported that prazosin directly improved insulin sensitivity . Prazosin has also been reported to improve HDL kinetics . Terazosin appears to have no effect on glucose tolerance or insulin sensitivity , although men with benign prostatic hypertrophy treated with terazosin have improved lipid values . No data is available for tamsulosin.
Doxazosin improved glucose and lipid metabolism in diabetic patients and in patients with impaired glucose tolerance [128, 129]. It has also been reported to improve insulin resistance, and increase LDL particle size [130, 131]. Doxazosin has also been described as acting synergistically with acarbose in patients with impaired glucose tolerance . When doxazosin was added to existing therapies in patients with inadequately treated hypertension and impaired glucose metabolism, blood pressure control was improved in over 1/3 of cases, with concomitant improvement in glucose and lipid parameters and a reduction in atherosclerotic cardiovascular disease risk . Similar metabolic benefit occurred when doxazosin was compared to bendrofluazide in hypertensive patients , and when doxazosin was compared to atenolol . Doxazosin also reduced serum concentrations of oxidized LDL-cholesterol (a more atherogenic lipid fraction) in hypertensives . Urapidil has no major effect on glucose metabolism, but favorably affects another cardiovascular risk marker, fibrinogen .
Clonidine, which acts by binding to central α-2-adrenergic and imidazoline receptors, appears to be metabolically neutral in terms of glucose and insulin effects ; more recently developed imidazoline agonists have not been widely studied from this perspective . However, rilmenidine has recently been reported to have similar blood pressure, lipid, and glucose effects to lisinopril in hypertensive women with metabolic syndrome .
The metabolic effects of antihypertensives are summarized in the Table.
|Class of agent||Glucose and insulin effects||Lipid effects|
|Thiazide (inc. chlorthalidone)1||↑||↑||↑||↓||↑||↑|
|Cardioselective β-blockers (β1)||↑||↑||↓||↑|
|Calcium channel blockers||↓||↓||↓||↑||↓||↓|
|Central α-agonists (e.g., clonidine)||neutral||neutral||neutral||neutral||neutral||neutral|
Current treatment recommendations for blood pressure control in patients with diabetes are based on these considerations of balancing metabolic, blood pressure, renal, neurologic (dizziness) and electrolyte effects. Initial treatment should include RAS blockers (either ACE inhibitors or ARBs), followed with a calcium channel blocker or thiazide-like diuretic as 2nd line. Current data suggests that the deleterious metabolic effects that may result do not override the benefit of blood pressure reduction , although the recent ACCOMPLISH study (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension) pointed out that combining the ACE inhibitor benazepril with amlodipine, compared to benazepril with hydrochlorothiazide, resulted in benefit in terms of reduction in cardiovascular events such as acute clinical events and revascularizations; blood pressure was comparable between the two groups .
Lifestyle changes (weight loss, exercise, reduction of alcohol intake, smoking cessation,) should not be ignored. Glucose control, while laudable conceptually, may be problematic (see elsewhere). Potassium monitoring should continue, and potassium-containing foods and use of nonsteroidal antiinflammatories may need to be limited . Combination agents, where available, might improve adherence . α–blockers, while powerful in terms of blood pressure and prostate effects, may contribute to orthostatic dizziness and may need to be limited or avoided . We should not forget that microalbuminuria is a marker of early diabetic nephropathy as well as a risk factor for microvascular and macrovascular cardiovascular disease  and should be monitored, with efforts expended to mitigate it. These overall recommendations are summarized in current American Diabetes Association (ADA) guidelines . The Figure represents a treatment strategy derived from ADA (143) and other (2) guidelines.
4. Genetic markers and treatment of hypertension in patients with the metabolic syndrome
As noted above, treatment of hypertension in the metabolic syndrome can exacerbate other of its components (e.g., glucose and lipid control). Further, hypertensive treatment in diabetics, may have less than the expected benefit in terms of preventing coronary disease and mortality. Is it possible that evolving genetic markers can help guide therapy more precisely?
The INVEST study observed that patients with more severe vascular disease, particularly those of Hispanic ethnicity, were at greater risk for developing diabetes, especially with hydrochlorothiazide treatment. This risk was attenuated by more aggressive BP control and use of a verapamil-trandolapril combination . There is developing data that suggests that the CYP3A5 genotype, which does not appear to contribute importantly to the risk of hypertension, may influence response to calcium channel blockers . Similarly, the KCNMB1 genotype (which contributes to polymorphisms in the large-conductance calcium and voltage-dependent potassium channel β1 subunit) may influence response to verapamil and potentially adverse outcomes .
Other data from Beitelshees and colleagues suggests that polymorphisms in the CACNA1C gene may help identify groups that benefit most from calcium channel blocker therapy, a group that benefits from β-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent . Similar analyses leading to possible future predictions are available for β-blocker treatment outcomes based on β-adrenergic receptor gene polymorphisms , and promoter polymorphisms in angiotensin-converting enzyme . This last group of analyses may explain the variation between populations in cardiovascular risk and treatment outcomes, since certain alleles are more frequent in African-Americans than in either Hispanics or Caucasians . Adducin is a ubiquitously expressed cytoskeleton protein that is coded by ADD1. Polymorphisms in this gene may lead to increased renal tubular sodium reabsorption and hypertension; certain alleles have been shown to manifest an excess risk for a cardiovascular event or death, particularly in African-Americans .
The prevalence of obesity, hypertension and type 2 diabetes mellitus, and, as a consequence, the metabolic syndrome, is increasing in the US. In this setting, it is important to individualize antihypertensive therapy and to monitor its metabolic consequences so that potential adverse effects that would negate some of the benefits of blood-pressure lowering are minimized. Strategies to improve blood pressure control in patients with metabolic syndrome, including decisions concerning the best pharmacological treatment for these patients, will have major morbidity and mortality consequences. The predominance of evidence favors a strategy to lower blood pressure to a level approaching the criteria for this syndrome (<130/80) [151, 152]. However, a goal blood pressure of <130/80 is not supported by current evidence. In hypertensives whose blood pressure is more than 20/10 above target, this frequently will require the initiation of a combination of antihypertensives .
Treatment with different antihypertensive drug classes has varied effects on glucose and lipid metabolism. Thiazide use in hypertensives has been associated with the development of glucose intolerance and diabetes. Studies suggest that the probability of worsening glucose metabolism and the development of new diabetes after thiazide initiation is associated with increasing body mass index. Thiazide use also results in small increases in total and LDL-cholesterol and triglycerides and decreases in HDL-cholesterol. These changes are more pronounced with high dose thiazides.
Non-selective or β1 selective β-blockers may also lead to decreased insulin sensitivity in hypertensive patients. On the other hand, β-blockers, such as carvedilol, that cause vasodilatation may not have these deleterious effects on insulin sensitivity and glucose metabolism. The effects of β-blockers on lipid metabolism may also vary according to β-blocker type. Nonselective β-blockers modestly increase serum triglycerides and tend to lower HDL-cholesterol, while cardioselective β1-blockers and those without intrinsic sympathomimetic activity have qualitatively similar but less pronounced effects. Vasodilating β-blockers appear to have even smaller deleterious effects on lipids.
ACE inhibitors and ARBs may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin II. These agents may be particularly useful in patients with microalbuminuria to slow the progression of renal disease. While there may be some small differences among different classes of CCBs, there is little net effect of these agents on glucose or lipid metabolism. The α-antagonists generally appear to improve glucose and lipid metabolism in diabetic and non-diabetic patients but the increase in cardiovascular endpoints in the ALLHAT study with doxazosin suggests that until there is evidence to the contrary, this class of antihypertensive should not be used as first line agents.
The choice of an antihypertensive also has important implications for the cost of medical care. Thiazide diuretics and β-blockers are considerably less expensive than most other antihypertensive medications and have been shown to be effective antihypertensive treatment in several major studies [6, 7, 44]. However, some of the medication cost savings would be negated if thiazide and β-blocker use is complicated by an increased probability of developing glucose intolerance and even diabetes with its attendant medication and other costs associated with its treatment and manifestations. Most of the studies we have reviewed have focused on one agent in comparison to another; there is scant data on net metabolic effects of combining drug classes. Furthermore, individual patient responses may vary from the expected.
The coexistence of hypertension, dyslipidemia and glucose intolerance increases the risk of coronary artery disease, stroke, peripheral vascular disease, nephropathy, neuropathy and retinopathy [154-156]. The metabolic syndrome is associated with cardiovascular disease and the development of diabetes [157-159]. In treated hypertensive patients, occurrence of new diabetes portends a risk for subsequent cardiovascular disease that is similar to that of other diabetics . The use of an antihypertensive that results in improvements in dyslipidemia, insulin sensitivity and glucose metabolism would be a logical choice in patients with metabolic syndrome, but this recommendation needs to be supported with clinical trials with hard clinical outcomes, especially total mortality.
National Kidney Foundation consensus conference on cardiovascular and kidney diseases and diabetes risk: an integrated therapeutic approach to reduce events. Kidney Int. Bakris G. Vassalotti J. Ritz E. Wanner C. Stergiou G. Molitch M. Nesto R. Kaysen G. A. Sowers J. R. Consensus C. K. D. Working Group. 2010 78 726 36
Treatment of hypertension in patients with diabetes--an update. J Am Soc Hypertens. Bakris G. L. Sowers J. R. Glies T. D. Black H. R. Izzo J. L. Jr Materson B. J. Oparil S. MA Weber 2010 4 62 7
Bakris GL, Sowers JR; American Society of Hypertension Writing Group.ASH position paper: treatment of hypertension in patients with diabetes-an update. J Clin Hypertens (Greenwich). 2008 10 707 13discussion 714-5.
Ong KL, Cheung BMY, ManYB, Lau CP, Lam KSL. Prevalence, awareness, treatment and control of hypertension among United States adults 1999-2004. 2007 49 69 75
Collins R. Peto R. Mac Mahon. S. Hebert P. Fiebach N. H. Eberlein K. A. et al. Blood pressure. stroke coronary heart. disease part. . short-term reductions. in blood. pressure overview. of randomised. drug trials. in their. epidemiological context. 1990 335 827 838
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee: The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. 2003 42 1206 1252
Blood pressure lowering treatment trialists’ collaboration.Effects of different blood-pressure-lowering regiments on major cardiovascular events: results of prospectively-designed overviews of randomised trials. 2003
Siegel D. Hulley S. B. Black D. M. MD Cheitlin Sebastian. A. Seeley D. G. Hearst N. Fine R. Diuretics serum. intracellular electrolyte. levels ventricular arrhythmias. in hypertensive. men J. A. M. 1992 267 1083 1089
Malik C. Wong N. D. Franklin S. S. Kamath T. V. L’Italien G. J. Pio J. R. et al. Impact of. the metabolic. syndrome on. mortality from. coronary heart. disease cardiovascular. disease all causes. in United. States adults. 2004 110 1245 50
Hypertension and the cardiometabolic syndrome. (Greenwich) Manrique C. Lastra G. Whaley-Connell A. Sowers J. R. 2005 7 471 6
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. American Heart Association; National Heart, Lung, and Blood Institute.Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. 2005 112 2735 2752
Hypertension is the most common component of metabolic syndrome and the greatest contributor to carotid arteriosclerosis in apparently healthy Japanese individuals Ishizaka N. Ishizaka Y. Toda E. Hashimoto H. Nagai R. Yamakado M. 2005 28 27 34
Prevalence of Metabolic Syndrome According to Adult Treatment Panel III and International Diabetes Federation Criteria: A Population-Based Study. Bener A. Sirie M. Musallam M. Khader Y. Al-Hamaq A. 2008 7 221 228
Flegal KM, Carroll MD, Ogden CL, Johnson CL.Prevalence and trends in obesity among US adults, 1999-2000. 2002 288 1723 1727
The disease burden associated with overweight and obesity. Must A. Spadano J. Coakley E. H. Field A. E. Coldz G. Dietz W. 1999 282 1523 1529
Mokdad A. H. Ford E. S. BA Bowman Vinicor. F. Giles W. H. Prevalence of. obesity diabetes. obesity-related health. risk factors. 20012003; 289 76 79
New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Sharma A. M. Engeli S. Pischon T. 2001 3 152 156
Glucose and insulin levels during diuretic therapy in hypertensive men and their association with serum and intracellular potassium and magnesium. Siegel D. Saliba P. Haffner S. 1994part 1]: 688 694
Sowers JR, Bakris GL.Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial]. 2000 342 969 970
Chen YD, Sheu WH, Swislocki AL, Reaven GM.High density lipoprotein turnover in patients with hypertension. 1991 17 386 93
Ford ES, Giles WH, Dietz WH.Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. 2002 287 356 359
DASH collaborative Research Group. Appel L. J. Moore T. J. Obarzanek E. Vollmer W. M. Svetkey L. P. Sacks F. M. et al. A. clinical trial. of the. effects of. dietary patterns. on blood. pressure D. A. S. 1997 336 1117 1124
Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome. Azadbakht L. Mirmiran P. Esmailzadeh A. Azizi T. Azizi F. 2005 28 2823 2831
Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trial. Whelton S. P. Chin A. Exin X. He J. 2002 136 493 503
Antihypertensive therapy and incidence of type 2 diabetes: a systematic review. Padwal R. Laupacis A. 2004 27 247 255
Hypertension and associated metabolic abnormalities-the role of insulin resistance and the sympathoadrenal system. Reaven G. M. Lithell H. Landsberg L. 1996 334 374 381
Swislocki AL, Hoffman BB, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. 1989 2 419 423
Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study. Dunder K. Lind L. Zethelius B. Berglund L. Lithell H. 2003 681 EOF 683 EOF
Hsueh WA, Lyon CJ, Quinones MJ.Insulin resistance and the endothelium. 2004 117 109 117
Long-term metabolic effects of antihypertensive drugs. Lind L. Pollare T. Berne C. Lithell H. 1994 128 1177 1183
Action to Control Cardiovascular Risk in Diabetes Study Group.Effects of intensive glucose lowering in type 2 diabetes. 2008 358 2545 59
ACCORD Study Group.Effects of combination lipid therapy in type 2 diabetes mellitus. 2010 362 1563 74
Metab Syndr Relat Disord. Siegel D. Swislocki A. L. The A. C. C. O. R. D. Study The. Devil is. in the. Details 2010Dec 18. [Epub ahead of print]
ACCORD Study Group.Effects of intensive blood-pressure control in type 2 diabetes mellitus. 2010 362 1575 85
Bloch MJ, Basile JN.Is there accord in ACCORD? Lower blood pressure targets in type 2 diabetes does not lead to fewer cardiovascular events except for reductions in stroke. 2010 12 472 7
Giles TD, Houston MC.Do diuretics diminish the predicted benefits on ischemic heart disease events of lowering blood pressure in hypertension? Messages from ALLHAT, ACCOMPLISH, and ACCORD. 2010 12 469 71
Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Franse L. V. Pahor M. Di Bari M. Somes G. W. Cushman W. C. Applegate W. B. 2000 35 1025 30
UK Prospective Diabetes Study (UKPDS).VIII. Study design, progress and performance. 1991 34 877 90
UKPDS: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. UK Prospective Diabetes Study Group. 1998 317 703 13
Gaede P. Lund-Andersen H. Parving H. H. Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes 2008 358 580 91
Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR.Long-term follow-up after tight control of blood pressure in type 2 diabetes. 2008 359 1565 76
Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. Cooper De Hoff. R. M. Gong Y. Handberg E. M. AA Bavry Denardo. S. J. Bakris G. L. Pepine C. J. 2010 304 61 8
Outcomes among hypertensive patients with concomitant peripheral and coronary artery disease. Findings from the INternational Verapamil-SR/Trandolapril STudy. AA Bavry Anderson. R. D. Gong Y. Denardo S. J. Cooper De Hoff. R. M. Handberg E. M. Pepine C. J. 2010 55 48 53
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic; the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). 2002 88 2981 2997
Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program.SHEP Cooperative Research Group. 1998 158 741 751
Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR; SHEP Collaborative Research Group.Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. 2005 95 29 35
Taylor EN, Hu FB, Curhan GC. Antihypertensive medications and the risk of incident type 2 diabetes. 2006 29 1065 1070
Siegel D. Meier J. Maas C. Lopez J. Swislocki A. L. M. The effect. of body. mass index. on fasting. blood glucose. after initiation. of thiazide. therapy in. hypertensive patients. 2008 21 438 42
Antihypertensive and biochemical effects of chlorthalidone. Tweeddale M. G. Ogilvie R. I. Ruedy J. 1977 22 519 527
Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Carlsen J. E. Kober L. Torp-Pedersen C. Johansen P. 1990 300 975 978
Neutel JM.Metabolic manifestations of low-dose diuretics. 1996 71S EOF 82S EOF
Conn JW. Hypertension, the potassium ion and impaired carbohydrate tolerance. 1965 273 1135 1143
Rowe JW, Tobin JD, Rosa RM, Andres R..Effect of experimental potassium deficiency on glucose and insulin metabolism. 1980 29 498 502
Rapoport MI, Hurd HF.Thiazide-induced glucose intolerance treated with potassium. 1964 113 405 408
Pollare T. Lithell H. Berne C. A. comparison of. the effects. of hydrochlorothiazide. captopril on. glucose lipid metabolism. in patients. with hypertension. 1989 321 868 873
Comparison of the hemodynamic and metabolic effects of low dose hydrochlorothiazide and lisinopril treatment in obese patients with high blood pressure. Reaven G. M. Clinkingbeard C. Jeppesen J. Maheux P. Pei D. Foote J. et al. 1995 8 461 466
Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Bramlage P. Pittrow D. Wittchen H. U. Kirch W. Boehler S. Lehnert H. et al. 2004 17 904 910
Zappe DH, Sowers JR, Hsueh WA, Haffner SM, Deedwania PC, Fonseca VA, et al.Metabolic and Antihypertensive Effects of Combined Angiotensin Receptor Blocker and Diuretic Therapy in Prediabetic Hypertensive Patients with the Cardiometabolic Syndrome. (Greenwich) 2008 10 894 902
Antihypertensive treatment and its implications on lipoprotein metabolism of patients in care by a hypertension and diabetes program in Brazil. . Martins R. D. Alves Rde. S. Silva G. G. Martins N. Vasconcelos S. Assreuy A. et al. 2008 21 6 567 574
Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lindholm L. H. Carlbert B. Samuelsson O. 2005 366 1545 1553
Bradley HA, Wiysonge CS, Volmink JA, Mayosi BM, Opie LH.How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. 2006 24 2131 2141
Re-examining the efficacy of beta-blockers for the treatment of hypertension: A meta-analysis Khan N. Mc Alister F. A. 2006 174 1737 1742
Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients. Lithell H. Pollare T. Vessby B. 1992 1 92 101
Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. Pollare T. Lithell H. Mörlin C. Präntare H. Hvarfner A. Ljunghall S. 1989 7 551 559
Sensitivity to insulin during treatment with atenolol and metoprolol: a randomized, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Pollare T. Lithell H. O. Selinus I. Brnce C. 1989 298 1152 1157
Comparison of the effects of atenolol and nifedipine on glucose, insulin, and lipid metabolism in patients with hypertension. Sheu W. H. H. Swislocki A. L. Hoffman B. Chen Y. D. I. Reaven G. M. 1991 4 199 205
Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities study. Gress T. W. Nieto F. J. Shahar E. Wooford M. R. Brancati F. L. 2000 342 905 912
Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (Findings from the International VErapamil SR-Trandolapril Study [INVEST]). Cooper-Dehoff R. JD Cohen Bakris. G. L. Messerli F. H. Erdine S. Hewkin A. C. et al. I. N. V. E. S. T. Investigators 2006 98 890 894
Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Hansson L. Lindholm L. H. Niskanen L. Lanke J. Hedner T. Niklason A. et al. 1999 353 611 616
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Dahlöf B. Devereux R. B. Kjeldsen S. E. Julius S. Beevers G. de Faire U. et al. Study L. I. F. E. Group 2002 359 995 1003
Effects of beta-blocking agents on insulin secretion and glucose disposal. Wicklmayr M. Rett K. Dietze G. Mehnert H. 1990 22 29 33
UK Prospective Diabetes Study Group.Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. 1998 317 713 720
Long term propranolol treatment and changes in body weight after myocardial infarction. Rossner S. Taylor C. L. Byington R. P. Furberg C. D. 1990 300 902 903
Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. 2002 45 623 634
Lithell H. Pollare T. Berne C. Saltin B. The metabolic and circulatory response to beta-blockade in hypertensive men is correlated to muscle capillary density. 1992 1 20 26
Sartori C. Scherrer U. Insulin nitric. oxide the sympathetic. nervous system. at the. crossroads of. metabolic cardiovascular regulation. 1999 17 1517 1525
Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. Jacob S. Rett K. Wicklmayr M. Agrawal B. Augustin H. J. Dietze G. J. 1996 14 489 494
Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension: a randomized, controlled trial. Giugliano D. Acampora R. Marfella R. De Rosa N. Ziccardi P. Ragone R. et al. 1997 126 955 959
Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension, a randomized controlled trial. Bakris G. L. Fonseca V. Atholi R. E. Mc Gill J. B. Messerli F. H. Phillips R. A. et al. 2004 292 2227 2236
Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes. Bakris G. L. Fonseca V. Katholi R. E. Mc Gill J. B. Messerli F. Phillips R. A. et al. Investigators G. E. M. I. N. I. 2005 46 1309 1315
Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome. (Greenwich) Jacob S. Henriksen E. J. 2004 6 690 696
Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study. Olsen M. H. Wachtell K. Beever G. Dahlöf B. de Simone G. Devereux R. B. et al. 2009 27 567 574
Bell DS, Bakris GL, McGill JB.Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients. 2009 11 234 238
Antihypertensive therapy and incidence of type 2 diabetes in an elderly cohort. Padwal R. Mamdani M. Alter D. A. Hux J. E. Rothwell D. M. Tu K. et al. 2004 27 2458 2463
Why blockage of the renin-angiotensin system reduces the incidence of new-onset diabetes. Jandeleit-Dahm K. A. Tikelis C. Reid C. M. Johnston C. I. ME Cooper 2005 23 463 473
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. Yusuf S. Sleight P. Pogue J. Bosch J. Davies R. Dagenais G. 2000 342 145 153
Moule SK, Denton RM.Multiple signaling pathways involved in the metabolic effects of insulin. 1997 41A EOF 49A EOF
Abstract. Nascimben L. Bothwell J. H. Dominguez D. Y. et al. Angiotensin I. I. stimulates insulin-independent. glucose uptake. in hypertrophied. rat hearts. 1997Suppl 4):S84.
Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. Schorb W. Peeler T. C. Madigan N. N. Conrad K. M. Baker K. M. 1994 269 19626 19632
Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Wan Y. Kurosaki T. Huang X. Y. 1996 380 541 544
Saad MJ, Velloso LA, Carvalho CR. Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and its association with phosphatidylinositol 3-kinase in rat heart. 1995 310 741 744
Effects of enalapril on the vascular wall in an experimental model of syndrome X. Miatello R. Risler N. Gonzalez S. Castro C. Ruttler M. Cruzado M. 2002 15 872 878
Khan B. V. Sola S. Lauten W. B. Natarajan R. Hooper W. C. Menon R. G. et al. Quinapril an. A. C. E. inhibitor reduces. markers of. oxidative stress. in the. metabolic syndrome. 2004 27 1712 1715
Inflammation and the metabolic syndrome: role of angiotensin II and oxidative stress. Ferder L. Inserra F. Martinez-Maldonado M. 2006 8 191 198
Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability. Imanishi T. Ikejima H. Tsujioka H. Kuroi A. Kobayashi K. Muragaki Y. Mochizuki S. Goto M. Yoshida K. Akasaka T. 2008 51 734 741
Influence of the angiotensin converting enzyme inhibitor ramipril on high-sensitivity C-reactive protein (hs-CRP) in patients with documented atherosclerosis. Mitrovic V. Klein H. H. Krekel N. Kreuzer J. Fichtlscherer S. Schirmer A. Paar W. D. Hamm C. W. 2005 94 336 342
Association of angiotensin-converting enzyme inhibitors and serum lipids with plaque regression in cardiac allograft vasculopathy. Bae J. H. Rihal C. S. BS Edwards Kushwaha. S. S. Mathew V. Prasad A. Holmes D. R. Jr Lerman A. 2006 82 1108 1111
Pleiotropic effects of angiotensin-converting enzyme inhibitors in normotensive patients with coronary artery disease. Krysiak R. Okopień B. 2008 60 514 523
Effect of sulfhydryl and non-sulfhydryl angiotensin-converting enzyme inhibitors on endothelial function in essential hypertensive patients. Pasini A. F. Garbin U. Nava M. C. Stranieri C. Pellegrini M. Boccioletti V. Luchetta M. L. Fabrizzi P. Lo Cascio. V. Cominacini L. 2007 20 443 450
Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. Kurtz T. W. Pravenec M. 2004 22 2253 2261
Kurtz TW.Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. 2005Suppl 1:S 9S16.
The role of renin-angiotensin system inhibition in the treatment of hypertension in metabolic syndrome: are all the angiotensin receptor blockers equal? Karagiannis A. Mikhailidis D. P. Athyros V. G. Kakafika A. I. Tziomalos K. Liberopoulos E. N. Florentin M. Elisaf M. 2007 11 191 205
Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Benndorf R. A. Rudolph T. Appel D. Schwedhelm E. Maas R. Schulze F. et al. 2006 55 1159 1164
The effects of telmisartan and amlodipine on metabolic parameters and blood pressure in type 2 diabetic, hypertensive patients. Negro R. Hassan H. 2006 7 243 246
Telmisartan treatment decreases visceral fat accumulation and improves serum levels of adiponectin and vascular inflammation markers in Japanese hypertensive patients. Chujo D. Yagi K. Asano A. Muramoto H. Sakai S. Ohnishi A. Shintaku-Kubota M. Mabuchi H. Yamagishi M. Kobayashi J. 2007 30 1205 1210
Effects of telmisartan on adiponectin levels and body weight in hypertensive patients with glucose intolerance. Makita S. Abiko A. Naganuma Y. Moriai Y. Nakamura M. 2008 57 1473 1478
Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. O’Brien E. Barton J. Nussberger J. Mulcahy D. Jensen C. Dicker P. et al. 2007 49 276 284
Azizi M. Renin inhibition. 2006 15 505 510
Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine. Nussberger J. Aubert J. F. Bouzourene K. Pellegrin M. Hayoz D. Mazzolai L. 2008 51 1306 1311
Effects of calcium antagonists on diabetic subjects: a review. Trost B. N. Weidmann P. 1987S 81S104.
Houston MC.The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics. 1988 115 640 656
Ramsay LE, Yeo WW,Jackson PR. Influence of diuretics, calcium antagonists, and alpha-blockers on insulin sensitivity and glucose tolerance in hypertensive patients. 1992Suppl 11:S 49S53; discussion S53-S54.
Russell RP.Side effects of calcium channel blockers. 1988II 42II44.
Metabolic effects of anti-hypertensive treatment with nifedipine or furosemide: a double-blind, cross-over study. Lind L. Berne C. Pollare T. Lithell H. 1995 9 137 141
Renal and cardiovascular considerations for the nonpharmacological and pharmacological therapies of obesity-hypertension. Zhang R. Thakur V. Morse S. Reisin E. 2002 16 819 827
Nathan S. Pepine C. J. Bakris G. L. Calcium antagonists. effects on. cardio-renal risk. in hypertensive. patients 2005 46 637 642
Comparison of renal and vascular protective effects between telmisartan and amlodipine in hypertensive patients with chronic kidney disease with mild renal insufficiency. Nakamura T. Inoue T. Suzuki T. Kawagoe Y. Ueda Y. Koide H. Node K. 2008 31 841 850
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine; the VALUE randomised trial. Julius S. Kjeldsen S. E. Weber M. Brunner H. R. Ekman S. Hansson L. et al. trial V. A. L. U. E. group 2004 363 2022 2031
The combined effect of calcium channel blocker Lercanidipine and antioxidants on low-grade systemic inflammation parameters in essential hypertension patients. Farah R. Shurtz-Swirski R. 2008 56 467 476
Effects of amlodipine-atorvastatin combination on inflammation markers and insulin sensitivity in normocholesterolemic obese hypertensive patients. Fogari R. Preti P. Zoppi A. Lazzari P. Corradi L. Fogari E. Ciccarelli L. Derosa G. 2006 62 817 822
Treatment with amlodipine and atorvastatin has additive effect on blood and plaque inflammation in hypertensive patients with carotid atherosclerosis. Martín-Ventura J. L. Muñoz-Garcia B. Blanco-Colio L. M. Martín-Conejero A. Madrigal-Matute J. Vega M. Ortega L. Serrano J. Egido J. 2008S 71 74
Effects of amlodipine and candesartan on oxidized LDL level in patients with mild to moderate essential hypertension. Muda P. Kampus P. Teesalu R. Zilmer K. Ristimäe T. Fischer K. Zilmer M. 2006 15 313 318
Swislocki AL, Hoffman BB, Sheu WH, Chen YD, Reaven GM.Effect of prazosin treatment on carbohydrate and lipoprotein metabolism in patients with hypertension. 1989B): 14 18
Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Pollare T. Lithell H. Selinus I. Berne C. 1988 31 415 420
Sheu WH, Swislocki AL, Hoffman BB, Reaven GM, Chen YD.Effect of prazosin treatment on HDL kinetics in patients with hypertension. 1990 3 761 768
Postsynaptic alpha 1-blockade with terazosin does not modify insulin sensitivity in nonobese normotensive subjects. Ferrari P. Rosman J. Neuner N. Shaw S. Riesen W. Weidmann P. 1991 18 106 110
Effect of terazosin on the lipid profile in patients with symptomatic benign prostatic hyperplasia. Akbay E. Bozlu M. Doruk E. Akbay E. Cayan S. Ulusoy E. 2001 67 156 159
Clinical usefulness of doxazosin in patients with type 2 diabetes complicated by hypertension: effects on glucose and lipid metabolism. Inukai T. Inukai Y. Matsutomo R. Okumura K. Takanashi K. Takebayashi K. Tayama K. Aso Y. Takemura Y. 2004 32 206 213
Effect of doxazosin therapy on glucose tolerance and lipid metabolism in hypertensive patients with impaired glucose tolerance. Shionoiri H. Ashino K. Yamanaka K. Shindo K. Hiroto S. Arita T. 1997 19 527 536
Effect of doxazosin on insulin resistance in hypertensive patients with obesity. Ueshiba H. Miyachi Y. 2003 35 532 536
Effect of doxazosin on the size of LDL particle in the type 2 diabetic patients with hypertension. Tamasawa N. Matsui J. Ogawa Y. Gotoh T. Hinata T. Murakami H. Zhi G. J. Suda T. 2000 14 135 139
Synergistic effect of doxazosin and acarbose in improving metabolic control in patients with impaired glucose tolerance. Derosa G. Cicero A. F. D’Angelo A. Ragonesi P. D. Ciccarelli L. Fogari E. Salvadeo S. A. Ferrari I. Gravina A. Fassi R. Fogari R. 2006 26 529 539
Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism. Pessina A. C. Ciccariello L. Perrone F. Stoico V. Gussoni G. Scotti A. Muggeo M. 2006 16 137 147
British South Asians with hypertension. Hobbs F. R. Khan T. Collins B. Doxazosin versus. bendrofluazide a. comparison of. the metabolic. effects in. British South. Asians with. hypertension 2005 55 437 443
Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study. Rabkin S. W. Huff M. W. Newman C. Sim D. Carruthers S. G. 1994 24 241 248
Kinoshita M. Shimazu N. Fujita M. Fujimaki Y. Kojima K. Mikuni Y. Horie E. Teramoto T. Doxazosin an. alpha1-adrenergic antihypertensive. agent decreases. serum oxidized. L. D. L. 2001 14 267 270
Urapidil treatment decreases plasma fibrinogen concentration in essential hypertension. Haenni A. Lithell H. 1996 45 1221 1229
Swislocki AL, Vestal RE, Reaven GM, Hoffman BB.Acute metabolic effects of clonidine and adenosine in man. 1993 25 90 95
Prichard BN, Graham BR. I1 imidazoline agonists.General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly. 2000 17 133 159Review.
Anichkov DA, Shostak NA, Schastnaya OV.Comparison of rilmenidine and lisinopril on ambulatory blood pressure and plasma lipid and glucose levels in hypertensive women with metabolic syndrome. 2005 21 113 9
Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. MA Weber Bakris. G. L. Jamerson K. Weir M. Kjeldsen S. E. Devereux R. B. Velazquez E. J. Dahlöf B. Kelly R. Y. Hua T. A. Hester A. Pitt B. Investigators A. C. C. O. M. P. L. I. S. H. 2010 56 77 85
Prevention of microalbuminuria in patients with type 2 diabetes: what do we know? J Clin Hypertens (Greenwich). Ruilope L. Izzo J. Haller H. Waeber B. Oparil S. Weber M. Bakris G. Sowers J. 2010 12 422 30Review.
American Diabetes Association.Standards of medical care in diabetes. Diabetes Care, 2011suppl 1): S 11S61.
Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). . Cooper-Dehoff R. JD Cohen Bakris. G. L. Messerli F. H. Erdine S. Hewkin A. C. Kupfer S. Pepine C. J. Investigators I. N. V. E. S. T. 2006 98 890 4
. Langaee T. Y. Gong Y. Yarandi H. N. Katz D. A. Cooper De Hoff. R. M. Pepine C. J. Johnson J. A. Association of. C. Y. P. A. polymorphisms with. hypertension antihypertensive response. to verapamil. 2007 81 386 91
. Beitelshees A. L. Gong Y. Wang D. Schork N. J. Cooper-Dehoff R. M. Langaee T. Y. MD Shriver Sadee. W. Knot H. J. Pepine C. J. Johnson J. A. Investigators I. N. V. E. S. T. genotype K. C. N. M. B. influences response. to verapamil. S. R. adverse outcomes. in the. I. Nternational V. Erapamil S. R. Trandolapril S. Tudy . I. N. V. E. S. T. 2007 17 719 29
Beitelshees A. L. Navare H. Wang D. Gong Y. Wessel J. Moss J. I. Langaee T. Y. Cooper De Hoff. R. M. Sadee W. Pepine C. J. Schork N. J. Johnson J. A. C. A. C. N. A. C. gene polymorphisms. cardiovascular disease. outcomes treatment response. Circ Cardiovasc. Genet 2009 2 362 70Epub 2009 Jun 3.
beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. . MA Pacanowski Gong. Y. Cooper-Dehoff R. M. Schork N. J. MD Shriver Langaee. T. Y. Pepine C. J. Johnson J. A. Investigators I. N. V. E. S. T. 2008 84 715 21Epub 2008 Jul 9.
Promoter polymorphisms in ACE (angiotensin I-converting enzyme) associated with clinical outcomes in hypertension. . Johnson A. D. Gong Y. Wang D. Langaee T. Y. Shin J. Cooper-Dehoff R. M. Schork N. J. Binkley P. Pepine C. J. Johnson J. A. Sadee W. 2009 85 36 44Epub 2008 Oct 22.
Alpha-adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES). . Gerhard T. Gong Y. Beitelshees A. L. Mao X. Lobmeyer M. T. Cooper De Hoff. R. M. Langaee T. Y. Schork N. J. MD Shriver Pepine. C. J. Johnson J. A. Investigators I. N. V. E. S. T. 2008 156 397 404Epub 2008 Jun 20.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Hansson L. Zanchetti A. Carruthers S. G. Dahlöf B. Elmfeldt D. Julius S. Menard J. Rahn K. H. Wedel H. Westerling S. 1998 351 1755 1762
Tight blood pressure control and risk of macrovascular and microvascular complication in type 2 diabetes:UKPDS38. UK Prospective Diabetes Study Group (no authors listed). 1998 317 703 713
Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (syst-Eur) Trial Investigator. 132. Staessen J. A. Fagard R. Thijs L. Celis H. Arabidze G. G. Birkenhäger W. H. et al. 1997 350 757 764
Treatment of cardiovascular and renal risk factors in the diabetic hypertensive. Sowers J. R. Haffner S. 2002 40 781 788
Sowers JR.Treatment of hypertension in patients with diabetes. 2004 164 1850 1857
Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Ninomiya J. K. L’Italien G. Criqui M. H. Whyte J. L. Gamst A. Chen R. S. 2004 109 42 46
Clustering of metabolic factors and coronary heart disease. Wilson P. W. Kannel W. B. Silbershatz H. D’Agostino R. B. 1999 159 1104 1109
Cardiovascular morbidity and mortality associated with the metabolic syndrome. Isomaa B. Almgren P. Tuomi T. Forsén B. Lahti K. Nissén M. et al. 2001 24 683 689
Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Stern M. P. Williams K. González-Villalpando C. Hunt K. J. Haffner S. M. 2004 27 2676 2681
Adverse prognostic significance of new diabetes in treated hypertensive subjects. Verdecchia P. Reboldi G. Angeli F. Borgioni C. Gattobigio R. Filippucci L. et al. 2004 43 963 969