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Query: UMLS:C0011860 (type 2 diabetes)
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The hypertensive and normotensive Appropriate Blood Pressure Control in Diabetes (ABCD) studies were prospective, randomized, interventional clinical trials with 5 years of follow-up that examined the role of intensive versus standard blood pressure control in a total of 950 patients with type 2 diabetes mellitus. In the hypertensive ABCD study, a significant decrease in mortality was detected in the intensive blood pressure control group when compared with the standard blood pressure control group. There was also a marked reduction in the incidence of myocardial infarction when patients were randomly assigned to initial antihypertensive therapy with angiotensin-converting-enzyme inhibition rather than calcium channel blockade. The results of the normotensive ABCD study included associations between intensive blood pressure control and significant slowing of the progression of nephropathy (as assessed by urinary albumin excretion) and retinopathy, and fewer strokes. In both the hypertensive and normotensive studies, mean renal function (as assessed by 24 h creatinine clearance) remained stable during 5 years of either intensive or standard blood pressure intervention in patients with normoalbuminuria (<30 mg/24 h) or microalbuminuria (30-300 mg/24 h) at baseline. By contrast, the rate of creatinine clearance in patients with overt diabetic nephropathy (>300 mg/24 h; albuminuria) at baseline decreased by an average of 5 ml/min/year in spite of either intensive or standard blood pressure control. Analysis of the results of 5 years of follow-up revealed a highly significant correlation of all-cause and cardiovascular mortality with left ventricular mass and severity of albuminuria.
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PMID:Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial. 1765 21

Metabolic syndrome (MetSyndr), a constellation of abnormalities [obesity, glucose intolerance, insulin resistance (IR), dyslipidemia (low HDL-cholesterol, high LDL-cholesterol and triglycerides (TG)], and elevated blood pressure (BP)], increases the risk of cardiovascular (CV) disease and premature death. From 10% to 30% of the adult population in industrialized countries has MetSyndr, which effectively predicts the development of type 2 diabetes mellitus (T2D) and CV disease. Because of the complex etiology of MetSyndr, a multi-targeted, integrated therapeutic approach is required to simultaneously treat high BP, obesity, lipid disorders and T2D (if present), to fully protect CV, cerebrovascular and renal systems. If lifestyle modification (weight control, diet, exercise, smoking cessation, moderation of alcohol intake) is ineffective, pharmaco-theraphy should be added to treat simultaneously the lipid- and non-lipid CV risk factors. Patients with HTN and MetSyndr should be started on angiotensin-converting enzyme (ACE) inhibitors, unless contraindicated. The ACE inhibitors and angiotensin receptor blockers (ARBs) reduce the odds of developing new onset T2D and also decrease albuminuria. The ACE inhibitors provide cardioprotective and renoprotective benefits beyond their effect on BP; they also improve IR. The ARBs are renoprotective in addition to being cardioprotective. Long-acting calcium channel blockers are also recommended in hypertensive patients with MetSyndr; these drugs also improve IR. Thiazides (at low doses) and selected ss-blockers can be given to patients with HTN and MetSyndr. Celiprolol in combination with diuretics has a favorable effect on glucose tolerance and IR in patients with HTN and MetSyndr, and spironolactone added to ACE inhibitor or ARB therapy provides additional reno- and CV protective benefits in patients with diabetic nephropathy. Carvedilol, a ss-blocker with vasodilating properties, added to ACE inhibitor or ARB therapy, is effective in preventing worsening of microalbuminuria in patients with HTN and MetSyndr; it also improves IR and glycemic control. Most patients eventually require two or more antihypertensive drugs to reach BP goal. It is recommended that therapy in patients whose BP is more than 20/10 mm Hg above target at diagnosis be initiated with a combination of antihypertensive drugs, administered either as individual drugs or as fixed-dose formulations. Treatment with fixed-dose combinations, such as irbesartan + hydrochlorothiazide provides good BP control in more than two-thirds of hypertensive patients with MetSyndr. Lipid and BP targets are reached in a high percent of patients with HTN and CV disease treated with a combination of amlodipine + atorvastatin. In conclusion, hypertensive patients with the MetSyndr be treated aggressively for each component of the syndrome to provide CV, cerebrovascular and renal protection.
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PMID:Metabolic syndrome: treatment of hypertensive patients. 1766 15

Heart disease and stroke are the most life-threatening consequences of diabetes mellitus, with mortality rates up to two to four times higher for persons with diabetes vs. those without and accounting for up to 65% of deaths. The cardiometabolic syndrome is a potent indicator of future risk of type 2 diabetes and concomitant increased potential for cardiovascular morbidity and mortality. Pharmacologic treatment is usually necessary to improve blood pressure and lipids, thereby decreasing the risk of cardiovascular disease. The reduction of cardiovascular and renal risk with type 2 diabetes and elevated blood pressure are compelling indications for thiazide diuretics, blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. Nevertheless, most patients with type 2 diabetes and elevated blood pressure will require two or more agents to lower blood pressure to the recommended goal of <130/80 mm Hg, and combination therapy may be beneficial. In patients with the cardiometabolic syndrome without type 2 diabetes, the present goal is to maintain BP <140/90 mm Hg, although recent data suggest potential decrease in the progression of prehypertension to hypertension with antihypertensive medication. Furthermore, blockers of the renin-angiotensin system may actually prevent newonset diabetes. It is reasonable for patients with type 2 diabetes and cardiovascular disease to achieve an optional low-density lipoprotein cholesterol (LDL-C) goal <70 mg/dL, and statin therapy should be considered regardless of baseline LDL-C level. In patients with the cardiometabolic syndrome without type 2 diabetes and calculated moderately high-risk status (two or more risk factors; 10-year risk, 10%-20%), the present goal for LDL-C is <130 mg/dL, with perhaps a therapeutic option of <100 mg/dL, and in patients with the cardiometabolic syndrome at lower risk, the LDL-C goal remains <160 mg/dL. Multifactorial management must be utilized to prevent progression of cardiovascular risk with the cardiometabolic syndrome and the ravages of cardiovascular disease in persons with type 2 diabetes, including antiplatelet therapy with aspirin.
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PMID:Management of cardiovascular risk in patients with type 2 diabetes mellitus as a component of the cardiometabolic syndrome. 1767 32

N-acetylaspartic acid (NAA) is converted into aspartate and acetate by aspartoacylase. Abnormal levels of the enzyme leads to accumulation of NAA and these changes have been observed in Canavan disease and type 2 diabetes. How upregulation of NAA affect the gastrointestine protein levels and the function is not known. Incubation of rat stomach tissue with NAA 1.5 mM, 1.5 microM and 1.5 nM induced inflammatory agents TNFalpha, p38MAPK, iNOS, PKC, COX2 and ICAM3; transcription factors phospho-NF-kBp65, cjun and cfos; contractile proteins MLCK and phospho MLC; and calcium channel alpha1C and calcium channel, voltage-dependent, beta 3 subunit compared to their respective control. Incubation of circular smooth muscle cells with the above doses of NAA induced contractility compared to the control. These studies suggest that NAA alters proteins levels and smooth muscle contractility and these changes likely to contribute to gastrointestinal disorder seen in these diseases.
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PMID:Upregulation of N-acetylaspartic acid alters inflammation, transcription and contractile associated protein levels in the stomach and smooth muscle contractility. 1794 58

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.
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PMID:Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects. 1798 25

Hypertension is a multifactorial disorder leading to pathophysiologic changes in target organs over time through diverse mechanisms. In addition, hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available fixed-dose antihypertensive combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. In addition, it is possible to select drug combinations whereby one drug offsets the negative effects of the other drug. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a renin-angiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist (ARB), and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease. Preliminary studies of fixed-dose combinations have shown reductions in left ventricular hypertrophy and improvements in markers of renal function. Additional studies currently underway will compare the effects of available fixed-dose combinations on cardiovascular morbidity and mortality, and markers of renal dysfunction.
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PMID:Fixed-dose combination antihypertensives and reduction in target organ damage: are they all the same? 1807 8

Nifedipine, a calcium channel blocker, has been reported to exert pleiotropic effects on atherosclerosis, mainly through its antioxidative properties. However, the effect of the calcium channel blocker on cognitive impairment associated with type 2 diabetes mellitus is not well known. Here, we examined the possibility that a calcium channel blocker could improve cognitive function in a type 2 diabetic mouse model, KK-A(y). KK-A(y) mice subjected to 20 trials of a passive avoidance task every week from 7 weeks of age exhibited impairment of the increase in avoidance rate and, moreover, exaggeration of its age-dependent decline, especially after 12 weeks of age. Oral administration of nifedipine at a nonhypotensive dose (0.001% in laboratory chow) to KK-A(y) mice from 10 weeks of age improved cognitive function. Nifedipine treatment decreased serum insulin level to one fifth of that in KK-A(y) mice without nifedipine. Moreover, nifedipine treatment significantly reduced superoxide anion production in the brain. Furthermore, treatment with nifedipine markedly reduced the mRNA level of Id-1, inhibitor of neural differentiation, in the brain hippocampus. We also observed the increase in blood flow in the brain in KK-A(y) mice with nifedipine treatment compared with nontreated mice. Taken together, our findings suggest that nifedipine ameliorates impaired cognitive function in type 2 diabetic mice, at least because of attenuation of hyperinsulinemia and superoxide production in the brain and possible upregulation of the neural differentiation-controlling gene, Id-1.
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PMID:Diabetes-associated cognitive impairment is improved by a calcium channel blocker, nifedipine. 1819 65

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.
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PMID:Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study. 1897 63

Treatment with different antihypertensive drug classes has varied effects on glucose metabolism. Thiazide diuretic use in hypertensives has been associated with the development of glucose intolerance and diabetes. Some findings suggest that the probability of worsening glucose metabolism and the development of new diabetes after thiazide initiation is associated with increasing body mass index. Nonselective or beta(1) selective beta-blockers may also lead to decreased insulin sensitivity in hypertensive patients. Newer beta-blockers that cause vasodilatation and beta-blockers that have intrinsic sympathomimetic activity may not have these deleterious effects on insulin sensitivity and glucose metabolism. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers 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 calcium channel blockers, there is little net effect of these agents on glucose metabolism. The prevalence of obesity, hypertension, and type 2 diabetes mellitus 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.
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PMID:Effects of antihypertensives on glucose metabolism. 1837 Jul 75

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) >or=60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), -0.9 m/s (-1.4 to -0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of -15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.
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PMID:Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering. 1842 91

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