Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels

AimsHypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.MethodsIn 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated.ResultsSwitching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker.ConclusionsIn 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin–angiotensin–aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.     

Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema

Background

Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.

Methods

We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.

Results

We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P < .00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P = .002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P < .0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).

Conclusion

In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.     

Vascular and metabolic properties of manidipine

The combination of renin-angiotensin system blockers with calcium channel blockers appears to be one of the most effective options for treating hypertension and diabetes.Nevertheless, not all calcium blockers behave in the same manner. Manidipine, unlike other third-generation dihydropyridine derived drugs, blocks T-type calcium channels present in the efferent glomerular arterioles, reducing intraglomerular pressure and microalbuminuria. In addition,T-type channels are related to proliferation, inflammation,fibrosis, vasoconstriction and activation of the renin-angiotensin system. The inhibition of these factors could explain the non-haemodynamic effects of manidipine as compared to other blockers.     

Treatment of hypertension in diabetic patients with nephropathy

In type 1 diabetes, hypertension is closely linked to the development of nephropathy. An association of hypertension and the impact of hypertension on the clinical course of type 2 diabetes, including the development of vascular complications, has been well established. However, the association with nephropathy in type 2 diabetes is less clear. Despite that, antihypertensive treatment has a crucial impact on the course of nephropathy in both types of diabetes. In this article, we discuss recent evidence focusing on the nephroprotective potential of various classes of antihypertensive agents and confront it with current recommendations for the treatment of hypertension in diabetic patients with nephropathy. Unlike type 1 diabetes, where the nephroprotection could be a good sole measure for assessing the efficiency of a particular agent or their combination, defining of the optimal antihypertensive agent or agents in type 2 diabetes requires consideration of both cardiovascular, cerebrovascular, and nephroprotective potentials of such a treatment. In both types of diabetes, recent data support the use of inhibitors of the renin-angiotensin system with or without diuretics as the initial therapy. In type 1 diabetes, additional beneficial effect can be expected from calcium channel blockers (CCBs). In type 2 diabetic patients, combining more agents may be necessary early in the course of nephropathy to affect both micro- and macrovascular targets. beta blockers should be applied early to enhance cardioprotectivity, followed by CCBs to achieve goal blood pressure. Although not supported by all recent data, aggressive blood pressure control (< 130/75 mm Hg) is warranted. Furthermore, multifactorial intervention targeting metabolic derangements and lifestyle, is a necessary complimentary measure that must accompany antihypertensive treatment.     

Benefit of Antihypertensive Treatment in the diabetic patients enrolled in the Systolic Hypertension in Europe (Syst-Eur) Trial

In this review we attempt to determine the role of calcium channel blockers in preventing cardiovascular sequelae in patients with both hypertension and diabetes mellitus. The data have been collected from three sources: post-hoc analyses of subgroups of diabetic patients in placebo-controlled hypertension trials (SHEP, Syst-Eur, Syst-China); stepped-care blood pressure-oriented trials (HOT, UKPDS); and comparative trials focusing primarily on metabolic aspects and intermediate endpoints (ABCD, FACET).On balance, the data seem to indicate that long-acting calcium channel blockers score remarkably well in preventing cardiovascular complications in diabetic hypertensive patients.     

Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers

Background and aimsCOVID-19 is already a pandemic. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with comorbidities. We aimed to evaluate the outcome in hypertensive patients with COVID-19 and its relation to the use of renin-angiotensin system blockers (RASB).MethodsWe have systematically searched the medical database up to March 27, 2020 and retrieved all the published articles in English language related to our topic using MeSH key words.ResultsFrom the pooled data of all ten available Chinese studies (n = 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Although the emerging data hints to an increase in mortality in COVID-19 patients with known hypertension, diabetes and CVD, it should be noted that it was not adjusted for multiple confounding factors. Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in these studies yet, although mechanistically and plausibly both, benefit and harm is possible with these agents, given that COVID-19 expresses to tissues through the receptor of angiotensin converting enzyme-2.ConclusionSpecial attention is definitely required in patients with COVID-19 with associated comorbidities including hypertension, diabetes and established CVD. Although the role of RASB has a mechanistic equipoise, patients with COVID-19 should not stop these drugs at this point of time, as recommended by various world organizations and without the advice of health care provider.     

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.     

Antihypertensive drugs and incidence of type 2 diabetes: Evidence and implications for clinical practice

The major antihypertensive drug classes appear to exert differing effects on glycemic control and diabetes incidence. Thiazide diuretic and β-blockers are potentially diabetogenic, whereas calcium channel blockers appear neutral. Inhibitors of the renin-angiotensin system are associated with improvements in glycemic control and may lower diabetes incidence, but it is not clear if this represents a truly preventive effect. Also, it should be noted that previous studies have reported inconsistent results, and the data to date are not definitive. We suggest that inhibitors of the renin-angiotensin system be used as first-line agents in uncomplicated hypertensive patients who are at high risk for developing type 2 diabetes. Thiazides and β-blockers should not be avoided in patients with compelling indications for these drugs. Many hypertensive patients (particularly those who are obese or have prediabetes) require several agents to achieve target blood pressure levels. Therefore, the choice of initial agent is far less important than ensuring that target blood pressure goals are reached.     

Several Conventional Risk Markers Suggesting Presence of Albuminuria Are Weak Among Rural Africans With Hypertension

The objective of this cross‐sectional study was to investigate risk markers indicating the presence of albuminuria in patients with hypertension in rural sub‐Saharan Africa (SSA). Urine albumin‐creatinine ratio, glycated hemoglobin (HbA_1c), blood pressure, anthropometry, and other patient characteristics including medications were assessed. We identified 160 patients with hypertension, of whom 68 (42.5%) were co‐diagnosed with diabetes mellitus (DM). Among the included participants, 57 (35.6%) had albuminuria (microalbuminuria [n=43] and macroalbuminuria [n=14]). A backward multivariate logistic regression model identified age (per 10‐year increment) (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.03–1.95), HbA_1c >53 compared with <48 mmol/mol (OR, 3.81; 95% CI, 1.74–8.35), and treatment with dihydropyridine calcium channel blockers (OR, 2.59; 95% CI, 1.09–6.16) as the variables significantly associated with albuminuria. Only dysregulated DM and age were the conventional risk markers that seemed to suggest albuminuria among patients with hypertension in rural SSA.     

Are calcium antagonists beneficial in diabetic patients with hypertension?

PURPOSE: We analyzed the available data to assess the effects of calcium antagonists in hypertensive patients with diabetes mellitus. METHODS: We performed a MEDLINE search of English-language articles published until April 2003, using the terms diabetes mellitus, hypertension or blood pressure, and therapy. Pertinent articles cited in the identified papers were also reviewed. We included prospective randomized studies of more than 12 months' duration that evaluated the effect of drug treatment on morbidity and mortality in diabetic patients with hypertension. We estimated the effect of treatment with calcium antagonists on morbidity and mortality in comparison with placebo, conventional therapy, and therapy that blocks the renin-angiotensin system. RESULTS: We identified 14 studies that reported outcomes in diabetic hypertensive patients. Compared with placebo, calcium antagonists reduced cardiovascular morbidity and mortality. Compared with conventional therapy, calcium antagonists had similar effects on coronary heart disease and total mortality, but may have reduced the risk of stroke (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.74 to 1.02; P = 0.08). However, they resulted in a lesser reduction of the risk of heart failure (OR = 1.33; 95% CI: 1.17 to 1.50). Calcium antagonists were less effective than blockers of the renin-angiotensin system in preventing heart failure (OR = 1.43; 95% CI: 1.10 to 1.84), but had similar effects on stroke, coronary heart disease, and total mortality. CONCLUSION: Calcium antagonists are safe and effective in reducing most types of cardiovascular morbidity and mortality in diabetic hypertensive patients, although their use is associated with a lesser reduction of risk of heart failure as compared with other treatments for hypertension.     

Small artery remodeling in diabetes mellitus

AimsTo briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment.Data synthesisThe development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries' smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, while in some secondary forms of hypertension, hypertrophic remodeling may be detected. Moreover, in non-insulin-dependent diabetes mellitus hypertrophic remodeling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effects on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations to the small resistance arteries with drugs blocking the renin-angiotensin system (ACE inhibitors, angiotensin II receptor blockers) was demonstrated.ConclusionAlterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin-angiotensin system blockade seems to be effective in preventing and/or regressing alterations in the microvascular structure.     

Reducing Cardiovascular Events in High-Risk Patients: The Challenge of Managing Hypertension in Patients With Diabetic Renal Disease

Hypertension is more prevalent and more difficult to control and is associated with a higher mortality rate in patients with diabetes than in nondiabetic patients. Elevated blood pressure contributes importantly to the development of albuminuria and progression of renal damage in diabetic nephropathy. Strong evidence indicates that the presence of albuminuria and overt nephropathy in patients with type 1 and type 2 diabetes is associated with a marked increase in the rate of fatal and nonfatal cardiovascular events. Blockade of the renin-angiotensin system in patients with type 2 diabetes with or without chronic kidney disease is associated with a significant reduction in risk for cardiovascular events. Renin-angiotensin system-blocking agents should be considered first-step pharmacologic therapy for hypertension in diabetic patients, with addition of other agents, if needed, to meet the recommended blood pressure goal of <130/80 mm Hg. In most instances, a diuretic is also needed to reduce blood pressure.     

PAIT-survey—Prevalence of albuminuria in patients with diabetes and hypertension in Turkey

Background

Albuminuria is an early marker of kidney disease in patients with diabetes and/or hypertension undetected or untreated albuminuria is a leading cause of chronic kidney disease and cardiovascular events, The purpose of the present survey was to assess the prevalence of albuminuria in patients with diabetes and hypertension, treated with a combinations of renin angiotensin aldosterone system inhibitors and dihydropyridine calcium channel blockers.

The impact of a family history of Type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus

Aims/hypothesis. There is substantial evidence for a role of genetic factors in the development of diabetic nephropathy. In Pima Indians, a link between susceptibility to diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus has been proposed. In this study, our aim was to examine the association between a family history of Type II diabetes and diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus. Methods. In a cross-sectional case-control study, we assessed the prevalence of Type II diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy (albuminuria > 300 μg/min in two of three overnight urine collections) compared with the parents of 54 Type I diabetic patients without nephropathy (albuminuria < 20 μg/min). Results. Thirty-four (25 %) of the patients with nephropathy compared with five (9 %) of the patients without nephropathy had a parental history of Type II diabetes (p = 0.019). A parental history of Type II diabetes was associated with a three-fold risk [odds ratio 2.95 (95 % confidence interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for sex, glycaemic control and family history of hypertension. Furthermore, there was an excess of risk factors for development of Type II diabetes (higher fasting plasma glucose concentrations, higher prevalence of hypertension, higher waist-hip ratio and a tendency towards more glucose intolerance) among previously non-diabetic parents of patients with nephropathy. Conclusion/interpretation. Genetic or environmental factors or both related to familial Type II diabetes increase susceptibility to diabetic nephropathy in patients with Type I diabetes. [Diabetologia (1999) 42: 519–526] Received: 30 September 1998 and in final revised form: 28 December 1998     

Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension

Summary Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes. [Diabetologia (1997) 40: 193–199] Received: 16 July 1996 and in revised form: 17 October 1996     

Prevalence of hypertension,control of blood pressure and treatment in hypertensive with type 2 diabetes in Hospital University Sains Malaysia

AimsTo determine the prevalence of hypertension, control of hypertension and patterns of antihypertensive medications in Malaysian type 2 diabetic patients who attended diabetes clinics in Hospital University Sains Malaysia (Tertiary Hospital).Materials and methodsThe study design was observational prospective longitudinal follow-up study; the study was conducted with sample of 1077 type 2 diabetes mellitus outpatient recruited whom attended the diabetes clinics at Hospital Universiti Sains Malaysia (HUSM) in Kelantan. The study period was from January till December 2008. Blood pressure was defined as >130/80 or use of antihypertension medications. Demographic characteristics of patients, level of blood pressure control, use of antihypertensive medications and patterns of antihypertensive therapy.ResultsThe prevalence of hypertension in Malaysian type 2 diabetic patients was 998 (92.7%),antihypertensive drugs were prescribed in 940 (94.2%) of hypertensive patients with type 2 diabetic mellitus. The achievement of blood pressure control (≤130/80 mmHg) was 471 (47.2%) %. The percentage of patients receiving one, two, three, and four drugs were 253 (25.3%), 311 (31.3%), 179 (17.9%), and 197 (19.7%) respectively. Calcium channel blockers were the most commonly prescribed antihypertensive agents 757 (75.7%) followed by Angiotensin-converting enzyme inhibitors 446 (44.6%), and Angiotensin receptor blockers 42.4 (42.4%).ConclusionThe prevalence of hypertension is high in Malaysian type 2 diabetic patients, hypertension was not controlled to the recommended levels of blood pressure in about one-half (52.8%) of diabetes patients. Calcium channel blockers were the most commonly prescribed antihypertensive agents. There is an urgent need to educate both patients and health care providers of importance of achieving target of treatment in order to reduce morbidity and mortality due to diabetes with hypertension.