Diabetes,hypertension, and cardiovascular derangements: Pathophysiology and management

Hypertension frequently coexists with diabetes mellitus, occurring twice as frequently in diabetic as in nondiabetic persons. It accounts for up to 75% of added cardiovascular disease (CVD) risk in people with diabetes, contributing significantly to the overall morbidity and mortality in this high-risk population. Patients with hypertension are two times more prone to have diabetes than are normotensive persons. Hypertension substantially increases the risk for coronary heart disease (CHD), stroke, retinopathy, and nephropathy. In patients with type 2 diabetes, hypertension usually clusters with the other components of the cardiometabolic syndrome, such as microalbuminuria, central obesity, insulin resistance, dyslipidemia, hypercoagulation, increased inflammation, and left ventricular hypertrophy (LVH). In type 1 diabetes, hypertension often occurs subsequent to the development of diabetic nephropathy. Hypertension in people with diabetes is characterized by volume expansion, increased salt sensitivity, isolated systolic blood pressure (BP) elevation, loss of the nocturnal dipping of BP and pulse, and increased propensity toward orthostatic hypotension and albuminuria. Among the treatment strategies tested in hypertensive diabetic persons, low-density lipoprotein (LDL)-cholesterol lowering to less than 100 mg/ dL and aggressive BP control to less than 130/80 mm Hg have proven effective in CVD risk reduction. The combination of two or more drugs is usually necessary to achieve the target BP.     

Treatment of hypertension in patients with diabetes

At least 17 million people in the United States have diabetes mellitus, and another 50 million have hypertension. These chronic diseases increasingly coexist in our aging population. Both diseases are important predisposing factors for the development of cardiovascular disease (CVD) and renal disease, and the coexistence of these risk factors is a very powerful promoter of CVD and renal disease. There is accumulating evidence that the rigorous treatment of hypertension and other risk factors such as dyslipidemia and hyperglycemia considerably lessens the burden of CVD and renal disease in patients with diabetes mellitus. There is considerable evidence that strategies addressing diet and exercise reduce the development of diabetes and are an important component of treatment in persons who have established diabetes. There are also considerable data suggesting that the treatment strategies that interrupt the renin-angiotensin system have special benefits in patients with diabetes and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. Data from a recent study indicate that the control of systolic blood pressure, using a diuretic agent as part of antihypertensive therapy, reduces the risk of stroke and other CVD end points. Recent reports indicate that angiotensin receptor-blocking agents decrease the rate of development of proteinuria and diabetic renal disease. These observations will likely have a significant impact on treatment of hypertension in patients with type 2 diabetes mellitus.     

Cardiovascular Implications of Albuminuria

Microalbuminuria is a major independent risk factor for cardiovascular disease (CVD) events in persons with diabetes or hypertension, the general population, and persons with known CVD. Although microalbuminuria is a stronger risk factor in men, women with increased albuminuria levels are also at a higher risk of CVD. Microalbuminuria is an indicator of generalized endothelial injury, a hallmark of systemic atherosclerosis. Treatments that decrease albuminuria, particularly agents that inhibit the renin-angiotensin system, reduce CVD risk in various populations, including those with and without diabetes or hypertension. Whether albuminuria should be a treatment target for CVD is not yet proven. Nevertheless, the measurement of albuminuria is clinically useful to identify high-risk individuals who should receive intensive risk factor management based on current treatment guidelines.     

Cardiovascular risk factors in diabetic patients with hypertension

Individuals with diabetes mellitus have cardiovascular disease (CVD) mortality comparable to nondiabetics who have suffered a myocardial infarction or stroke. Aggressive management of risk factors such as hypertension, dyslipidemia, and platelet dysfunction in persons with diabetes has been shown to reduce morbidity and mortality in prospective randomized controlled clinical trials. Accordingly, there are national mandates to lower blood pressure to less than 130/85 mm Hg, reduce low-density lipoprotein cholesterol to less than 100 mg/dL, and institute aspirin therapy in adult patients with diabetes. Although not definitively shown to reduce CVD, there are also recommendations to control the level of glycemia, as well. This article discusses CVD risk factors in the diabetic patient with hypertension.     

Pathogenesis and Treatment of Microalbuminuria in Patients With Diabetes: The Road Ahead

The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death.     

Cardiac risk factors in patients with diabetes mellitus and major depression

OBJECTIVE: The prevalence of major depression is approximately 2-fold higher in patients with diabetes mellitus compared to medical controls. We explored the association of major depression with 8 cardiac risk factors in diabetic patients with and without evidence of cardiovascular disease (CVD). DESIGN: A mail survey questionnaire was administered to a population-based sample of 4,225 patients with diabetes to obtain data on depression status, diabetes self-care (diet, exercise, and smoking), diabetes history, and demographics. On the basis of automated data we measured diabetes complications, glycosylated hemoglobin, medical comorbidity, low-density lipid levels, triglyceride levels, diagnosis of hypertension, and evidence of microalbuminuria. Separate analyses were conducted for subgroups according to the presence or absence of CVD. SETTING: Nine primary care clinics of a nonprofit health maintenance organization. MAIN RESULTS: Patients with major depression and diabetes were 1.5- to 2-fold more likely to have 3 or more cardiovascular risk factors as patients with diabetes without depression (62.5% vs 38.4% in those without CVD, and 61.3% vs 45% in those with CVD). Patients with diabetes without CVD who met criteria for major depression were significantly more likely to be smokers, to have a body mass index (BMI) > or = 30 kg/m2, to lead a more sedentary lifestyle, and to have HbA1c levels of >8.0% compared to nondepressed patients with diabetes without heart disease. Patients with major depression, diabetes, and evidence of heart disease were significantly more likely to have a BMI > or = 30 kg/m2, a more sedentary lifestyle, and triglyceride levels > 400 mg/dl than nondepressed diabetic patients with evidence of heart disease. CONCLUSIONS: Patients with major depression and diabetes with or without evidence of heart disease have a higher number of CVD risk factors. Interventions aimed at decreasing these risk factors may need to address treatment for major depression in order to be effective.     

Oxidative Stress in Insulin-Resistant Conditions

The risk of cardiovascular disease (CVD) in patients with diabetes mellitus is increased more than 3-fold and is the major cause of mortality and morbidity in diabetic patients. Historically, diabetes has been considered an inadequate insulin response leading to elevated plasma glucose levels with morbidities attributable to hyperglycemia. However, diabetes represents a complex pathology that often includes hypertension, dyslipidemia, endothelial dysfunction, microalbuminuria, platelet disaggregation, abnormal fibrinolysis, and chronic inflammation. Furthermore, oxidative stress has been shown to contribute to the pathology of diabetic CVD, having implications in the development of hypertension, renal disease, and stroke. Hypertension is a common feature of diabetes and is the primary contributor to CVD, which highlights the importance of blood pressure control (<130/80 mm Hg). Recent investigations have also implicated the renin-angiotensin-aldosterone system in promoting oxidative stress-induced endothelial dysfunction, inflammation, and insulin resistance. These pathophysiologic considerations will be important in developing prevention strategies for CVD in diabetes. Further research is needed to identify antioxidant and insulin-sensitizing agents that will improve CVD outcomes in patients with diabetes.     

Renal and retinal microangiopathy after 15 years of follow-up study in a sample of Type 1 diabetes mellitus patients

PURPOSE: In the present study, the objective is to determine the epidemiological risk factors in the appearance of diabetic retinopathy and nephropathy in 112 Type 1 diabetic patients after 15 years. METHODS: A 15-year follow-up study was done in a cohort of 112 consecutive Type 1 (IDDM) diabetes mellitus patients without diabetic retinopathy or nephropathy at enrolment in 1990. We studied the incidence of diabetic retinopathy and/or microalbuminuria. The epidemiological risk factors included in the study were gender, diabetes duration, HbA(1c) levels, arterial hypertension, levels of triglycerides and fractions of cholesterol (HDL-cholesterol and LDL-cholesterol). RESULTS: The incidence of diabetic retinopathy was 55.40% at the end of study; the risk factors associated were duration of diabetes mellitus (P<.001), high levels of HbA(1c) (P=.009), presence of arterial hypertension (P=.007) and high levels of LDL-cholesterol (P=.002). The incidence of microalbuminuria was 41.07% and that of overt nephropathy, 19.60%; the risk factors associated were high levels of HbA(1c) (P<.001) and presence of arterial hypertension (P=.023). At the end of study, four groups of patients were formed: patients without microalbuminuria or retinopathy, patients with microalbuminuria only, patients with retinopathy only and patients with retinopathy and microalbuminuria. From the results of the discriminate analysis, we may assume that for the development of retinal lesions only, in the diabetes mellitus, the duration of the disease, the high levels of HbA(1c) and the arterial hypertension are most important, and for the development of renal and retinal lesion simultaneously, the important factor is poor control of glycemia measured by levels of HbA(1c) and arterial hypertension. CONCLUSIONS: In conclusion, microalbuminuria correlated well with severe forms of diabetic retinopathy, and at the end of the study, two groups of patients had been configured: the first group had developed only diabetic retinopathy, and the second, their patients with diabetic retinopathy together with renal lesion (microalbuminuria). For the first group, the duration of diabetes mellitus was the most important risk factor, and for the second group, the levels of HbA(1c) and blood pressure were the most important.     

Cardiovascular risk in diabetes: a brief review

Cardiovascular disease (CVD) is the major cause of the morbidity and mortality associated with diabetes in the US. A 2- to 3-fold incidence of CVD occurs in both type 1 and type 2 diabetic individuals over that in age- and gender-matched non-diabetic persons. Recent encouraging data demonstrating a decline in CVD mortality in the general US population do not reflect such a decline in the diabetic population, particularly in women.Increased risk for CVD is related to duration of diabetes and hyperglycemia, as well as hypertension, dyslipidemia, insulin resistance, gender, coagulation abnormalities, and other factors. Health care providers need to advocate for an uncompromising, multi-component attack on all modifiable risk factors for CVD, including glucose control, in the person with diabetes mellitus. This review focuses on known modifiable risk factors for CVD associated with diabetes, potential targets for primary and secondary prevention.     

Diabetic cardiomyopathy

Individuals with diabetes are at a significantly greater risk of developing cardioymyopathy and heart failure despite adjusting for concomitant risks such as coronary artery disease or hypertension. This has led to the increased recognition of a distinct disease process termed as "diabetic cardiomyopathy." In this article, we perform an extensive review of the pathogenesis and treatment of this disease. From a clinical perspective, physicians should be aware of this entity, and early screening should be considered because physical evidence of early diabetic cardiomyopathy could be difficult to detect. Early detection of the disease should prompt intensification of glycemic control, concomitant risk factors, use of pharmacologic agents such as β-blockers and renin-angiotensin-aldosterone system antagosists. From a research perspective, more studies on myocardial tissue from diabetic patients are needed. Clinical trials to evaluate the development of diabetic cardiomyopathy and fibrosis in early stages of the disease, as well as clinical trials of pharmacologic intervention in patients specifically with diabetic cardiomyopathy, need to be conducted.     

Diabetes Mellitus in the Aging: Epidemiologic and Therapeutic Considerations

Diabetes mellitus is prevalent in older persons and a major risk factor for the development of cardiovascular disease. Impaired glucose tolerance without overt diabetes has also been shown to be associated with an increased risk of cardiovascular disease. Elderly patients with non-insulin-dependent diabetes mellitus are at increased risk for both symptomatic and asymptomatic myocardial infarction, and appear to have worse outcomes than nondiabetic persons with these same conditions. Older diabetic persons also have a greater risk than nondiabetics of developing systemic hypertension and stroke. Treatment of diabetes in the elderly can be divided into treatment of the hyperglycemia itself and treatment of other cardiovascular risk factors. It is unknown whether treatment of hyperglycemia in older patients will decrease the risk of cardiovascular and cerebrovascular disease, but it is proposed that treating diabetes along with other commonly associated risk factors for cardiovascular disease may provide the best outlook for such patients.     

Primary renal disease as a cardiovascular risk factor

Cardiovascular disease (CVD) is the No. 1 cause of death in patients with end-stage renal disease (ESRD) and is approximately 3 to 5 times that of non-uremic control subjects. Moreover, higher rates of CVD are seen in patients with moderate and even mild renal dysfunction, particularly if the patient has hypertension or diabetes. Recent studies have indicated that even modest elevations in serum creatinine and urinary albumin excretion are associated with increased CVD risk, not only in persons with diabetes or hypertension but also in the general population. In addition, recent studies have suggested that targeting the kidney and/or kidney specific endpoints (via the renin-angiotensin-aldosterone-kinin system) in the treatment of hypertension, diabetes, and heart failure slows progression of renal disease and reduces the risk of extra-renal micro- and macrovascular complications. We conclude that it is important to screen for renal disease in those with hypertension, diabetes, and other CVD risk factors because it predicts those who are at high risk for major CVD events.     

The impact of Type 2 diabetes and microalbuminuria on future cardiovascular events in patients with clinically manifest vascular disease from the Second Manifestations of ARTerial disease (SMART) study

Aims Type 2 diabetes mellitus and microalbuminuria are important risk factors for cardiovascular disease (CVD). Whether these two complications are important and independent risk factors for future CVD events in a high‐risk population with clinically manifest vascular disease is unknown. The objectives of this study were to examine the impact of Type 2 diabetes and microalbuminuria on future CVD events. Methods Patients with clinically manifest vascular disease (coronary, cerebral and peripheral vascular disease) from the Second Manifestation of Arterial disease study were followed up for 4 years. Data obtained from 1996–2006 were analysed. At baseline, there were 804 patients with Type 2 diabetes mellitus (mean age 60 years) and 2983 patients without. Incident CVD (n = 458) was defined as hospital‐verified myocardial infarction, stroke, vascular death and the composite of these vascular events. Results Both Type 2 diabetes [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.16, 1.75] and microalbuminuria (HR 1.86, 95% CI 1.49, 2.33) increased the risk of new cardiovascular events in univariate analyses. From multivariable models, presence of diabetes remained significantly and independently related to incident CVD (HR 1.42, 95% CI 1.11, 1.80). Presence of microalbuminuria also remained significantly independently related to incident CVD (HR 1.38, 95% CI 1.07, 1.77). In diabetes‐stratified analyses, the effect of microalbuminuria on CVD risk was observed only in patients with diabetes. In microalbuminuria‐stratified analyses, the significant and independent effect of diabetes on CVD risk was shown only in the non‐microalbuminuric group. Conclusions In this high‐risk population, both microalbuminuria and Type 2 diabetes are important and independent risk factors for future CVD.     

糖尿病并发心血管疾病的机理研究进展

心血管疾病 (CVDs)是糖尿病常见的并发症和主要死因。糖尿病并发CVDs的主要危险因素包括 :高血压、肥胖、动脉粥样硬化、脂质代谢失常、微蛋白尿、内皮功能失常、血小板高凝聚性、凝血 血纤溶系统活性失常以及糖尿病心肌病等。本文简要综述了糖尿病患者脂质代谢异常、内皮功能失常、蛋白质非酶糖化、氧化应激等病理生理生化变化促使动脉粥样硬化形成和CVDs发生的分子机理。     

Microalbuminuria--a risk factor for diabetic nephropathy and cardiovascular disease

In developed countries diabetics patients are the most numerous group with renal replacement therapy (USA 34%). The main and diagnostically irreplaceable criterion of incipient diabetic nephropathy is microalbuminuria which is usually associated with hypertension and poor glycaemic compensation. With advancing microalbuminuria progresses diabetic retinopathy and neuropathy. The increased transcapillary albumin escape rate and changes of some haemocoagulation factors in diabetics patients with microalbuminuria indicate that endothelial dysfunction is involved. In type 1 diabetes microalbuminuria is an indicator of increased mortality in which participate in particular cardiovascular diseases and to a minor extent renal failure. In type 2 diabetes microalbuminuria is an independent risk of generalized vascular disease. Microalbuminuria is also in non-diabetic subjects with hypertension associated with abnormalities such as impaired glucose tolerance and insulin resistance, an unflavourable lipidogram and altered diurnal blood pressure rhythm. The results of a coronarographic investigation revealed that the risk of severe coronary artery disease is more than double in subjects with microalbuminuria. Hypertension and hypercholesterolaemia are causal risk factors of cardiovascular diseases and concurrent microalbuminuria implies a higher expression of already existing microvascular damage in hormonal and metabolic disorders with an atherogenic potential.     

Loss of the female advantage with cardiovascular disease for women with diabetes.

BACKGROUND: The relative risk of cardiovascular disease (CVD) associated with diabetes is greater for women than men, and diabetic women did not experience temporal declines in CVD mortality observed for the general population and diabetic men. OBJECTIVE: To examine sex differences in CVD risk factors for persons with diabetes over time. DESIGN: Population-based historical cohort study. METHODS: The provider-linked medical records of all Rochester, MN, residents assigned a clinical diagnosis of diabetes were reviewed to confirm case status and assign diagnosis date. Data on fasting glucose, obesity, persistent proteinuria, smoking, hypertension, and dyslipidemia were obtained at diagnosis for confirmed incidence cases. RESULTS: There were 1330 diabetes cases 1970- 1989. Compared to men, women at diagnosis were older and more likely hypertensive, had similar levels of fasting glucose and persistent proteinuria, and less likely to smoke. Among persons diagnosed at younger ages, women were more likely than men to be obese. Comparison with published data for the Rochester population revealed the excess obesity and hypertension associated with diabetes were highest for women < age 55 y. Temporal trends in CVD risk factors did not differ between diabetic men and women.     

Cardiovascular disease in recent onset diabetes mellitus

Diabetes is associated with a marked increased risk of atherosclerotic vascular disorders, including coronary, cerebrovascular, and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidemia, hypertension, smoking, obesity, lack of exercise, and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in the diabetic population. Furthermore, recently, macrovascular complications of diabetes have been shown to start before the onset of diabetes. Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT). Since insulin resistance-related postprandial metabolic derangements are thought to play a central role in the development and progression of CVD in patients with IGT, amelioration of postprandial metabolic disturbance is a therapeutic target for the prevention of CVD in these high-risk patients. Therefore, in this paper, we review the molecular mechanisms for the increased risk of CVD in recent onset diabetes mellitus, especially focusing on postprandial dysmetabolism. We also discuss here the potential therapeutic strategies that specially target the mechanisms responsible for vascular alterations in diabetes.     

Microalbuminuria and hypertension with focus on type 1 and type 2 diabetes

Microalbuminuria and hypertension with Over the past decade, there has been considerable focus on the concept of microalbuminuria, not only because it predicts renal disease in type 1 and type 2 diabetes, but also because it relates to premature mortality in the diabetic and in the general population. More importantly, intervention at this stage is now possible with the perspective of preserving glomerular filtration rate (GFR) and ameliorating cardiovascular disease and ensuing strong end-points. INITIAL STUDIES: The concept of microalbuminuria was introduced about 20 years ago and since then there has been a multitude of studies and papers on this subject using the original definition, but not always, in the US. Before that time it was suggested, mainly from the US, that diabetic renal disease was an untreatable relentlessly progressive condition. GENETIC STUDIES: There is an overwhelming number of studies on genetics and diabetes and also covering the genetics of diabetic complications including nephropathy. However, so far the results are extremely disappointing. Patients at risk cannot be identified and genetic analyses are of no value as a guide to treatment. The notion that the development of complications is controlled mainly by a special genetic pattern is increasingly doubtful. In genetic studies, it is rather phenotypic well-accepted risk factors that dominate. STRUCTURAL BASIS OF MICROALBUMINURIA: Patients with microalbuminuria have significant abnormalities in the kidney, including glomeruli. This is quite clear in patients with type 1 diabetes, but is also seen in type 2 diabetes, where on the other hand, other risk factors such as hypertension and dyslipidaemia also seem to be of importance, including loss of autoregulation. Renal biopsies are generally not indicated in the management of diabetic patients. MICROALBUMINURIA AND EARLY MORTALITY: It is quite clear that microalbuminuria predicts early mortality both in type 1 and type 2 diabetes. The association to other risk factors may partly explain this--but this does not account for the whole picture. Endothelial dysfunction as well as inflammatory and arteriosclerotic abnormalities in blood vessels may be a relevant hypothesis that needs to be further explored along with other possibilities. CLINICAL COURSE AND ASSOCIATED ABNORMALITIES: The risk factor for progression in normoalbuminuric patients to microalbuminuria is higher than normal albumin excretion (strongest factor), poor glycaemic control, elevated blood pressure, and to some extent smoking. The clinical course of microalbuminuria is usually progressive, but with the more effective intervention now available we encounter that the so-called natural history (without intervention) is increasingly difficult to study. Microalbuminuria is clearly associated with a number of abnormalities, almost in all organs, but GFR is generally well preserved in spite of more advanced structural lesions. Therefore, microalbuminuria is an important marker for more pronounced diabetic vascular disease in general as well as for nephropathy. Regression to normoalbuminuria only rarely occurs during standard unchanged nonintensive treatment. TREATMENT STRATEGIES: The best possible glycaemic control is important in preventing and ameliorating the course of normo- and micro-albuminuria. Another major treatment strategy, especially in microalbuminuric patients, is antihypertensive treatment including inhibition of the renal angiotensin aldosterone system. Numerous new studies are available, both in type 1 and type 2 diabetes, documenting that not only microalbuminuria but also renal and cardiovascular complications in these patient are also far better controlled by early detection and treatment. Therefore, screening for microalbuminuria should be a strategy in all diabetes management followed by effective intervention as outlined in this paper.     

Antihypertensive treatment in type II diabetes and diabetic nephropathy

Hypertension is very prevalent in patients with type II diabetes. Beside increasing the cardiovascular risk, hypertension has several deleterious effects on the kidney: hypertension promotes the development of diabetic nephropathy, the progression from microalbuminuria to overt diabetic nephropathy and progression to end stage renal disease. In this review, we analyze systematically the benefit of antihypertensive therapy in patients with type II diabetes, with either normo-albuminuria, microalbuminuria or overt nephropathy. General considerations are developed about the general use of antihypertensive drugs in this population. An approach based on the prevention of the global or absolute cardiovascular risk is further recommended due to the very high cardiovascular burden in this diabetic patients.     

Update on the Prevention of Type 2 Diabetes

Diabetes has emerged as the modern day epidemic that is currently affecting over 220 million people worldwide and claiming at least 1.1 million lives in 2005 alone. The rise in diabetes is largely attributed to the epidemic of obesity together with sedentary lifestyle as well as unhealthy dietary habits. Despite evidence that glycemic control as well as control of other cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia decreases morbidity and mortality in the diabetic population, control of glycemia and other CVD risk factors remains largely suboptimal making the concept of prevention of diabetes very appealing to control CVD risk, especially that such a risk is already increased in people in the prediabetic stage. Several large controlled trials have been completed testing various options for diabetes prevention. In this paper we present an update on prevention of type 2 diabetes highlighting the major recent trials completed to date in this very important area of investigation.