Diabetes and Cardiovascular Disease: an Update.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of mortality in people with diabetes. Our aim was to review the pathophysiology of CVD in diabetes, review related landmark trials, and discuss the cardiovascular benefit of glucose-lowering agents. We have also discussed the role of controversial anti-platelet therapy. RECENT FINDINGS: Recent studies have shown the impact of glucose-lowering agents on CVD in people with diabetes. Statins are now recommended for all patients with diabetes over the age of 40 regardless of the LDL level given the cardiovascular benefit of these drugs. Current recommendations suggest a blood pressure < 130/80 for individuals with high cardiovascular risk. Cardiovascular risk reduction should be an important part of the management of diabetes. Focusing solely on glycemic control may not be the best therapeutic strategy. Multifactorial risk reduction should be taken into account. Lipid-lowering agents and anti-hypertensives should be a corner stone of treatment of diabetes. With currently available data, glucose-lowering agents with cardiovascular benefit should be started early in the disease process.

Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors.

OBJECTIVES: To summarize data supporting the effects of antidiabetes agents on glucose control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: Studies reporting on the effects of antidiabetes agents on glycemic control, body weight, lipid levels, and blood pressure parameters are reviewed and summarized for the purpose of selecting optimal therapeutic regimens for patients with type 2 diabetes. RESULTS: National guidelines recommend the aggressive management of cardiovascular risk factors in patients with type 2 diabetes, including weight loss and achieving lipid and blood pressure treatment goals. All antidiabetes pharmacotherapies lower glucose; however, effects on cardiovascular risk factors vary greatly among agents. While thiazolidinediones, sulfonylureas, and insulin are associated with weight gain, dipeptidyl peptidase-4 inhibitors are considered weight neutral and metformin can be weight neutral or associated with a small weight loss. Glucagon-like peptide-1 receptor agonists and amylinomimetics (e.g. pramlintide) result in weight loss. Additionally, metformin, thiazolidinediones, insulin, and glucagon-like peptide-1 receptor agonists have demonstrated beneficial effects on lipid and blood pressure parameters. CONCLUSION: Management of the cardiovascular risk factors experienced by patients with type 2 diabetes requires a multidisciplinary approach with implementation of treatment strategies to achieve not only glycemic goals but to improve and/or correct the underlying cardiovascular risk factors.

Dysglycemia/prediabetes and cardiovascular risk factors.

Obesity and diabetes are becoming a pandemic in developing and industrialized countries. Based on the current criteria, 24.1 million Americans have diabetes, and another 57 million have prediabetes. The term prediabetes refers to people who have impaired fasting glucose (100-125 mg/dL), impaired glucose tolerance (2-hour postglucose load of 140-199 mg/dL), or both. Many persons with prediabetes already have microvascular disease consequences (eg, blindness, amputations, kidney failure) similar to those seen in patients with a diagnosis of diabetes. However, it is not established whether prediabetes should be considered a coronary heart disease risk equivalent. Whether dysglycemia is a surrogate for a more complex metabolic condition and/or directly increases cardiovascular disease (CVD) risk remains unclear. However, many studies have shown that hyperglycemia, through various mechanisms, can lead to premature atherosclerosis. In this regard, several diabetes prevention trials have shown that strategies that reduce the rate of conversion to diabetes can also modify CVD risk factors.

Hypertension in obesity.

Hypertension and obesity are major components of the cardiometabolic syndrome and are both on the rise worldwide, with enormous consequences on global health and the economy. The relationship between hypertension and obesity is multifaceted; the etiology is complex and it is not well elucidated. This article, reviews the current knowledge on obesity-related hypertension. Further understanding of the underlying mechanisms of this epidemic will be important in devising future treatment avenues.

Diabetes and Hypertension: Clinical Update.

The presence of hypertension in individuals with type 2 diabetes augments the risk for cardiovascular morbidity and mortality. In this regard, data support that management of hypertension in this high-risk population is a critical risk reduction strategy. In recent years, a number of work groups have redefined hypertension, management strategies, and targets. In this context, there is still considerable discussion on an appropriate target for blood pressure in the diabetic population. However, despite this discussion on target blood pressure, it is widely recognized that there is considerable residual risk for heightened cardiovascular events in the hypertensive, diabetic population despite widespread awareness and treatment. There has been increasing interest in management strategies for blood pressure reduction in this high-risk population that complement traditional antihypertensive agents. Large-scale clinical trials have shown that hypoglycemic agents can complement blood pressure reduction and have a favorable effect on cardiovascular outcomes such as the sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. In the diabetic population, consideration should be given to the blood pressure lowering effects of the newer hypoglycemic agents when working toward additional glycemic control in patients with hypertension.

Treatment of hypertension in diabetes: a contemporary approach with a focus on improving cardiovascular outcomes.

Diabetes mellitus and hypertension are interrelated conditions that predispose patients to cardiovascular disease. The 2015 American Diabetes Association guidelines recommend a blood pressure goal of <140/90 but indicates that a lower goal can be set for some individuals if this can be achieved without undue burden. Renin angiotensin system blockers remain the main stay of treatment in hypertensive diabetics together with lifestyle interventions. Guidelines indicate that combination therapy may be initiated in patients who have a blood pressure 20/10 over the target BP. As discussed in this review, there are several diabetic medications that have antihypertensive effects. Management of hypertension in diabetes mellitus is an important factor in reducing cardiovascular disease in conjunction with other cardiovascular disease prevention strategies such as use of stains and aspirin. Patients will benefit from multidisciplinary team expertise including a primary care provider, endocrinologist, hypertension specialist, diabetic educator and dietician.

Type 2 diabetes mellitus and hypertension: an update.

Patients with hypertension and type 2 diabetes are at increased risk of cardiovascular and chronic renal disease. Factors involved in the pathogenesis of both hypertension and type 2 diabetes include inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, impaired insulin-mediated vasodilatation, augmented sympathetic nervous system activation, altered innate and adaptive immunity, and abnormal sodium processing by the kidney. The renin-angiotensin-aldosterone system blockade is a key therapeutic strategy in the treatment of hypertension in type 2 diabetes. Emerging therapies for resistant hypertension as often exists in patients with diabetes, include renal denervation and carotid body denervation.

Hypertension in obesity.

Obesity and HTN are on the rise in the world. HTN seems to be the most common obesity-related health problem and visceral obesity seems to be the major culprit. Unfortunately, only 31% of hypertensives are treated to goal. This translates into an increased incidence of CVD and related morbidity and mortality. Several mechanisms have been postulated as the causes of obesity-related HTN. Activation of the RAAS, SNS, insulin resistance, leptin, adiponectin, dysfunctional fat, FFA, resistin, 11 Beta dehydrogenase, renal structural and hemodynamic changes, and OSA are some of the abnormalities in obesity-related HTN. Many of these factors are interrelated. Treatment of obesity should begin with weight loss via lifestyle modifications, medications, or bariatric surgery. According to the mechanisms of obesity-related HTN, it seems that drugs that blockade the RAAS and target the SNS should be ideal for treatment. There is not much evidence in the literature that one drug is better than another in controlling obesity-related HTN. There have only been a few studies specifically targeting the obese hypertensive patient, but recent trials that emphasize the importance of BP control have enrolled both overweight and obese subjects. Until we have further studies with more in-depth information about the mechanisms of obesity-related HTN and what the targeted treatment should be, the most important factor necessary to control the obesity-related HTN pandemic and its CVD and CKD consequences is to prevent and treat obesity and to treat HTN to goal.

Phosphate Metabolism in Cardiorenal Metabolic Disease.

Hyperphosphatemia is a major risk factor for cardiovascular disease, abnormalities of mineral metabolism and bone disease, and the progression of renal insufficiency in patients with chronic renal disease. In early renal disease, serum phosphate levels are maintained within the 'normal laboratory range' by compensatory increases in phosphaturic hormones such as fibroblast growth factor-23 (FGF-23). An important co-factor for FGF-23 is Klotho; a deficiency in Klotho plays an important role in the pathogenesis of hyperphosphatemia, renal tubulointerstitial disease, and parathyroid and bone abnormalities. Clinical hyperphosphatemia occurs when these phosphaturic mechanisms cannot counterbalance nephron loss. Hyperphosphatemia is associated with calcific uremic arteriolopathy and uremic cardiomyopathy, which may explain, in part, the epidemiologic connections between phosphate excess and cardiovascular disease. However, no clinical trials have been conducted to establish a causal relationship, and large, randomized trials with hard endpoints are urgently needed to prove or disprove the benefits and risks of therapy. In summary, hyperphosphatemia accelerates renal tubulointerstitial disease, renal osteodystrophy, as well as cardiovascular disease, and it is an important mortality risk factor in patients with chronic kidney disease.

Adrenal steroids and the metabolic syndrome.

The many similarities between the metabolic syndrome and Cushing's syndrome led to the hypothesis that excess glucocorticoids (GC) are part of the pathogenesis linking their features. We review recent work that confirms the initial similarities (obesity, glucose intolerance, hypertension, and hyperlipidemia) and extends them to associated features of both syndromes (osteopenia, hypogonadism, leukocytosis, depression, and muscle weakness). Recent studies report that these features also occur in subclinical Cushing's syndrome, hypercortisolemic depression, and the transgenic overexpression of 11beta-hydoxysteroid dehydrogenase type 1 (11beta-HSD1) in mouse models of excess GC in adipose tissue. Reducing excess GC--in the clinical syndromes and in the mouse model-reverses many of these features. Because local tissue excess GC may have a central role in the pathogenesis of the metabolic syndrome, selective 11beta-HSD1 inhibitors are under active development by several pharmaceutical companies.

Stroke prevention in diabetes and obesity.

Stroke is an important cause of morbidity and mortality, and is an economic burden. Diabetes and obesity are two important modifiable risk factors for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Risk-factor modification is the most important aspect of prevention of stroke in diabetes and obesity. This includes lifestyle modifications and different therapeutic modalities to control conditions, such as diabetes, hypertension, dyslipidemia and arrhythmia. Recent landmark studies have shown the beneficial effects of statins in diabetic patients even with close to normal or normal low-density lipoprotein cholesterol. Obesity, which is a risk factor for diabetes, hypertension and hyperlipidemia has been shown to be an independent risk factor for stroke. Increased leptin, dysregulation of adipocyte proteins, increased insulin resistance and C-reactive protein may be factors involved in the increased incidence of cardiovascular morbidity and mortality directly related to obesity. Visceral fat is a much bigger health risk than subcutaneous fat. Lifestyle interventions and pharmacotherapeutic agents have been used to manage obesity. In morbidly obese patients, surgical intervention seems to be the best method of treatment with a long-lasting favorable metabolic outcome. In the 21st Century, with the advanced medical knowledge and the therapeutic modalities available, it should be possible to reduce the incidence of stroke associated with diabetes and obesity.

Polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common reproductive endocrinopathy of women during their childbearing years. A significant degree of controversy exists regarding the etiology of this syndrome, but there is a growing consensus that the key features include insulin resistance, androgen excess, and abnormal gonadotropin dynamics. Familial and genetic factors cause predisposition to PCOS. Insulin resistance and adiposity put women with PCOS at a higher risk for diabetes, hypertension, dyslipidemia, and cardiovascular disease. Even though the adverse health consequences associated with PCOS are substantial, most women are not aware of these risks. Early recognition and treatment of metabolic sequelae should be the main focus of clinicians. Lifestyle modifications, mainly a balanced diet, weight loss, and regular exercise, are of utmost importance. On the pharmacologic front, various therapies including metformin, thiazolidinediones, and others appear to be very promising in the management of cardiometabolic aspects of PCOS.

Hypertension in pregnancy.

Hypertension in pregnancy contributes significantly to both maternal and neonatal morbidity and mortality. Among different forms of pregnancy-associated hypertension, preeclampsia-eclampsia has the highest impact on morbidity and mortality. Chronic hypertension may result in preterm and small for gestational age infants, even when it is mild-to-moderate. Chronic hypertension is a risk factor for superimposed preeclampsia and results in higher rates of adverse outcome. Preeclampsia is a multisystemic disease that is thought to be initiated by abnormalities in placental perfusion and endothelial dysfunction, ultimately resulting in multiorgan failure. Preeclampsia is more common in women of minority ethnicity who are socioeconomically disadvantaged. Pharmacologic therapy for hypertensive disorders in pregnancy is limited by concerns regarding the safety of both mother and fetus. Although treatment of severe hypertension is not debated, there is no consensus on the rationale for pharmacologic therapy of mild-to-moderate hypertension in pregnancy.