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Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.
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PMID:Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes. 1796 80

The metabolic syndrome (MS), a cluster of risk factors, such as obesity, hyperglycemia, hypertension and dyslipidemia, contributes to the development of cardio-vascular diseases and type 2 diabetes mellitus (DM2). Insulin resistance (IR) plays a key role in MS being strongly linked to abdominal visceral fat. Treatment for obese patients with MS should aim at improving IR, delaying the onset of DM2 and at reducing cardio-vascular risk. Weight loss, first therapeutic target, may be obtained through life-style modifications and anti-obesity drugs or bariatric surgery, at need. In these patients drug therapy is necessary if therapeutic life-style changes are not sufficient. Some drugs have adverse metabolic effects, therefore the therapeutic choices must be specific and rational. Metformin, Thiazolidinediones and Acarbose are anti-hyperglycemic drugs of choice: they reduce the incidence of DM2 and IR (or improve insulin sensitivity) and they decrease or stabilize the visceral adipose tissue mass (Thiazolidinediones increases subcutaneous fat only). Also Angiotensin II receptor blockers and Angiotensin-converting enzyme inhibitors reduce the incidence of DM2 and insulin resistance and they are first-line antihypertensive drugs in MS. Calcium channel blockers, Alpha-1 antagonists and Alpha-2 agonists drugs are metabolically neutral and slight weight gains are related to the hydro-sodium retention. Beta-blockers and Diuretics, except for Indapamide and Anti-aldosterone drugs, can reduce insulin sensitivity, impair lipid profile and increase DM2 incidence; they are not first-line therapy yet they are necessary in selected cases only. Statins, Fibrates and omega-3 Fatty acids are indicated to normalize dyslipidemia. Low doses of acetylsalicylic acid are also recommended.
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PMID:[Therapeutic options for metabolic syndrome in obese patients]. 1806 54

Cardiovascular manifestation of diabetes has remarkable therapeutic and prognostic implications. Diabetic cardiomyopathy is a distinct heart muscle disease in patients with well-controlled diabetes mellitus that cannot be ascribed to coronary artery disease, hypertension or any other known cardiac disease. It is characterized by left ventricular diastolic dysfunction that can be detected in 52-60% of well-controlled type II diabetic subjects using contemporary Doppler techniques. Pathophysiologically, hyperglycaemia causes myocardial necrosis and fibrosis, as well as the increase of myocardial free radicals and oxidants, which decrease nitric oxide levels, worsen the endothelial function and induce myocardial inflammation. Insulin resistance with hyperinsulinaemia and decreased insulin sensitivity are responsible for left ventricular hypertrophy. Clinical manifestations of diabetic cardiomyopathy are dispnoea, arrhythmias, atypical chest pain or dizziness. The treatment of diabetic cardiomopathy should be initiated as early as diastolic dysfunction is identified. Various therapeutic options include improving diabetic control with both diet and drugs (metformin and thiazolidinediones), use of ACE inhibitors, beta blockers and calcium channel blockers. Daily physical activity and reduction in body mass index may improve glucose homeostasis by reducing the glucose/insulin ratio, and the increase of both insulin sensitivity and glucose oxidation by the skeletal and cardiac muscles. Metformin and thiazolidinendiones are used to treat insulin resistance, but have different mechanisms of action. Metformin reduces free fatty amino acids effluvium from fat cells, thereby suppressing hepatic glucose production and indirectly improving peripheral insulin sensitivity and the endothelial function. In contrast, thiazolidinediones improve peripheral insulin sensitivity by reducing circulating free fatty amino acids, but also increasing production of adiponectin, which improves insulin sensitivity. Beta-adrenoceptor blocking agents are effective in preventing or reversing myocardial dilatation and remodelling, while ACE inhibitors facilitate blood flow through microcirculation in coronary vascular bed, fat and skeletal muscle, as well as improve insulin action at the cellular level.
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PMID:[Diabetic cardiomyopathy: old disease or new entity?]. 1808 46

The prevalence of type 2 diabetes is rising at an alarming rate worldwide. Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the diabetic population. Future CAD risk should be routinely assessed in patients with diabetes as specific subgroups might benefit from information derived from cardiac stress testing and other diagnostic procedures. Risk factor control is of paramount importance in all cases and it usually requires sustained lifestyle modifications, coupled with pharmacological interventions. Statins and angiotensin-converting enzyme (ACE) inhibitors are the first-line agents for the treatment of dyslipidaemia and hypertension, respectively. Microvascular, but not macrovascular, complications of diabetes are effectively prevented by good glycaemic control. Metformin is considered the first-choice agent in overweight diabetic subjects, while the role of thiazolidinediones is currently the focus of medical research. The diagnosis of acute coronary events in patients with diabetes is often challenging because of the high prevalence of silent ischaemia in these subjects. All acute cardiac events need to be promptly treated and myocardial reperfusion attempted without delay. Maintaining glucose levels as close to normal as possible, during and shortly after an acute event, improves prognosis in patients with diabetes. Risk factor control remains the cornerstone of secondary prevention; beta-blockers, ACE-inhibitors and antiplatelet agents confer additional symptomatic and survival benefit. Similar therapeutic principles also apply to patients with type 1 diabetes. This article addresses the complex problem of managing patients with diabetes and coronary artery disease.
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PMID:Medical management of the diabetic patient with coronary artery disease. 1899 70

Evidence-based guidelines for the treatment of type 2 diabetes mellitus focus on three areas: intensive lifestyle intervention that includes at least 150 minutes per week of physical activity, weight loss with an initial goal of 7 percent of baseline weight, and a low-fat, reduced-calorie diet; aggressive management of cardiovascular risk factors (i.e., hypertension, dyslipidemia, and microalbuminuria) with the use of aspirin, statins, and angiotensin-converting enzyme inhibitors; and normalization of blood glucose levels (hemoglobin A1C level less than 7 percent). Insulin resistance, decreased insulin secretion, and increased hepatic glucose output are the hallmarks of type 2 diabetes, and each class of medication targets one or more of these defects. Metformin, which decreases hepatic glucose output and sensitizes peripheral tissues to insulin, has been shown to decrease mortality rates in patients with type 2 diabetes and is considered a first-line agent. Other medications include sulfonylureas and nonsulfonylurea secretagogues, alpha glucosidase inhibitors, and thiazolidinediones. Insulin can be used acutely in patients newly diagnosed with type 2 diabetes to normalize blood glucose, or it can be added to a regimen of oral medication to improve glycemic control. Except in patients taking multiple insulin injections, home monitoring of blood glucose levels has questionable utility, especially in relatively well-controlled patients. Its use should be tailored to the needs of the individual patient.
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PMID:Management of blood glucose in type 2 diabetes mellitus. 2064 60

Hyperglycaemia is a typical feature of metabolic syndrome (MeTS) and one of its independent diagnostic criteria. The term includes impaired glucose homeostasis (impaired fasting glucose and impaired glucose tolerance) and type 2 diabetes mellitus. Although glycaemic control has been shown to lower the risk of microvascular events, the effect of intensive glycaemic control on macrovascular outcomes is less clear. Epidemiological studies show hyperglycaemia, particularly the postprandial one, to be a clear risk factor for cardiovascular (CV) mortality and morbidity. However, the intervention studies are less conclusive. The large interventional studies published in 2008 and 2009 (UKPDS, VADT, ACCORD, ADVANCE, RECORD) advocate the controlling of nonglycemic risk factors (through blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle modifications) as the primary strategies for reducing the burden of CV disease in people with diabetes, and demonstrated the need for individualized approach to the patients' care in terms of blood glucose control. The patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap CV benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycaemic control (hypoglycaemia) may outweigh its benefits in other patients, such as those with a very long duration ofdiabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. According to the latest recommendations of the Czech Diabetes Society that are in line with the European and US standards the best way to protect type 2 diabetic patients against coronary and cerebrovascular disease is to target all cardiovascular risk factors (blood pressure treatment, including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors hypertension, dyslipidemia, obesity and other symptoms of metabolic syndrome. The target HbA1c levels in patients with the low CV risk shoul be below 4.5%. Less strict goals (HbA1c below 6%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes. The individual targets should be achieved safely (without hypoglycaemias). Slow advancing in diabetes compensation is preferred. Lifestyle changes are the cornerstone of therapy. Metformin is the drug of choice; its administration, together with lifestyle changes, should be initiated immediately after the diagnoses of diabetes. If monotherapy does not provide satisfactory glucose control, other oral antidiabetic agents or insulin are added to the combination. Since it is not known which hypoglycaemic agents are beneficial from the perspective of long-term patient prognosis, the selection is liberal. Contraindication of the various farmaceuticals must be respected. It is possible to use a range of different combinations, metformin is administered with a glitazone (zero risk of hypoglycaemias is the advantage) with sulphonylurea derivatives (low price is the advantage) with glinides, with incretins, acarbose, antiobesity agents or insulin. The next step is a triple combination of hypoglycaemic agents with different mechanisms of action. Therapy also includes education focusing on changes to dietary and lifestyle habits, including smoking cessation, and education related to the prevention of complications, with particular regard to prevention of diabetic foot and atherosclerosis.
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PMID:[Treatment of diabetes in metabolic syndrome]. 1973 68

Type 2 diabetes is associated with substantially increased cardiovascular mortality. The need to reduce the progression of atherosclerosis alongside lowering blood glucose levels is now well established. Ideally, pharmaceutical treatment should address both of these needs. This review summarises current evidence of the anti-atherosclerotic effects exerted by oral antidiabetic agents. Metformin has so far consistently succeeded in reducing cardiovascular morbidity and mortality and exerting beneficial effects on lipids. Of the new agents, thiazolidinediones (rosiglitazone and pioglitazone) have been most widely studied. They have a favourable effect on fat distribution and improve lipid profile, fibrinolysis and endothelial function. Moreover, they reduce blood pressure and inflammatory markers, attenuate the progression of carotid intima-media thickness (CIMT) and may reduce the rates of coronary restenosis following percutaneous coronary intervention. Glinides (repaglinide and nateglinide) have also been documented to improve endothelial function and lipid profile, to reduce oxidative stress, platelet activity and inflammatory markers, and to diminish the progression of CIMT. Finally, acarbose may significantly reduce new cases of hypertension and cardiovascular events, as well as diminishing the progression of CIMT in patients with impaired glucose tolerance. Interestingly, some of these beneficial effects appear to be independent of the antidiabetic action. Thus, oral antidiabetic agents are now emerging as useful tools for the attenuation of the atherosclerotic activity and for the protection of the vasculature in patients with type 2 diabetes.
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PMID:Oral antidiabetic agents: anti-atherosclerotic properties beyond glucose lowering? 1975 90

Metformin is quite an old drug, but it is optimal for the control of glycemia in Type 2 diabetes. It was reported, 15 years ago, that insulin resistance was abnormally high in most polycystic ovary syndrome (PCOS) patients. Starting from that moment, increasing numbers of studies were performed to demonstrate the efficacy of metformin in controlling and/or modulating several aspects of PCOS, which is the most common cause of menstrual irregularity, inesthetisms and infertility. Metformin induces higher glucose uptake, thus inducing a lower synthesis/secretion of insulin. Such an effect permits the possible restoration of the normal biological functions that are severely affected by the compensatory hyperinsulinemia reactive to the increased peripheral insulin resistance. These are the basis of the many positive effects of this drug, such as the restoration of menstrual cyclicity, ovulatory cycles and fertility, because abnormal insulin levels affect the hypothalamus-pituitary-ovarian function, as well as the use of glucose in peripheral tissues. Metformin improves the impairments typically observed in hyperinsulinemic PCOS patients, reducing the possible evolution towards metabolic syndrome and Type 2 diabetes; and when pregnancy occurs, it consistently reduces the risk of gestational diabetes, eclampsia and hypertension. PCOS seems to be the perfect physiopathological condition that might have higher benefits from metformin administration, obviously after Type 2 diabetes. This review focuses on the many aspects of PCOS and on the possible issues of this disease for which metformin might be a putative optimal treatment.
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PMID:Use of metformin in the treatment of polycystic ovary syndrome. 2059 21

We shall open our overview of issues related to obesity and hyperlipoproteinemia (HLP) or dyslipidemia with a notoriously known truth (that some are still reluctant to accept): HLP/DLP is not obesity. It is certainly not possible to put an equal sign between subcutaneous fat and the level of plasma lipids and lipoproteins. On the other hand, it is obvious that there is a number of connecting links between HLP/DLP and obesity. These associations on one side and differences on the other are the focus of this review paper. (1) HLP/DLP as well as obesity represent a group of high incidence metabolic diseases (gradually evolving from epidemic to pandemic) that affect several tens of percent of inhabitants. (2) Both HLP/DLP and obesity often occur concurrently, often as a result of unhealthy lifestyle. However, genetic factors are also been studies and it is possible that mutual predispositions for the development of both diseases will be identified. At present, it is only possible to conclude that obesity worsens lipid metabolism in genetically-determined HLP. (3) Both these metabolic diseases represent a risk factor for other pathologies, cardiovascular diseases are the most important common complication of both conditions (central type of obesity only). Concurrent presence of HDL/DLP and obesity is often linked to other diagnoses, such as type 2 diabetes mellitus (DM2T), hypertension, pro-coagulation or pro-inflammatory states; all as part of so called metabolic syndrome. (4) Patients with metabolic syndrome and, mainly, central obesity usually have typical dyslipidemia with reduced HDL-cholesterol (HDL-C) and sometimes hypertriglyceridaemia. Current treatment of HDL/DLP aims to first impact on the primary aim, i.e. LDL-cholesterol (LDL-C), and than influence HDL-C. (5) It seems that the therapeutic efforts in HLP/DLP and obesity will go in the same direction. I will skip the trivial (and difficult to accept by patients) dietary changes. Pharmacotherapy, however, (very scarce with respect to obesity) may bring positive effects on lipids and BMI. Metformin used to be considered as a drug that could improve lipid profile and lead to body weight reduction. Even though larger studies did not provide an unambiguous evidence for this, metformin keeps its position as a first line oral antidiabetic (not only) in patients with T2DM, HLP and obesity. Positive effect on lipids, mainly HDL-C is reported with pioglitazone. This drug, unlike other glitazones, does not bring body weight reduction but at least does not have a negative effect. Other antidiabetics with a positive effect on lipids and body weight include incretins, liraglutid in particular. Liraglutid importantly decreases triglyceride levels and has anorectic effect. Furthermore, metabolic effects of bariatric surgery should not be overlooked. Bariatric surgery brings weight reduction as well as it improves lipid profile and compensation of diabetes mellitus (DM). It should be mentioned here that bariatric surgery has been used for the treatment of HLP as early as 1980s. The results of the 25-year follow up within the POSCH study (ideal bypass indicated for HLP), presented in 2010, confirm a decrease in overall as well as cardiovascular mortality in an operated group, even though patients who did not undergo surgery were significantly more frequently treated with statins.
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PMID:[Dyslipidemia and obesity 2011. Similarities and differences]. 2149 5

Diabetes accounts for millions of office visits each year to primary care offices in the United States. Successful care of the patient with type 2 diabetes requires not only focus on glucose management but also on comorbidities such as hypertension, dyslipidemia and obesity which are closely linked to microvascular and macrovascular complications. Primary care clinicians must stay abreast of frequently published diabetes literature and new treatments to care for these increasingly complex patients. Metformin and its effect on B12 absorption continues to be an issue encountered by clinicians in daily clinical practice. There has also been recent discussion regarding the increased risk of diabetes with statins; data to date on this issue have been conflicting. Rosiglitazone continues to face public scrutiny and there are now Food and Drug Administration regulations regarding its increased risk of cardiovascular disease. Liraglutide and saxagliptin represent new treatment options for type 2 diabetes, increasing the available options for treating this complex disease. A review of the primary literature involving these topics is provided.
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PMID:Recent diabetes issues affecting the primary care clinician. 2188 36


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