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In many industrialized nations, obesity is now considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as the metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia and hypertension, which are all recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public health problem. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining bodyweight loss. For example, phentermine may result in modest bodyweight loss through suppression of appetite, but potential cardiovascular adverse effects exist and the efficacy is mainly short-term. Sibutramine, an inhibitor of serotonin and norepinephrine (noradrenaline) reuptake, may increase satiety and result in modest bodyweight loss. However, cardiovascular adverse effects may occur in susceptible patients. Nonetheless, sibutramine is one of the few drugs that has been approved by the US Food and Drug Administration (FDA) for bodyweight loss. Orlistat, a lipase inhibitor, is also approved by the FDA for bodyweight loss but may have bothersome gastrointestinal adverse effects, especially among patients who do not adhere to the recommended low-fat diet. Ongoing studies continue to evaluate other drug treatments that may result in bodyweight reduction through a number of different mechanisms. It is anticipated that the development of effective and well tolerated antiobesity drugs will elevate the pharmacologic treatment of obesity to the status of other cardiovascular risk factors and metabolic disorders. This may be especially important given that dyslipidemia, hypertension and type 2 diabetes mellitus are often secondary to, or exacerbated by, obesity.
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PMID:Pharmacotherapy of obesity: currently marketed and upcoming agents. 1472 70

In the normal population, the prevalence of obesity is almost 20%. It is a condition influenced by genetic factors, so that individual behavior cannot be regarded as its sole cause. The amount of food is essentially determined by the hormone leptin, the feedback regulation of which can be disturbed by a modification of the molecule or a mutation of the receptor. A further important determinant is energy consumption, which is subject to large individual variations, which partly result from thermogenesis. With regard to the fat distribution, it is concentrated on the trunk in the android form as compared to the hips in the gynecoid form. The android form is subject to a higher incidence of cardiovascular morbidity and mortality. The indirect determination of body fat by measuring the body mass index (weight [kg]/body weight [m(2)]) is hence less reliable than measuring the waist (women > 80 cm, men > 94 cm). The effects of generalized obesity on cardiovascular function are chiefly an increase of blood volume and an eccentric left ventricular hypertrophy. This first of all results in diastolic dysfunction, which can give rise to a disturbance of systolic function in left ventricular dilatation. Concentric hypertrophy develops in the presence of arterial hypertension. This is twice as frequent in obese patients than in the normal population, which is due to increased activity of the sympathetic nervous system and stimulation of the renin-angiotensin system. A disturbance of lipid metabolism is observed four to six times more frequently. The qualitative change in LDL fraction with a raised concentration of low density LDL particles appears to be of crucial importance. With increasing fat mass, the sensitivity to insulin is lowered, so that in obesity the risk of developing diabetes mellitus type 2 is tripled. Since there has been a dramatic increase in the numbers of overweight children and adolescents (from 10.5% to 15.5% within the past five years), prevention programs should be started in good time. A reduction in calorie intake and an altered dietary composition (55% complex carbohydrates, 30% fat and 15% to 20% protein) on the one hand, and increased physical activity on the other hand continue to be the central components. The latter is especially effective when it regularly gives rise to an increased turnover of fatty acids as a result of an increased energy metabolism at moderate intensity. This leads to adaptation, i. e. an increase in the activity of lipoprotein lipase. If prevention programs and/or changes in lifestyle do not give rise to the desired weight reduction, medication is indicated in some adults. Sibutramine (Reductil and orlistate (Xenical) lead to an additional weight loss of up to 10%. However, consistent treatment of any cardiovascular risk factors present is more important. Treatment of arterial hypertension is of greatest prognostic significance, especially in concomitant diabetes mellitus. In individual cases and after thorough discussion of indication surgical options should be considered.
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PMID:[Obesity and cardiovascular diseases-theoretical background and therapeutic consequences]. 1524 61

The conventional cardiovascular risk factors such as smoking, hyperlipoproteinemia, arterial hypertension and diabetes are responsible for nearly 75% of myocardial infarction events. Since obesity is associated with a two- or threefold increased risk for arterial hypertension and diabetes, the reduction of body weight presents a basic and causal approach. Indeed 60% of the German population is overweight, and every fifth person has obesity. A low-calorie diet and higher quality nutrition as well as increased physical activity is the main therapeutic strategy. The maximum fat supply in a 1200 kcal/d diet should be less than 70 g. Training should be of low intensity, below the anaerobic threshold (50-70% of VO2max), in order to obtain optimal metabolic effect in combination with maximal fat reduction. Should the newly adopted lifestyle not result in a satisfactory loss of weight, medication can be applied in addition. Sibutramin (Reductil) or Orlistat (Xenical) can in individual cases be of help and lead to a further weight loss of up to 10%. It has been demonstrated that such weight loss can evoke the same positive effects of glucose metabolism in patients with impaired glucose tolerance as can metformin. Nevertheless, from a prognostic point of view, in patients with coronary artery disease and manifest diabetes, insulin therapy is required. Although arterial hypertension carries with it four times the risk of stroke and twice that of myocardial infarction, the majority of the population does not receive adequate treatment. Even after an acute cardiac event, in every second patient, an elevated blood pressure of > 140/90 mm Hg at the beginning of the rehabilitation period is found. In approximately 80% of the patients, a guideline-based therapy can be achieved during the follow-up phase. Comparable results apply to LDL-cholesterol patients as well. For patients with chronic coronary artery disease, it is highly important that medication and change in lifestyle be continued. Patients need to receive standardized information and ongoing medical care.
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PMID:[Modification of conventional risk factors in coronary artery disease]. 1528 4

The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.
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PMID:[Pharmacological treatment of obesity]. 1538 15

Orlistat is an inhibitor of gastrointestinal lipases and, therefore, prevents the absorption of dietary fat. This agent reduces weight in obese adults and adolescents with or without comorbidities (including type 2 diabetes mellitus, hypercholesterolaemia, hypertension, metabolic syndrome) who received up to 4 years of therapy in conjunction with a hypocaloric diet. In obese patients, orlistat in combination with a hypocaloric diet improved metabolic risk factors and reduced the risk of developing type 2 diabetes. Furthermore, this agent was cost effective in patients with obesity, particularly those with type 2 diabetes. Orlistat is generally well tolerated, with gastrointestinal adverse events being most commonly reported. Orlistat, in addition to lifestyle and dietary intervention, is thus an attractive option for the treatment of patients with obesity, especially those with associated comorbidities or at risk of developing type 2 diabetes.
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PMID:Orlistat: a review of its use in the management of patients with obesity. 1556 54

Orlistat is an inhibitor of gastrointestinal lipases and, therefore, prevents the absorption of dietary fat. This agent reduced weight in obese adults and adolescents with or without co-morbidities (including type 2 diabetes mellitus, hypercholesterolemia, hypertension, metabolic syndrome) who received up to 4 years of therapy in conjunction with a hypocaloric diet. In obese patients, orlistat in combination with a hypocaloric diet improved metabolic risk factors and reduced the risk of developing type 2 diabetes. Furthermore, this agent was cost effective in patients with obesity, particularly those with type 2 diabetes. Orlistat is generally well tolerated, with gastrointestinal adverse events being most commonly reported. Orlistat, in addition to lifestyle and dietary intervention, is thus an attractive option for the treatment of patients with obesity, especially those with associated co-morbidities or at risk of developing type 2 diabetes.
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PMID:Spotlight on orlistat in the management of patients with obesity. 1578 49

The association between obesity and hypertension is well known. The hemodynamic features of obesity-related hypertension are an expansion of extracellular volume inducing hypervolaemia and increased cardiac output, with activation of both the sympathetic nervous system and the renin--angiotensin system. It is suggested that obesity-related hypertension may be considered as a subset of essential hypertension, and treated as an identity. Orlistat and sibutramine both reduce body weight in the obese patients. The use of orlistat in obese hypertensive patients is associated with a small decrease in blood pressure, whereas sibutramine may increase the blood pressure. Thus, orlistat may be preferred in the obese hypertensive patients. Diuretics and beta-blockers decrease insulin sensitivity, which is an unwanted effect in obesity, and should be used with caution in obese hypertensive patients. The calcium channel blockers have no or minor effects on insulin sensitivity and may be considered for use in obese hypertensive patients. Inhibitors of the effects of angiotensin may be the antihypertensive drugs of choice for obese hypertensive patients, as in addition to reducing blood pressure, ACE inhibitors and AT(1) receptor antagonists have no effect or improve insulin sensitivity, and are renoprotective. More clinical trials are needed for the centrally acting antihypertensives (clonidine, rilmenidine) in obese hypertensive patients, as they inhibit the sympathetic nervous and renin--angiotensin systems, which are overactive in this population.
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PMID:Clinical evidence for drug treatments in obesity-associated hypertensive patients--a discussion paper. 1583 64

The association between obesity and cardiovascular disease is well established, and up to 60% of overweight or obese patients have hypertension. Dietary interventions associated with modest weight loss are effective in controlling blood pressure and in reducing use of antihypertensive drug therapy in overweight and obese patients. However, long-term maintenance of weight loss is achieved only in a small proportion of patients. Orlistat and sibutramine may help to achieve and maintain weight loss but may not be sufficient to control blood pressure in overweight and obese hypertensive patients. Consequently, antihypertensive drug therapy is often necessary in addition to weight loss interventions. Few studies have investigated different antihypertensive drugs, specifically in overweight and obese patients with hypertension. Based on studies involving obese and nonobese patients, first-line treatment options include a diuretic alone or an angiotensin-converting enzyme (ACE) inhibitor alone. If monotherapy is inadequate for blood pressure control, combination therapy with diuretic and ACE inhibitor and/or combining either of these drugs with a calcium channel blocker are reasonable treatment options. Additional studies to further clarify the management of these patients are warranted.
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PMID:Management of hypertension in overweight and obese patients: a practical guide for clinicians. 1615 73

Orlistat (tetrahydrolipstatin) is an inhibitor of gastrointestinal lipases, especially pancreatic lipase. It is used as an adjunct to diet and exercise in order to achieve weight loss in obese individuals (body mass index > 30 kg/m2) or in overweight individuals (body mass index > 27 kg/m2) with other risk factors for atherosclerotic vascular disease, such as hypertension, dyslipidaemia or diabetes. Short- and long-term studies of up to 4 years duration have shown the drug to have significant benefits in weight loss, as well as in the reduction in lipids, glucose and haemoglobin A1c, and in time to onset of Type 2 diabetes compared with diet alone or placebo groups. The incremental amount of weight loss that orlistat produces is modest, but sufficient to result in improvement in obesity comorbidities such as elevated blood pressure, dyslipidaemia and hyperglycaemia compared with diet and exercise alone. Orlistat should only be prescribed for individuals who are motivated to adhere to lifestyle modifications, especially dietary fat restriction.
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PMID:The use of orlistat in the treatment of obesity, dyslipidaemia and Type 2 diabetes. 1625 79

There is a 50 % prevalence of obesity with arterial hypertension. This ratio can increase up to 80 %, depending on body mass index. Important pathogenetic origins are quantity of visceral body fat along with the activation of neuroendocrineum (sympathicus, renin-angiotensin system), an induction of insulin resistance with hyperinsulinemia, and a direct compression of the medulla by fat deposits in the kidneys, which results in hemodynamic changes and an increase in blood pressure. The primary aim is a reduction in weight by means of a balanced diet and life style modification, which can be augmented by weight reducing medication. Orlistat lowers blood pressure and body weight simultaneously, whereas sibutramine accomplishes this only under certain circumstances. Interestingly, blood pressure increases again over the course of 10 years following weight reducing surgical procedures, despite ongoing weight loss. Antihypertensive differential therapy should be focused on pathophysiology and concomitant and target organ disease. Thus ACE inhibitors (alternatively angiotensin receptor blockers), in combination with low dose diuretics, should be preferentially administered, followed by calcium antagonists. Beta blockers should be used if definite cardiac indications are present.
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PMID:[Therapy of obesity-associated hypertension]. 1628 Nov 61


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