Medicines Help With Weight Loss

The incidence of overweight and obesity has doubled worldwide since 1980. The causes are manifold. In most cases, the excess pounds are due to sufferers consuming more calories than they are expending. Today’s lifestyle contributes a lot to this: high-calorie fast food and hardly any fiber as well as little exercise through sedentary activities or leisure activities such as computers and television.

The body mass index

When does one speak of overweight or obesity? The body mass index (BMI; body weight in kg divided by height in m 2 ) is used to determine normal weight. According to the World Health Organization (WHO) classification, body weight is considered normal if the BMI is between 20 and 25. A BMI value over 25 is considered overweight. People with a BMI over 30 are obese. A higher BMI (between 24 and 26) is only recommended for old and frail people. In the case of very old people, a value of up to 29 is even prognostically favorable.

American women and men are also getting fatter. According to the Federal Statistical Office, a total of 51 percent of adults were overweight in 2009, 60 percent of whom were men. 16 percent of men and 14 percent of women were already obese. Regardless of age, more men than women put on too many pounds.

What are the World Health Organization Doing?

In 2008, the WHO estimated that around one in ten adults worldwide, i.e. 1.5 billion people, are overweight, of which 500 million are obese. By 2015, the numbers are expected to increase to 2.3 billion and 700 million, respectively. Of particular concern is the rise in obesity among children. Around 15 percent of all adolescents worldwide are already obese.

Peptide Injections for Weight Loss

Overweight and obesity are risk factors for cardiovascular diseases such as heart attack and stroke as well as for type 2 diabetes. Studies have shown that free fatty acids and pro-inflammatory immune mediators such as cytokines are produced in excess fatty tissue, especially in the abdominal area. These are involved in the development of insulin resistance and lipid metabolism disorders, impair the function of the vessel wall and promote the occurrence of thrombosis and atherosclerosis. Studies have also found an association with certain cancers, such as endometrial cancer in women and colon cancer in men, and some musculoskeletal disorders such as osteoarthritis.

The seriousness of Sleep Apnea

Sleep apnea syndrome, which is associated with increased mortality, occurs more frequently in overweight people. Being overweight seems to impair fertility and promote depression. The risk of diabetes and cardiovascular diseases is also increased in overweight children (1-4).

 

Control center hypothalamus

In order to develop new effective and safe therapies that help fight the pounds, it is necessary to understand the complex mechanisms that regulate food intake and body weight.

The central regulation of appetite and the control of energy balance essentially take place in the arcuate nucleus of the hypothalamus. Here are neuron systems that receive stimulatory or inhibitory signals from the gastrointestinal tract, pancreas, and adipose tissue. Feedback from other areas of the brain that signal stress, feelings or reward also arrives in the hypothalamus (see graphic).

Physiological regulation of body weight and energy expenditure by signals from the periphery. A feeling of satiety is mediated by leptin, peptide YY (PYY), cholecystokinin (CCK), insulin, glucagon, glucagon-like peptide 1 (GLP-1), and amylin (in red). In contrast, ghrelin stimulates appetite (green).
Physiological regulation of body weight and energy expenditure by signals from the periphery. A feeling of satiety is mediated by leptin, peptide YY (PYY), cholecystokinin (CCK), insulin, glucagon, glucagon-like peptide 1 (GLP-1), and amylin (in red). In contrast, ghrelin stimulates appetite (green).

In the arcuate nucleus there are two populations of neurons that produce appetite-regulating neuropeptides. The orexigenic system releases neuropeptide Y (NPY) and agouti-related peptide (AgRP) that stimulate appetite. The anorexigenic system produces melanotropin (α-MSH) and cocaine amphetamine-regulated transcript (CART), both of which inhibit appetite. Both systems are linked to each other via negative feedback.

The Role of the Proteohormone Leptin

The proteohormone leptin plays a key role in regulating body weight. Leptin is released into the blood from fat cells in response to various stimuli such as food intake or elevated blood glucose levels. In addition, insulin, glucocorticoids or estrogens stimulate release, while fasting, an activated sympathetic nervous system and androgens reduce the leptin concentration in the plasma. The hormone binds to specific leptin receptors in the arcuate nucleus. As a result, it inhibits the release of neuropeptide Y and at the same time stimulates the release of melanotropin. A feeling of satiety sets in; Energy turnover and heat generation are increased. As a result, the fat cells shrink and the amount of storage fat decreases.

 

Leptin concentrations are usually higher in overweight people than in people of normal weight. The cause is assumed to be “resistance to leptin”. This means that the sensitivity of the leptin receptors in the hypothalamus is reduced due to the persistently high hormone concentrations or there is a primary receptor defect. Like leptin, insulin inhibits the release of neuropeptide Y via receptors in the arcuate nucleus and at the same time stimulates the appetite-inhibiting melanotropin.

Best Peptides for Weight Loss

According to EMA guidelines, new anti-obesity drugs must result in a weight loss of at least ten percent of the initial weight within twelve months.
According to EMA guidelines, new anti-obesity drugs must result in a weight loss of at least ten percent of the initial weight within twelve months.

Various hormones in the gastrointestinal tract also have a satiating or appetite-stimulating effect (see graphic). The concentration of the hormone ghrelin produced by the gastric parietal cells increases with falling glucose concentrations in the “empty” stomach shortly before eating and stimulates appetite via the neuropeptide Y neurons. Gastrointestinal hormones such as peptide YY (PYY), cholecystokinin (CCK), glucagon, glucagon-like peptide (GLP-1) and amylin, on the other hand, have a satiating effect. While peptide YY directly inhibits the release of neuropeptide Y via a special receptor in the hypothalamus, the other gastrohormones activate ascending vagal nerve tracts and receptors in the brainstem.

The Hungry Hypothalamus

The release of neuropeptide Y from the arcuate nucleus stimulates the hunger center in the lateral hypothalamus, which in turn releases neuropeptides such as orexins and melanin-concentrating hormone (MCH). Melanotropin activates the satiety center in the ventro-medial hypothalamus by releasing corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), oxytocin and GLP-1, which is produced not only in the gastrointestinal tract but also in neurons. These mediators stimulate vagal nerve pathways in the brainstem that lead to the gastrointestinal tract, where they increase or limit appetite (5).

 

Different attack points

Understanding of the physiological processes that control food intake and body weight has increased in recent years, leading to the development of new drugs. The anti-obesity drugs that have been approved or are being developed are divided into three groups:

peripherally active substances that inhibit food absorption in the gastrointestinal tract,
centrally active substances that reduce the feeling of hunger, and
Analogues of gastrointestinal hormones.

The European regulatory authority EMA has issued guidelines for the development of new appetite suppressants. New active ingredients must be shown to lead to a weight loss of at least ten percent compared to the initial weight within twelve months. The weight reduction must be at least five percent greater than in the placebo group.

The EMA Report

In addition to a clinically relevant weight reduction, the EMA also requires proof that the substance effectively lowers cardiovascular risk factors such as high blood pressure and elevated lipid and glucose levels. Patients with a BMI of at least 30 who are otherwise healthy or patients with a BMI of at least 25 who already have complications such as high blood pressure should take part in the studies. Appetite suppressants must be taken over a longer period of time, as the effect usually disappears immediately after stopping. To ensure safe therapy, the EMA requires that drug side effects, especially cardiovascular and psychiatric, be carefully investigated (6).

 

In the USA, four drugs are currently approved for the supportive treatment of overweight patients: orlistat, amfepramone, phenylpropanolamine and D-norpseudoephedrine.

 

inhibition of fat absorption

 

Peripherally effective anti-obesity drugs inhibit food intake in the gastrointestinal tract and thus support weight loss without having a specific effect on the feeling of hunger. Orlistat is a specific and long-lasting inhibitor of gastrointestinal lipases. The therapeutic effect begins in the lumen of the stomach and upper small intestine through covalent binding to the active serine residue of gastric and pancreatic lipases. The inactivated enzyme can no longer hydrolyze dietary fats in the form of triglycerides into free fatty acids and monoglycerides; However, esterified dietary fats are not resorbed.

How Effective is it?

The effectiveness increases depending on the dose. After one year of treatment, 41 percent of those treated with orlistat 120 mg and 21 percent of those treated with placebo had lost more than 10 percent of their body weight (see table). Orlistat did not produce clinically relevant weight loss in all study participants. Only people who had already lost more than five percent of their weight in the first three months continued to lose weight. Orlistat, 60 mg three times a day, blocks the absorption of about a quarter of the dietary fat consumed. The weight loss only lasted for a short time. Within a year of the end of the study, the patients had returned to their initial weight. Up to a third discontinued treatment prematurely due to lack of efficacy or gastrointestinal side effects.

Study results on the effectiveness of approved or developmental appetite suppressants
active ingredient percent of patients with more than 10 percent weight loss
verum group placebo group
within 6 months
Tesofensine 0.5 mg 35 7
Tesofensine 1 mg 74 7
Exenatide 2 mg once weekly 10
Pramlintide 720 mcg + Metreleptin 10 mg 56 35
21*
within 12 months
Orlistat 360 mg 41 21
Orlistat 180 mg 16 7
Phentermine 7.5mg + Topiramate 46mg 37 7
Phentermine 15 mg + Topiramate 92 mg 48 7
Naltrexone 32 mg + Buproprion 360 mg 42 20
Lorcaserin 20 mg 23 8th
Rimonabant 20 mg 27 8th
Liraglutide 3 mg 35 10
*) Pramlintide or metreleptin alone

Gastrointestinal problems such as lower abdominal pain, flatulence, urge to defecate, diarrhea, greasy stools and faecal incontinence are the most common side effects caused by inhibited fat absorption. In North America, orlistat has also been linked to cases of acute pancreatitis and oxalate-induced kidney damage.

What the Scientists Say

Clinical study results indicate that weight loss also delays the onset of type II diabetes mellitus, as the risk factors associated with obesity are favorably influenced. Total and LDL cholesterol decreased while HDL cholesterol levels increased. In addition, blood sugar and serum insulin concentration as well as blood pressure fell.

 

Orlistat has been available in pharmacies without a prescription in a dosage of 60 mg three times a day since April 2009. The pharmacy team should consider a few important points when advising and dispensing (see box).

Advice on Orlistat

Orlistat should not be taken for more than six months. If there is no significant weight loss after three months, the therapy should be discontinued.
A low-fat diet is very important during therapy. The incidence of gastrointestinal symptoms such as pelvic pain, bloating, urgency, diarrhea and fecal incontinence may increase when orlistat is taken with high-fat meals.
Orlistat can interfere with the absorption of fat-soluble vitamins. Therefore, the client should take a multivitamin supplement before bedtime.

Orlistat is contraindicated when anticoagulants are administered at the same time, as it can increase Quick’s value (7-11).
Cetilistat, another lipase inhibitor, is in clinical development. The available data show a comparable effectiveness to orlistat. However, cetilistat appears to cause fewer gastrointestinal side effects (12). Active substances such as fatostatin, which influence lipogenesis, are in a very early stage of development. Statements on efficacy and tolerability are not yet available (13).

 

Centrally acting appetite suppressants

 

Centrally acting appetite suppressants release more catecholamines or serotonin or both. This centrally inhibits the feeling of hunger and thereby reduces food intake.

 

Currently only the indirect sympathomimetics amfepramone, phenylpropanolamine and D-norpseudoephedrine are approved in the USA as centrally acting appetite suppressants. All require a prescription. They release adrenergic amines from the presynaptic nerve endings. As shown in animal studies, the appetite-suppressing effect is based on an excitation of the neurons in the lateral hypothalamus, which suppresses the feeling of hunger.

 

An analysis of 17 double-blind, placebo-controlled studies for amfepramone showed that the average weight loss, based on the patient’s starting weight, was 4 to 6 percent after four weeks, 5 to 7 percent after eight weeks and 7 to 10 percent after twelve weeks, depending on the duration of treatment (14).

What’s the Price of Weight Loss?

Weight loss comes at the cost of significant abuse and dependency potential and serious side effects. Therefore, indirect sympathomimetics should no longer be recommended for weight loss. The substances do not act selectively in the hypothalamus, but also develop their effect in other brain regions and in the periphery. As a result, the most common side effects are nervousness, restlessness, sleep disorders and dizziness, but psychosis and depression also occur. Sympathomimetics increase blood pressure and heart rate. Cardiac arrhythmias can occur. A rare but serious and often fatal side effect is pulmonary arterial hypertension. Sympathomimetics are therefore only approved for short-term therapy of four weeks, and amfepramone for a maximum of twelve weeks (15).

Away with the fat: Those who take lipase inhibitors should eat a low-fat diet. This can help reduce unpleasant side effects.
Away with the fat: Those who take lipase inhibitors should eat a low-fat diet. This can help reduce unpleasant side effects.

A low-dose combination of topiramate and phentermine is in clinical development. Phentermine is an amphetamine-like substance that causes a feeling of satiety through general sympathetic activation. It is approved in the USA as an appetite suppressant. The mechanism of action of topiramate, used to treat epilepsy and migraine, is unclear.

 

Recent studies showed better effectiveness than, for example, orlistat after twelve months of treatment with the combination. Weight loss of 10 percent or more compared to baseline weight was observed in about half of the patients in the higher dose group (table). In the lower-dose group, this was still the case for a third, but only for 7 percent in the placebo group.

 

The treatment was generally well tolerated. The most commonly reported side effects were dry mouth, constipation and abnormal sensations such as tingling. However, the incidence of psychiatric and cognitive adverse events such as depression, anxiety, and attention deficit disorder increased in a dose-dependent manner. Due to severe psychiatric side effects such as depression and deformities (cleft lips and palate) in the newborns of mothers treated with topiramate, the US FDA rejected an initial application for approval of the weight-loss combination in October 2010 (16, 17).

 

Intervention in serotonin metabolism

 

Sibutramine is a centrally acting appetite suppressant that inhibits norepinephrine, serotonin and dopamine re-uptake. Weight loss averaged 9 percent of baseline weight over 18 months, less than orlistat. However, a post-marketing study showed a higher risk of heart attack, stroke and premature death in patients treated with sibutramine. This led to the revocation of the authorization in January 2010

 

The new reuptake inhibitor tesofensine, which like sibutramine inhibits the reuptake of norepinephrine, serotonin and dopamine, is in clinical development. The data so far indicate a stronger effectiveness compared to orlistat. Three-fourths of patients treated with tesofensine 1 mg weighed one-tenth less than at baseline within six months, while only 7 percent of those on diet managed to achieve this goal (table). Blood pressure was not affected by tesofensine. However, some study participants experienced an accelerated heart rate and psychological changes such as agitation and mood changes.

 

Bupropion, a dopamine and norepinephrine reuptake inhibitor, and the opioid antagonist naltrexone mediate their appetite-suppressing effects through increased release of α-MSH, which curbs the feeling of hunger in the hypothalamus. The combination of both active ingredients showed a comparable effectiveness as orlistat. In a year-long study, the combination resulted in more than 10 percent weight loss in 40 percent of those treated; in the placebo group, only one in five achieved this result. The most common side effects were nausea, headache and constipation. Nausea was also the most common reason for dropping out of the study. Increased depression was not observed.

 

In February 2011, however, the US regulatory authority rejected the approval and called for further studies to investigate the cardiovascular effects of the combination. The reason for this was a transient increase in blood pressure in some study participants (20).

 

Another approach to activating the serotonin system is pursued with lorcaserin. Lorcaserin selectively activates 5-HT 2C type serotonin receptors , which in turn stimulate the release of α-MSH in the hypothalamus while inhibiting the release of appetite-enhancing peptides such as neuropeptide Y and agouti-related peptide. The mechanism of action is similar to previously used appetite suppressants such as fenfluramine and dexfenfluramine. In contrast to these substances, however, lorcaserin shows hardly any agonistic effects on the 5-HT 2B receptors, which are associated with severe side effects such as heart valve damage and pulmonary hypertension.

 

In the clinical studies, almost a quarter of the participants achieved a weight loss of more than 10% after 12 months of taking lorcaserin, compared to 8% in the diet-only group (21). The most common side effects were headache, dizziness and nausea. Characteristic side effects of other serotonergic drugs such as depression, anxiety disorders and suicidal thoughts were not more common than in the placebo group. An increased risk of heart valve damage was not observed. However, experiments in rats showed an increased risk of cancer, which was one reason for the FDA’s refusal of approval. To date, no marketing authorization application has been submitted for lorcaserin in Europe.

Cardiovascular risk factors

In 2007, Rimonabant, the only representative of the endocannabinoid modulators to date, was taken off the market. Endocannabinoids are neurotransmitters that, among other things, increase the feeling of hunger in the hypothalamus via receptors. By blocking the cannabinoid-1 receptor in the hypothalamus, rimonabant reduced feelings of hunger. A quarter of the patients treated for more than a year lost more than 10 percent of their baseline weight, compared to 8 percent in the placebo group. Cardiovascular risk factors such as high blood fat and blood glucose levels were also reduced.

 

However, serious side effects such as depression, suicidal ideation and convulsions have been reported in post-marketing experience with rimonabant. This led to the withdrawal of the approval. No other cannabinoid receptor antagonists are currently in development (22).

 

Analogues of intestinal hormones

 

Gastrointestinal hormone analogues are already used to treat type 2 diabetes. Because of the weight loss observed in studies, some drugs for the treatment of obesity are being clinically tested.

 

The two GLP-1 analogues exenatide and liraglutide showed comparable efficacy in the studies. About one-tenth of patients treated with exenatide lost more than 10 percent of their baseline weight within six months (table). When given liraglutide, one-third lost more than 10 percent of their baseline weight within a year. Only 15 percent of the patients who received orlistat in this study achieved this result. Nausea is the side effect most frequently observed with both substances. A few cases of acute pancreatitis have been observed, particularly with exenatide. Both substances are injected subcutaneously.

What is pramlintide Exactly?

Also in clinical trials is pramlintide, an amylin analogue, in combination with metreleptin, a recombinant leptin. These active ingredients must also be injected subcutaneously. The first study results indicate a significantly stronger weight-lowering effect of the combination compared to the administration of the individual substances, but also with regard to orlistat. Amylin appears to enhance the leptin response in obesity. More than half of all patients who received the combination lost more than 10 percent of their body weight within six months. With pramlintide and metreleptin alone, this was only achieved by 35 and 21 percent, respectively. Nausea and injection site reactions were the most common side effects (23-25).