**7. Anti-obesity medications**

glucose, which is commonly observed with tolbutamide. All of these drugs contain the sulfonylurea molecule, but different substitutions result in differences in pharmacokinetics and duration of action. Glibenclamide should be avoided in the elderly and patients with mild renal impairment because of the risk of hypoglycemia because several of its metabolites are

The sulfonylureas cross the placenta and stimulate insulin release by fetal β cells, causing severe hypoglycemia at birth. Consequently, their use is contraindicated during pregnancy, and gestational diabetes is treated by diets supplemented with insulin when required [113].

In general, sulfonylureas are well tolerated. The observed side effects are hematological, including hypoglycemia, leukopenia, agranulocytosis, thrombocytopenia, and hemolytic anemia, gastrointestinal, including nausea, vomiting, and cholestatic jaundice (rare), and allergic reactions. Sulfonylureas may also cause weight gain, and their binding to plasma proteins can be potentiated by other drugs used concomitantly, which may cause hypoglyce‐ mia. This condition is the most problematic adverse event and may be prolonged, which can have severe consequences in elderly patients, patients treated with multiple drugs and those with impaired renal function. Moreover, sulfonylureas stimulate appetite and can occasionally

Sulfonylureas have structural characteristics that allow them to be given in much lower doses than the first-generation sulfonylureas. Nevertheless, the different sulfonylureas are equally effective in lowering blood glucose concentrations. There are, however, differences in absorp‐ tion, metabolism and effective dose [114], which is partly caused by the formation of active metabolites [115]. These drugs also cause greater suppression of overnight hepatic glucose output, thereby lowering fasting blood glucose concentrations. These benefits may be coun‐

The US Food and Drug Administration (FDA) approved glimepiride in 1995 for the treatment of T2DM alone and in combination with metformin or insulin. It has prolonged action and lasts over 24 hours. Glimepiride has advantages with respect to its clinical and pharmacological profile, and it has also been shown to cause a low incidence of severe hypoglycemia compared

Regarding hypoglycemia, the findings observed in certain studies differ. In a systematic review and meta-analysis [118], glimepiride was found to cause increased hypoglycemia compared to other sulfonylureas and even more than other secretagogues. In other studies, the longacting sulfonylureas, such as chlorpropamide and glibenclamide, were shown to have an increased likelihood of causing hypoglycemia [112, 119]. In a UK survey, the rate of diagnosis of hypoglycemia was higher for glibenclamide compared to other representatives of the same

With regard to weight gain, in the UK Prospective Diabetes Study [34], the mean weight change after 10 years of follow up ranged from a minimum of 1.7 kg as a result of glibenclamide use

excreted in the urine and are moderately active [113].

cause allergic rashes and bone marrow injury [113].

terbalanced by an increased risk of hypoglycemia [112].

to other representatives of its class [116, 117].

**6.3. Glimepiride**

160 Treatment of Type 2 Diabetes

class [120].

Obesity (body mass index (BMI) above 30 kg/m2 ) is common in many diabetic patients, and it is important to highlight the rising prevalence of these two health conditions in the modern world [124]. Being obese or overweight produces important risk factors for type 2 diabetes and is associated with many serious health conditions, such as heart disorders and cancer, which lead to increased mortality, especially in individuals over 65. In patients previously diagnosed with type 2 diabetes, the presence of obesity can lead to a worsen‐ ing of the metabolic disorders associated with diabetes, such as hyperglycemia, hyperten‐ sion and hyperlipidemia [125, 126]. Thus, weight loss is required to improve glycemic control in the patient as well as to reduce the cardiovascular risk factors, which will likely reduce the risk of mortality in those individuals [127-129].

A systematic review published in 2011 [126] reported data from two clinical trials that showed a reduction of 30% to 50% in the incidence of diabetes in overweight and obese patients (with elevated plasma glucose levels) after behavioral interventions that lead to weight loss. However, the results arising from actions aimed at the prevention of obesity and changes in the obesogenic environment are often insufficient and produce insignificant weight loss that is usually regained over time. For these individuals, more invasive treatments are required to produce a sufficient weight reduction. Bariatric surgery has been a widely used intervention in obese patients because it promotes rapid and significant weight loss. However, the risks of surgery mean that this intervention is reserved for patients with morbid obesity. Thus, the FDA advises pharmacological intervention for patients with BMI ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) when in the presence of co-morbidities related to obesity [125, 130-132].

Numerous medications have been used for weight loss in recent decades; however, the occurrence of adverse side effects has restricted their current use [125]. In the 1990s, the drugs fenfluramine and dexfenfluramine (sympathomimetic amines that promote appetite suppres‐ sion) were withdrawn from the market because of the risk of heart damage. The European Medicines Agency (EMA) suggested the withdrawal of various anti-obesity drugs, such as diethylpropion (amfepramone), mazindol and phentermine (also sympathomimetic amines inhibiting appetite), in the 2000s because of the high risk of adverse events. In 2006, rimonabant (first selective blocker of endocannabinoid receptor subtype 1-CB1) became available in 56 countries; however, because of its adverse psychiatric events, this drug was never approved by the FDA and was withdrawn from the European market in 2009. Additionally, after clinical trials assessing the safety and tolerability of sibutramine (an appetite suppressant that acts as a selective inhibitor of the reuptake of norepinephrine and serotonin), the FDA considered the option to restrict access to this substance or withdraw it from the market, causing the suspen‐ sion of marketing authorization in 2010 [130, 133].

From the drugs approved before 2012, several sympathomimetic amines are available. These include phentermine, diethylpropion, benzphetamine and phendimetrazine, which are approved for short-term weight management (≤ 12 weeks), and orlistat (a potent reversible inhibitor of gastric and pancreatic lipase capable of preventing the absorption of up to 30% of dietary fat), which is the only anti-obesity drug for long-term use [130, 134, 135]. In 2012, the FDA approved two new drugs for obesity control: lorcaserin (agonist of the serotonin receptor 5-HT2C) and extended release phentermine-topiramate (association between a sympathomi‐ metic amine appetite suppressant and an anticonvulsant). The mechanism responsible for weight loss when using extended release phentermine-topiramate is believed to be the subsequent increase in activity of the neurotransmitter gamma-aminobutyric acid (GABA), although the exact association mechanism remains unclear. Both drugs were approved for long-term use [131, 136, 137].

Depression is a common side effect observed in patients with type 2 diabetes, which may be associated with a lack of glycemic control, increased risk of complications, lack of adherence to treatment and even the presence of obesity or overweightness [137, 138]. A meta-analysis in 2001 by Anderson et al. showed that the prevalence of depression was twice as high in individuals with T2DM than in those without this health condition. Thus, reducing the incidence of depression and improving the quality of life of diabetic patients, especially those who are also obese, are highly relevant clinical objectives [139-141]. The treatment of depres‐ sion in diabetics is usually accomplished by the use of serotonin reuptake inhibitors, such as fluoxetine and sertraline. These drugs not only act on depression but also promote weight loss, which is highly desired in obese or overweight diabetics [68, 142].
