Trattamento Farmacologico Obesità

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1 Trattamento Farmacologico Obesità 1983: primo farmaco utilizzato per trattare l obesità da allora ogni trattamento provato nei pz obesi ha mostrato effetti collaterali inaccettabili Amfetamina e abuso Durata del trattamento Ultimamente lesioni valvolari (fenfluramina, fentermina )

2 Meccanismi per il trattamento dell obesità Riduzione del food intake Alterazione assorbimento e/o metabolismo

3 Farmaci che aumentano il metabolismo Efedrina + caffeina FDA approval, but not for obesity Beta3 agonists in sviluppo

4 Farmaci che alterano assorbimento e/o metabolismo Orlistat è l unico farmaco approvato da FDA per il trattamento dell obesità Inibitore delle lipasi pancreatiche Effetto dose dipendente: scarsi effetti in diete low-fat Riduzione colesterolo, ma integrare vit liposolubili Orlistat non è assorbito

5 Peptidi e food intake Leptina Assenza peptide = ob/ob Assenza recettore = db/db NPY Y1 & Y5 antagonists CCK Peptide analogs Metabolism inhibitors Glucagone GLP-1

6 Farmaci che riducono il food intake Simpaticomimetici Buon assorbimento orale Emivita breve (unica eccezione sibutramina) Effetti collaterali: secchezza fauci, costipazione, astenia, insonnia. Addictive properties? Attenzione cardiovascolare

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10 Associazione fenfluramina /fentermina 1996: > 18M prescrizioni

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15 Bupropion/Naltrexone (marketed as ContraveVR ). Bupropion/naltrexone was FDA approved for weight loss in September 2014(26). Bupropion s primary mechanism of action is via dopaminergic and noradrenergic stimuli without inhibition of monoamine-oxidase (MAO) or reuptake of serotonin. Inhibiting reuptake of dopamine and/or norepinephrine decreases the reward pathway that various foods can induce. The second component of ContraveVR is naltrexone, which is a pure opioid antagonist and blocks an opioid pathway that may slow weight loss. Four 56-week multicenter, double-blind, placebo-controlled trials (CONTRAVEVR Obesity Research, or CORI, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of bupropion/naltrexone in conjunction with lifestyle modification in a placebo-controlled cohort of 4536 patients. The COR-I, COR-II, and COR-BMOD trials enrolled patients with BMI 30 kg/m2 or greater or overweight (BMI 27 kg/m2 or greater) and at least one comorbidity (27-29). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m2 with type 2 diabetes with or without hypertension and/or dyslipidemia. The primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight. In the 56-week COR-I trial, the mean change in body weight was 25.4% in patients assigned to bupropion/naltrexone 360/32 mg compared with 21.3% in the placebo group. The clinically significant cut off of 5% reduction in body weight from baseline occurred in 42% of treatment group patients vs. 17% of placebo patients (26). In the COR-Diabetes trial, 44.5% of patients receiving bupropion/naltrexone lost 5% of their body weight after 56 weeks vs. 18.9% of patients on placebo (P <.001) (30). Patients using bupropion/naltrexone also showed a 0.6% reduction in HbA1c from baseline, compared to a 0.1% reduction in placebo. In all of the COR trials, secondary cardiovascular endpoints were met, including statistically significant improvements in waist circumference (WC), visceral fat, HDL cholesterol, and triglycerides (31).

16 Phentermine/Topiramate. Low-dose, controlled-release phentermine plus topiramate (as one capsule) was approved by the FDA in 2012 as a long-term treatment for obesity for adults with a body mass index of 30 kg/m2 or with a BMI 27 kg/m2 with at least 1 weight-related comorbidity. Phentermine is an adrenergic agonist that promotes weight loss by activation of the sympathetic nervous system and release of endorphins with a subsequent decrease in food intake and increased resting energy expenditure. This occurs by modulating activity of anorectic or orexigenic peptides in hypothalamic nuclei (14). Topiramate is an FDA approved medicine for epilepsy and migraine prophylaxis that has been shown to reduce body weight by promoting taste aversion and decreasing caloric intake. Phentermine/topiramate is available in 4 doses: 3.75/23 mg (starting dose), 7.5/46 mg (lowest treatment dose), 11.25/69 mg, or 15/92 mg (maximum treatment dose). The 52-week CONQUER trial randomized 2487 patients who were obese with a mean BMI of 36.6 kg/m2 and comorbidities including hypertension, dyslipidemia, diabetes or pre-diabetes, or abdominal obesity to either placebo, mid-treatment dose (7.5/46 mg), or maximum treatment dose (15/92 mg) with results showing 6.6% and 8.6% placebo subtracted weight loss in the lower dose and maximum dose arms respectively (19). A 2-year extension of the CONQUER trial was published (SEQUEL) demonstrating a 2-year mean placebo subtracted weight loss of 8.7% in the top group and 7.5% in the mid-dose group (20). Improvement in systolic and diastolic blood pressure, triglycerides, and greater increases in HDL were seen in subjects treated with phentermine/topiramate compared with placebo in the CONQUER trials (19). Improvements in fasting glucose and insulin levels were seen in the SEQUEL study and a 54% and 76% reduction in progression to type 2 diabetes in the 2 treatment groups was noted in patients without diabetes at baseline (20).

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