several epidemiological studies have confirmed the close relationship between diabetes and obesity ; more than 80% of patients with type 2 diabetes are estimated to be overweight or obese . as the prevalence of obesity increases , the risk of type 2 diabetes is likely to increase . between 1980 and 1990 , the majority of korean patients with diabetes were nonobese ; however , as the prevalence of obesity has increased in korea , the majority of patients with diabetes are now obese . according to the diabetes fact sheet in korea 2012 ,
the prevalence of type 2 diabetes was 10.1% in 2010 , and 75% of diabetic patients were overweight or obese ( i.e. , a mean body mass index [ bmi ] of 25.2 kg / m ) . type 2 diabetes and obesity have a complex relationship , and obesity is linked to insulin resistance , the precursor to type 2 diabetes .
obese adults are at increased risk of several chronic diseases , including cardiovascular disease , stroke , cancer , and type 2 diabetes .
furthermore , the risk of death is increased 20% to 40% in overweight adults and 2- to 3-fold in obese compared with normal weight adults .
thus , treatment of obesity is crucial for the prevention of several health problems and for delayed onset of diabetes .
moreover , weight reduction may affect the incidence of diabetes . according to the diabetes prevention program study
, every kilogram of weight loss is correlated with a 16% reduction in the development of type 2 diabetes .
moderate weight reduction in obese patients with type 2 diabetes is associated with a decrease in insulin resistance , improved glycemic parameters , and reductions in diabetic complications and several cardiovascular disease - related risk factors .
the action for health diabetes ( look ahead ) study found that an 8.6% weight loss together with intensive lifestyle intervention was associated with significant improvements in cardiovascular risk factors in 5,145 overweight or obese participants with type 2 diabetes .
it is difficult for patients with diabetes to reduce and maintain their weight with lifestyle changes alone .
several oral hypoglycemic agents used to treat diabetes , such as sulfonylureas , glinides , and thiazolidinediones , and insulin are associated with significant weight gain that may impair metabolic conditions .
thus , alternative antiobesity medications or bariatric surgery may be a necessary adjunct for obese patients with diabetes .
several placebo - controlled studies have shown that various medications help promote weight loss in obese patients with type 2 diabetes .
the focus of our review is antiobesity medications for the long - term treatment of obese patients with type 2 diabetes .
the us food and drug administration ( fda ) approved the following drugs for use in adults with a bmi 30 ( obese ) or 27 ( overweight ) who had at least one weight - related condition such as type 2 diabetes , hypertension , or dyslipidemia .
the recommended dose is 120 mg three times daily before meals . a lower dose ( 60 mg ) is available as an over - the - counter preparation in the united states .
one- and 2-year studies evaluating orlistat treatment for obesity have shown significant improvements in glycemic control and in blood pressure and lipid profiles . in a large 4-year prospective study of 3,305 participants with bmi of 30 kg / m and normal or impaired glucose tolerance ( the xenical in the prevention of diabetes in obese subjects study ) , the orlistat - treated group exhibited significant mean weight loss ( 5.8 kg vs. 3.0 kg in the placebo group ; p<0.001 ) and reduced progression to type 2 diabetes ( risk reduction of 37.3% in the orlistat group ; p=0.0032 ) .
a korean study in which patients were administered orlistat for 24 weeks reported a modest but significant mean weight loss of -2.73 kg ( mean weight change , -3.50%0.38% ) and significant improvements in lipid profiles , fasting insulin , waist circumference , blood pressure , fasting plasma glucose ( -10.414.62 mg / dl ) , and glycosylated hemoglobin ( hba1c , -0.87% ) .
the most common adverse effects of orlistat include flatus with discharge and oily spotting or fecal urgency , and the drug interferes with the absorption of fat soluble vitamins , although not tremendously .
lorcaserin is a selective serotonin 2c ( 5-ht2c ) receptor agonist that suppresses appetite via stimulation of melanocortin receptor 4 .
the drug has low affinity for the 5-ht2b receptor , which is associated with the development of valvular heart disease and the cause of the withdrawal of agents such as dexfenfluramine . in 2012 , the fda approved lorcaserin 10 mg twice daily based on the findings of the pivotal randomized , placebo - controlled trials : behavioral modification and lorcaserin for overweight and obesity management ( bloom ) , behavioral modification and lorcaserin second study for obesity management ( blossom ) , and bloom - diabetes mellitus ( bloom - dm ) . the bloom and blossom trials investigated the effect of lorcaserin on overweight or obese nondiabetic patients and found a ~3% placebo - corrected weight change in the group treated with lorcaserin ( 20 mg / day ) ( bloom , -3.6% ; blossom , -2.9% ; both p<0.05 ) .
moreover , a significantly higher proportion of patients in the lorcaserin group lost 5% of their baseline body weight compared with the placebo group ( approximately 47% vs. 20% , respectively in the bloom ; 47% vs. 25% , respectively in the blossom trials ) .
furthermore , improvements in fasting glucose and triglyceride levels and blood pressure were observed in the lorcaserin groups .
the bloom - dm study included 604 overweight and obese patients with type 2 diabetes who were treated with metformin and/or sulfonylurea and randomized to lorcaserin 10 or 20 mg / day or placebo groups for 52 weeks .
consistent with the results of the bloom and blossom trials , the lorcaserin - treated groups achieved weight losses of -3.4% ( 10 mg ) and -3.1% ( 20 mg )
. a significantly higher proportion of patients in the lorcaserin groups lost 5% of their initial body weight ( 10 mg , 44.7% ; 20 mg , 37.5% ) compared with patients administered placebo ( 16.1% ) .
the reduction in mean hba1c was significantly greater in the lorcaserin - treated groups than in the placebo group ( 10 mg , -1.0% change from baseline ; 20 mg , -0.9% change ; and placebo , -0.4% change ; p<0.001 ) . a significantly higher proportion of patients in the lorcaserin groups achieved hba1c 7% compared with patients treated with placebo ( 10 mg , 52.2% ; 20 mg , 50.4% ; and placebo , 26.3% ) .
however , symptomatic hypoglycemia was more frequent in the lorcaserin groups ( 10 mg , 10.5% ; 20 mg , 7.4% ) than in the placebo group ( 6.3% ) .
the adverse events associated with lorcaserin include headache , dizziness , fatigue , nausea , dry - mouth , and constipation .
no statistically significant difference in the occurrence of fda - defined valvular disease was found between the lorcaserin and placebo groups .
however , the postmarketing trials were required to evaluate the long - term cardiovascular effects of lorcaserin .
phentermine / topiramate ( pt ) extended - release ( er ) is a combination of the fda - approved medications phentermine and topiramate in an er formulation .
phentermine is indicated for short - term weight loss in overweight or obese adults who exercise and eat a reduced calorie diet .
topiramate is indicated for the treatment of certain types of seizures in people who have epilepsy and to prevent migraine headaches .
the exact mechanism underlying the weight loss action of topiramate is not known ; however , it may be associated with a combination of features such as an effect on sodium channels , enhancement of gaba - activated chloride channels , and inhibition of carbonic anhydrase isoenzymes .
pt is available at a higher dose ( 15 mg phentermine/92 mg topiramate er ) for select patients .
discontinuation or an increase in dosage is recommended for patients who have not lost 3% of their baseline weight .
treatment should be discontinued if a weight loss > 5% of baseline is not achieved with 15/92 mg per day .
fda approval of pt was based on three phase iii clinical trials performed to evaluate the efficacy of the drug ( equip , conquer , sequel ) . in the equip trial ,
1,276 obese adults without diabetes were assigned randomly to a low- ( 3.75/23 mg / day ) or high- ( 15/92 mg / day ) dose pt or placebo group for 56 weeks . at the conclusion of the study ,
the patients in the low- and high - dose pt and placebo groups lost 5.1% , 10.9% , and 1.6% of their baseline body weight , respectively ( p<0.0001 ) .
moreover , the results revealed improvements in waist circumference , triglyceride levels , and blood pressure .
the conquer trial included 2,487 overweight and obese patients with two or more weight - related comorbidities such as hypertension , prediabetes , type 2 diabetes , dyslipidemia , and abdominal adiposity .
the participants were assigned to pt ( 7.5/46 or 15/92 mg ) or placebo groups for 56 weeks . at the conclusion of the trial ,
the subjects in the 7.5/46 mg group achieved a -8.1 kg change in body weight ( mean change -7.8% ) , those in the 15/92 mg group a -10.2 kg change ( mean change -9.8% ) , and those in the placebo group a -1.4 kg change ( mean change -1.2% ) . a higher percentage of subjects in the pt groups achieved a 5% weight loss after 1 year compared with those receiving placebo ( 62% , 70% , and 21% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p<0.001 for both groups vs. placebo ) .
moreover , weight loss was maintained for a second year in the sequel trial , a 52-week extension of the conquer trial .
the conquer trial revealed an overall significant improvement in hba1c ( % change from baseline : 0% , -0.1% , and 0.1% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p<0.0001 for both groups vs. placebo ) and in fasting glucose levels ( % change from baseline : -0.01% , -0.07% , and 0.13% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p=0.0047 for 7.5/46 mg vs. placebo and p<0.0001 for 15/92 mg vs. placebo ) at week 56 .
the progression to type 2 diabetes among participants without diabetes was lower in the pt - treated patients ( 2.8% in the 7.5/46 mg and 1.7% in the 15/92 mg ) compared with those receiving the placebo ( 3.6% ) .
the relative risk of type 2 diabetes versus placebo was 0.78 ( 95% confidence interval [ ci ] , 0.40 to 1.50 ) for the 7.5/46 mg and 0.47 ( 95% ci , 0.25 to 0.88 ) for the 15/92 mg doses of pt .
an improvement in glycemic control was observed in the sequel trial . at the conclusion of the trial ( 108 weeks ) ,
fasting glucose levels were significantly reduced from baseline in the 15/92 mg dose group ( the least - squared change in fasting glucose was 0.1 in the 7.5/46 mg , -1.2 in the 15/92 mg , and 3.7 in the placebo groups ; p=0.0048 for 15/92 mg vs. placebo ) . in the participants without type 2 diabetes at baseline , the progression of type 2 diabetes decreased during the 1-year extension . the annualized incidence rates for progression to type 2 diabetes were 0.9% , 1.7% , and 3.7% in the 7.5/46 , 15/92 mg , and placebo groups , respectively , among the study participants without diabetes at baseline .
these results revealed a 54% reduction in the progression to type 2 diabetes in the low- ( 7.5/46 mg ) and a 76% reduction in the high - dose ( 15/92 mg ) groups compared with the placebo group . among participants with type 2 diabetes at baseline ,
hba1c did not change markedly from baseline in the placebo group ( 0% ) , whereas treatment with 7.5/46 and 15/92 mg pt led to 0.4% and 0.2% reductions in hba1c , respectively .
however , the results of the sequel trial should be interpreted with caution because , as an extension of the conquer trial , it may be subject to selection bias .
common drug - related side effects include paresthesias , nausea , dizziness , constipation , and dry mouth .
the reported neuropsychiatric adverse events include depression , anxiety , insomnia , and disturbances in attention .
furthermore , pt may increase heart rate by two beats per minute ; however , the fda judged that the potential risk posed by an elevated heartbeat was outweighed by improvements in cardiovascular risk factors such as blood pressure . in september 2014 , the fda approved naltrexone / bupropion ( nb ) sustained - release ( sr ) tablets as a treatment option for chronic weight management .
naltrexone was approved previously to treat alcohol and opioid dependence , and bupropion was approved for the treatment of depression or as an aid for smoking cessation .
naltrexone is an opioid receptor antagonist , and bupropion acts on adrenergic and dopaminergic receptors in the hypothalamus .
the combining of bupropion and naltrexone was based on the theory that naltrexone may block the compensatory mechanisms associated with bupropion that prevent sustained weight loss .
the efficacy of nb was evaluated by the contrave obesity research ( cor ) program consisting of the cor - i , cor - ii , cor trial with intensive behavior modification ( cor - bmod ) , and cor - diabetes trials ( table 1 ) .
the cor - i , cor - ii , and cor - bmod trials evaluated overweight / obese patients without diabetes . following treatment for 1 year , the group receiving naltrexone 32 mg / bupropion 360 mg lost 4 to 5 kg ( approximately -4% weight loss from baseline body weight ) more than the placebo group , and 48% to 66% of the patients in the nb group lost 5% of their baseline body weight .
the cor - diabetes trial evaluated the safety and efficacy of nb in 505 overweight or obese patients with type 2 diabetes over a 56-week period .
participants were assigned to the naltrexone 32 mg sr / bupropion 360 mg sr or placebo group . compared with the placebo group ,
the patients treated with nb lost significantly more weight ( -5.0% vs. -1.8% ; p<0.001 ) , and a higher proportion lost 5% of their body weight ( 44.5% vs. 18.9% ; p<0.001 ) .
furthermore , baseline hba1c was significantly reduced in the patients receiving nb compared with the placebo group ( -0.6% vs. -0.1% , respectively ; p<0.001 ) , and 44.1% of patients receiving nb achieved < 7% hba1c compared with 26.3% in the placebo group ( p<0.001 ) .
the cardiovascular safety of naltrexone 32 mg sr / bupropion 360 mg sr is currently under investigation ( clinical trial reg no .
the most common adverse events include nausea , constipation or diarrhea , headache , vomiting , dizziness , insomnia , and dry mouth .
the nb provides a boxed warning to alert users to the increased risk of suicidal thoughts and behaviors associated with bupropion .
the nb has a dose - related risk of seizures and may elevate blood pressure and heart rate .
liraglutide is a human glucagon - like peptide 1 analog that may be administered once a day because of its prolonged half - life of 13 hours .
the efficacy of the drug was well established in the liraglutide effect and action in diabetes ( lead ) studies , a series of phase iii randomized , controlled trials .
the approved doses for the treatment of diabetes are 1.2 and 1.8 mg in the united states and 0.6 and 0.9 mg in japan .
the lead-3 trial comprised 746 patients with type 2 diabetes assigned to liraglutide ( 1.2 or 1.8 mg ) or glimepiride ( 8 mg ) treatment groups for 52 weeks .
the hba1c reductions from baseline were -0.84% and -1.14% in the 1.2 and 1.8 mg groups , respectively , and body weight was reduced by -2.05 kg from baseline in the 1.2 mg group and -2.45 kg in the 1.8 mg group , whereas a significant weight gain ( 1.12 kg ) was observed in patients treated with glimepiride .
the recommend dose is 3 mg in contrast to 1.2 or 1.8 mg for diabetes .
the satiety and clinical adiposity - liraglutide evidence in nondiabetic and diabetic subjects ( scale ) trial consists of four clinical trials designed to demonstrate the safety and efficacy of liraglutide 3 mg for weight management . the scale obesity and prediabetes phase iiia trial involving 3,731 patients found that patients treated with liraglutide lost an average of 8% of their body weight in 56 weeks compared with 2.6% in the placebo group . moreover , significantly more patients in the liraglutide group lost 5% of their baseline body weight compared with those taking the placebo ( 63.5% vs. 26.6% , respectively ) , and 32.8% of the liraglutide group lost > 10% of their baseline body weight ( 10.1% in the placebo group ) .
the scale - diabetes trial was a 56-week randomized , placebo - controlled trial designed to investigate the potential of liraglutide 3 mg in obese or overweight patients with type 2 diabetes . in this trial ,
846 overweight or obese patients with diabetes were assigned randomly to liraglutide 3 mg or 1.8 mg or placebo groups .
after 56 weeks , the 3 and 1.8 mg liraglutide groups achieved weight loses of 6% and 5% , respectively , compared with 2% in the placebo group . furthermore ,
50% of the patients in the 3 mg group and 35% of those in the 1.8 mg group achieved 5% weight loss compared with 13% in the placebo group , and approximately 69% of the patients treated with liraglutide 3 mg achieved the hba1c target of < 7% ( clinical trial reg no .
concerned by the lack of long - term data for liraglutide in the treatment of obesity and a variety of safety issues , such as gallbladder disease , pancreatitis , breast and thyroid cancers , and increased heart rate , the fda advisory panel recommended that these issues be addressed in postmarketing studies .
however , the panel agreed that the ongoing cardiovascular outcomes trial of the liraglutide effect and action in diabetes : evaluation of cardiovascular outcome results study would be sufficient to characterize the cardiovascular risk of the liraglutide .
the recommended dose is 120 mg three times daily before meals . a lower dose ( 60 mg ) is available as an over - the - counter preparation in the united states .
one- and 2-year studies evaluating orlistat treatment for obesity have shown significant improvements in glycemic control and in blood pressure and lipid profiles . in a large 4-year prospective study of 3,305 participants with bmi of 30 kg / m and normal or impaired glucose tolerance ( the xenical in the prevention of diabetes in obese subjects study ) , the orlistat - treated group exhibited significant mean weight loss ( 5.8 kg vs. 3.0 kg in the placebo group ; p<0.001 ) and reduced progression to type 2 diabetes ( risk reduction of 37.3% in the orlistat group ; p=0.0032 ) .
a korean study in which patients were administered orlistat for 24 weeks reported a modest but significant mean weight loss of -2.73 kg ( mean weight change , -3.50%0.38% ) and significant improvements in lipid profiles , fasting insulin , waist circumference , blood pressure , fasting plasma glucose ( -10.414.62 mg / dl ) , and glycosylated hemoglobin ( hba1c , -0.87% ) .
the most common adverse effects of orlistat include flatus with discharge and oily spotting or fecal urgency , and the drug interferes with the absorption of fat soluble vitamins , although not tremendously .
lorcaserin is a selective serotonin 2c ( 5-ht2c ) receptor agonist that suppresses appetite via stimulation of melanocortin receptor 4 .
the drug has low affinity for the 5-ht2b receptor , which is associated with the development of valvular heart disease and the cause of the withdrawal of agents such as dexfenfluramine . in 2012 , the fda approved lorcaserin 10 mg twice daily based on the findings of the pivotal randomized , placebo - controlled trials : behavioral modification and lorcaserin for overweight and obesity management ( bloom ) , behavioral modification and lorcaserin second study for obesity management ( blossom ) , and bloom - diabetes mellitus ( bloom - dm ) . the bloom and blossom trials investigated the effect of lorcaserin on overweight or obese nondiabetic patients and found a ~3% placebo - corrected weight change in the group treated with lorcaserin ( 20 mg / day ) ( bloom , -3.6% ; blossom , -2.9% ; both p<0.05 ) .
moreover , a significantly higher proportion of patients in the lorcaserin group lost 5% of their baseline body weight compared with the placebo group ( approximately 47% vs. 20% , respectively in the bloom ; 47% vs. 25% , respectively in the blossom trials ) .
furthermore , improvements in fasting glucose and triglyceride levels and blood pressure were observed in the lorcaserin groups .
the bloom - dm study included 604 overweight and obese patients with type 2 diabetes who were treated with metformin and/or sulfonylurea and randomized to lorcaserin 10 or 20 mg / day or placebo groups for 52 weeks .
consistent with the results of the bloom and blossom trials , the lorcaserin - treated groups achieved weight losses of -3.4% ( 10 mg ) and -3.1% ( 20 mg )
. a significantly higher proportion of patients in the lorcaserin groups lost 5% of their initial body weight ( 10 mg , 44.7% ; 20 mg , 37.5% ) compared with patients administered placebo ( 16.1% ) .
the reduction in mean hba1c was significantly greater in the lorcaserin - treated groups than in the placebo group ( 10 mg , -1.0% change from baseline ; 20 mg , -0.9% change ; and placebo , -0.4% change ; p<0.001 ) . a significantly higher proportion of patients in the lorcaserin groups achieved hba1c 7% compared with patients treated with placebo ( 10 mg , 52.2% ; 20 mg , 50.4% ; and placebo , 26.3% ) . however , symptomatic hypoglycemia was more frequent in the lorcaserin groups ( 10 mg , 10.5% ; 20 mg , 7.4% ) than in the placebo group ( 6.3% ) .
the adverse events associated with lorcaserin include headache , dizziness , fatigue , nausea , dry - mouth , and constipation .
no statistically significant difference in the occurrence of fda - defined valvular disease was found between the lorcaserin and placebo groups .
however , the postmarketing trials were required to evaluate the long - term cardiovascular effects of lorcaserin .
phentermine / topiramate ( pt ) extended - release ( er ) is a combination of the fda - approved medications phentermine and topiramate in an er formulation .
phentermine is indicated for short - term weight loss in overweight or obese adults who exercise and eat a reduced calorie diet .
topiramate is indicated for the treatment of certain types of seizures in people who have epilepsy and to prevent migraine headaches .
the exact mechanism underlying the weight loss action of topiramate is not known ; however , it may be associated with a combination of features such as an effect on sodium channels , enhancement of gaba - activated chloride channels , and inhibition of carbonic anhydrase isoenzymes .
pt is available at a higher dose ( 15 mg phentermine/92 mg topiramate er ) for select patients .
discontinuation or an increase in dosage is recommended for patients who have not lost 3% of their baseline weight .
treatment should be discontinued if a weight loss > 5% of baseline is not achieved with 15/92 mg per day .
fda approval of pt was based on three phase iii clinical trials performed to evaluate the efficacy of the drug ( equip , conquer , sequel ) . in the equip trial ,
1,276 obese adults without diabetes were assigned randomly to a low- ( 3.75/23 mg / day ) or high- ( 15/92 mg / day ) dose pt or placebo group for 56 weeks . at the conclusion of the study ,
the patients in the low- and high - dose pt and placebo groups lost 5.1% , 10.9% , and 1.6% of their baseline body weight , respectively ( p<0.0001 ) .
moreover , the results revealed improvements in waist circumference , triglyceride levels , and blood pressure .
the conquer trial included 2,487 overweight and obese patients with two or more weight - related comorbidities such as hypertension , prediabetes , type 2 diabetes , dyslipidemia , and abdominal adiposity .
the participants were assigned to pt ( 7.5/46 or 15/92 mg ) or placebo groups for 56 weeks . at the conclusion of the trial ,
the subjects in the 7.5/46 mg group achieved a -8.1 kg change in body weight ( mean change -7.8% ) , those in the 15/92 mg group a -10.2 kg change ( mean change -9.8% ) , and those in the placebo group a -1.4 kg change ( mean change -1.2% ) .
a higher percentage of subjects in the pt groups achieved a 5% weight loss after 1 year compared with those receiving placebo ( 62% , 70% , and 21% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p<0.001 for both groups vs. placebo ) .
moreover , weight loss was maintained for a second year in the sequel trial , a 52-week extension of the conquer trial .
the conquer trial revealed an overall significant improvement in hba1c ( % change from baseline : 0% , -0.1% , and 0.1% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p<0.0001 for both groups vs. placebo ) and in fasting glucose levels ( % change from baseline : -0.01% , -0.07% , and 0.13% in the 7.5/46 , 15/92 mg , and placebo groups , respectively ; p=0.0047 for 7.5/46 mg vs. placebo and p<0.0001 for 15/92 mg vs. placebo ) at week 56 .
the progression to type 2 diabetes among participants without diabetes was lower in the pt - treated patients ( 2.8% in the 7.5/46 mg and 1.7% in the 15/92 mg ) compared with those receiving the placebo ( 3.6% ) .
the relative risk of type 2 diabetes versus placebo was 0.78 ( 95% confidence interval [ ci ] , 0.40 to 1.50 ) for the 7.5/46 mg and 0.47 ( 95% ci , 0.25 to 0.88 ) for the 15/92 mg doses of pt .
an improvement in glycemic control was observed in the sequel trial . at the conclusion of the trial ( 108 weeks ) ,
fasting glucose levels were significantly reduced from baseline in the 15/92 mg dose group ( the least - squared change in fasting glucose was 0.1 in the 7.5/46 mg , -1.2 in the 15/92 mg , and 3.7 in the placebo groups ; p=0.0048 for 15/92 mg vs. placebo ) . in the participants without type 2 diabetes at baseline , the progression of type 2 diabetes decreased during the 1-year extension .
the annualized incidence rates for progression to type 2 diabetes were 0.9% , 1.7% , and 3.7% in the 7.5/46 , 15/92 mg , and placebo groups , respectively , among the study participants without diabetes at baseline .
these results revealed a 54% reduction in the progression to type 2 diabetes in the low- ( 7.5/46 mg ) and a 76% reduction in the high - dose ( 15/92 mg ) groups compared with the placebo group . among participants with type 2 diabetes at baseline ,
hba1c did not change markedly from baseline in the placebo group ( 0% ) , whereas treatment with 7.5/46 and 15/92 mg pt led to 0.4% and 0.2% reductions in hba1c , respectively .
however , the results of the sequel trial should be interpreted with caution because , as an extension of the conquer trial , it may be subject to selection bias .
common drug - related side effects include paresthesias , nausea , dizziness , constipation , and dry mouth .
the reported neuropsychiatric adverse events include depression , anxiety , insomnia , and disturbances in attention .
, pt may increase heart rate by two beats per minute ; however , the fda judged that the potential risk posed by an elevated heartbeat was outweighed by improvements in cardiovascular risk factors such as blood pressure .
in september 2014 , the fda approved naltrexone / bupropion ( nb ) sustained - release ( sr ) tablets as a treatment option for chronic weight management .
naltrexone was approved previously to treat alcohol and opioid dependence , and bupropion was approved for the treatment of depression or as an aid for smoking cessation .
naltrexone is an opioid receptor antagonist , and bupropion acts on adrenergic and dopaminergic receptors in the hypothalamus .
the combining of bupropion and naltrexone was based on the theory that naltrexone may block the compensatory mechanisms associated with bupropion that prevent sustained weight loss .
the efficacy of nb was evaluated by the contrave obesity research ( cor ) program consisting of the cor - i , cor - ii , cor trial with intensive behavior modification ( cor - bmod ) , and cor - diabetes trials ( table 1 ) .
the cor - i , cor - ii , and cor - bmod trials evaluated overweight / obese patients without diabetes . following treatment for 1 year
, the group receiving naltrexone 32 mg / bupropion 360 mg lost 4 to 5 kg ( approximately -4% weight loss from baseline body weight ) more than the placebo group , and 48% to 66% of the patients in the nb group lost 5% of their baseline body weight .
the cor - diabetes trial evaluated the safety and efficacy of nb in 505 overweight or obese patients with type 2 diabetes over a 56-week period .
participants were assigned to the naltrexone 32 mg sr / bupropion 360 mg sr or placebo group . compared with the placebo group ,
the patients treated with nb lost significantly more weight ( -5.0% vs. -1.8% ; p<0.001 ) , and a higher proportion lost 5% of their body weight ( 44.5% vs. 18.9% ; p<0.001 ) .
furthermore , baseline hba1c was significantly reduced in the patients receiving nb compared with the placebo group ( -0.6% vs. -0.1% , respectively ; p<0.001 ) , and 44.1% of patients receiving nb achieved < 7% hba1c compared with 26.3% in the placebo group ( p<0.001 ) .
the cardiovascular safety of naltrexone 32 mg sr / bupropion 360 mg sr is currently under investigation ( clinical trial reg no .
the most common adverse events include nausea , constipation or diarrhea , headache , vomiting , dizziness , insomnia , and dry mouth .
the nb provides a boxed warning to alert users to the increased risk of suicidal thoughts and behaviors associated with bupropion .
the nb has a dose - related risk of seizures and may elevate blood pressure and heart rate .
liraglutide is a human glucagon - like peptide 1 analog that may be administered once a day because of its prolonged half - life of 13 hours .
the efficacy of the drug was well established in the liraglutide effect and action in diabetes ( lead ) studies , a series of phase iii randomized , controlled trials .
the approved doses for the treatment of diabetes are 1.2 and 1.8 mg in the united states and 0.6 and 0.9 mg in japan .
the lead-3 trial comprised 746 patients with type 2 diabetes assigned to liraglutide ( 1.2 or 1.8 mg ) or glimepiride ( 8 mg ) treatment groups for 52 weeks .
the hba1c reductions from baseline were -0.84% and -1.14% in the 1.2 and 1.8 mg groups , respectively , and body weight was reduced by -2.05 kg from baseline in the 1.2 mg group and -2.45 kg in the 1.8 mg group , whereas a significant weight gain ( 1.12 kg ) was observed in patients treated with glimepiride .
the recommend dose is 3 mg in contrast to 1.2 or 1.8 mg for diabetes .
the satiety and clinical adiposity - liraglutide evidence in nondiabetic and diabetic subjects ( scale ) trial consists of four clinical trials designed to demonstrate the safety and efficacy of liraglutide 3 mg for weight management .
the scale obesity and prediabetes phase iiia trial involving 3,731 patients found that patients treated with liraglutide lost an average of 8% of their body weight in 56 weeks compared with 2.6% in the placebo group . moreover , significantly more patients in the liraglutide group lost 5% of their baseline body weight compared with those taking the placebo ( 63.5% vs. 26.6% , respectively ) , and 32.8% of the liraglutide group lost > 10% of their baseline body weight ( 10.1% in the placebo group ) .
the scale - diabetes trial was a 56-week randomized , placebo - controlled trial designed to investigate the potential of liraglutide 3 mg in obese or overweight patients with type 2 diabetes . in this trial ,
846 overweight or obese patients with diabetes were assigned randomly to liraglutide 3 mg or 1.8 mg or placebo groups .
after 56 weeks , the 3 and 1.8 mg liraglutide groups achieved weight loses of 6% and 5% , respectively , compared with 2% in the placebo group . furthermore ,
50% of the patients in the 3 mg group and 35% of those in the 1.8 mg group achieved 5% weight loss compared with 13% in the placebo group , and approximately 69% of the patients treated with liraglutide 3 mg achieved the hba1c target of < 7% ( clinical trial reg no .
concerned by the lack of long - term data for liraglutide in the treatment of obesity and a variety of safety issues , such as gallbladder disease , pancreatitis , breast and thyroid cancers , and increased heart rate , the fda advisory panel recommended that these issues be addressed in postmarketing studies .
however , the panel agreed that the ongoing cardiovascular outcomes trial of the liraglutide effect and action in diabetes : evaluation of cardiovascular outcome results study would be sufficient to characterize the cardiovascular risk of the liraglutide .
exercise and monitoring food intake are important components of a weight loss regime ; however , it is difficult for patients to reduce and maintain their weight by lifestyle changes alone ; thus , safe and effective long - term anti - obesity drugs may be a necessary adjunct to lifestyle modification .
the five drugs currently approved or pending fda approval for long - term treatment of obesity are orlistat , lorcaserin , pt , nb , and liraglutide ( table 2 ) .
these medications have been shown to reduce weight by 5% to 10% , improve glycemic profiles significantly , and reduce cardiovascular risk in patients with diabetes .
however , possible adverse events should be monitored , and these medications must be considered as part of a comprehensive management regime for obese patients with diabetes .
further study of neuropeptide - y , 3-adrenergic receptors , oxyntomodulin , and amylin analogues are warranted for the development of future antiobesity medications .
 type 2 diabetes and obesity have a complex relationship ; obesity is linked to insulin resistance , the precursor to type 2 diabetes . 
 the management of obesity is an important method to delay onset of diabetes and improve the glycemic durability of antidiabetic agents . 
 however , insulin and some of the oral hypoglycemic agents used to treat diabetes cause significant weight gain , and it is difficult for patients with diabetes to reduce and maintain their weight by life - style changes alone . 
 thus , antiobesity medications or bariatric surgery may be a necessary adjunct for certain obese patients with diabetes . in 2012 , the u.s . 
 food and drug administration ( fda ) approved lorcaserin and phentermine / topiramate extended - release for the management of chronic weight , and approval for naltrexone / bupropion sustained - release as an adjunct to exercise and reduced caloric intake followed in 2014 . 
 liraglutide is pending fda approval for antiobesity drug . here 
 we review the efficacy of approved and new promising drugs for the management of obesity . 
INTRODUCTION
FDA-APPROVED MEDICATIONS FOR LONG-TERM TREATMENT OF OBESITY
Orlistat
Lorcaserin
Phentermine/topiramate extended-release
Naltrexone/bupropion sustained-release
Liraglutide
CONCLUSIONS