Clinical Significance
Due to counteractive adaptive biological responses observed during periods of decreased food intake and increased energy expenditure, sustained weight loss can rarely be achieved exclusively only by these methods.[8][9] The reduction in energy expenditure rate and the increase in appetite observed after weight loss both correlate with hormonal changes that promote weight regain.
Despite this adaptive mechanism that impairs continued weight loss, the recommendation is that all individuals should adopt a healthy, well-balanced eating pattern, ideally supervised, and maintain a regular physical activity of at least 30 to 60 min of aerobic activity on most days of the week to aid in providing weight and fat loss, improvement in cardiometabolic parameters, and weight maintenance.[10]
Non-pharmacologic Therapy
Lifestyle intervention - Before the initiation of weight loss drug therapy, it is important to have established a lifestyle intervention program, ideally with close monitoring by a dietitian, and long term follow-up as performed in long term trials.[11][12] Discussion of these different ways of lifestyle intervention is beyond the scope of this article, which focuses on medication therapy; however, pharmacologic therapy should be a consideration after all these non-pharmacologic approaches are optimized.
Diet - Dietary adherence is essential for the success of weight loss, regardless of the type of diet chosen. In a study that compared different types of diet, the response was proportional to the adherence.[13]
Very low-calorie diets can provide faster initial weight loss; however, due to the body's hormonal adaptation, they are challenging to maintain long-term. It is crucial to adhere to a dietary program that continues to provide a negative calorie balance in the long term, and the initiation of medication therapy can help to overcome the stagnation usually observed after the initial months on diet and lifestyle intervention.
Intermittent fasting dietary patterns can also be considered as a feasible alternative, although studies have shown inconsistent efficacy. A one-year trial with 100 obese individuals compared three groups: alternate-day fasting (patients alternated 25 percent of total energy consumed on fasting days and 125 percent consumed on free days) versus caloric restriction (75 percent of total energy needs ingested daily) versus non-intervention control. After 6 and 12 months, mean weight loss was similar for individuals in the alternate fasting group (-6.8% [95% CI, -9.1% to -4.5%] and -6.0% [95% CI, -8.5% to -3.6%, respectively]) and in the daily constant calorie restriction group (-6.8% [95% CI, -9.1% to -4.6%] and -5.3% [95% CI, -7.6% to -3.0%], respectively), when both were compared to the control group, with similar efficacy.[14]
More importantly, regardless of the diet or lifestyle program chosen, and due to obesity being a chronic disease with an adaptative mechanism, continued surveillance and follow-ups are mandatory to provide better long-term outcomes.
Exercise - Keeping a negative calorie balance by increasing energy expenditure through physical activity is also an important tool in weight loss maintenance. A study published in 2017 revealed that aerobic and anaerobic exercise combined are more efficient than both modalities isolated in the weight loss.[15] The recommendation is for approximately 30 minutes or more, five to seven days a week, to prevent weight gain and to improve cardiovascular health in adults.[16]
Behavior therapy - This is an important tool to help patients make long-term changes in their eating behavior by modifying and monitoring their food intake, modifying their physical activity, and controlling stimuli in the environment that trigger binge eating.
Pharmacologic Therapy
After changes in lifestyle to continue obtaining the positive effects of weight loss, it can be beneficial to initiate approved weight loss medications, especially in the case of failure to continue losing weight, or when weight regain has happened. This intervention can also be considered concomitantly to the initiation of a weight loss program after a discussion of risks and benefits with patients.
Indications: Drug therapy can merit consideration with a BMI >30 kg/m, or a BMI of 27 to 29.9 kg/m in the presence of weight-related complications, in patients who have failed to achieve weight loss goals (at least 5 percent of total body weight in 3 to 6 months) after implementing comprehensive lifestyle intervention. It is important to mention that the initiation of drug therapy should always be accompanied by the maintenance of behavioral and lifestyle changes since, without this combination, medications usually have low success rates.[17][18]
The approved medications usually promote weight loss by decreasing appetite and hunger, increasing satiety, and ultimately reducing caloric absorption or ingestion. Despite that, it is still a challenge to achieve long term weight maintenance and overcome the physiologic trend of regaining the weight that was previously lost.
When deciding to initiate pharmacologic therapy, an individualized approach is necessary, taking into consideration the patient's comorbidities, preferences, insurance coverage, and costs. Single agents are usually preferable to combination therapy. However, different medications can work in combination to optimize response as long as the clinician weighs both safety and interaction profiles.[19]
The goals of obesity medication therapy should be realistic, since setting unrealistic expectations can lead to frustration and treatment abandonment. Treatment should focus on short-term as well as long-term weight reduction, avoidance of weight gain, improvement of health parameters, and management of side effects.[20]
Clinical studies of weight loss medications have traditionally considered a weight loss of 5 to 10% to be significant since this is the percentage recommended by the FDA in trials, and it is associated with clinical improvement in metabolic risk profile.[21] Secondary weight loss outcomes in these trials have also looked at the proportion of individuals with 10% or more weight loss and change in weight from baseline.
Upon initiation of weight loss therapy, it is important to emphasize that drugs can work differently in every patient as the response and side effects can vary significantly. Patients also need to be explained that it is common to achieve a plateau after the initial weight loss, and often when drug treatment is interrupted, weight regain can be expected.
1) Liraglutide is the only glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for the treatment of obesity in patients without diabetes. The other drugs in the class have the positive effect of weight loss, but they have only been FDA-approved as anti-diabetic medications; therefore, they should not be used in patients without diabetes.
GLP-1 is an incretin peptide secreted by the gut following oral food intake. It inhibits gastric emptying and glucagon release and induces glucose-dependent insulin release from the beta cell in the pancreas. The GLP-1RA can be added as a second or third choice to the treatment of type 2 diabetes when patients have not achieved glycemic control. Along with SGLT-2 inhibitors, GLP-1RA is ideal for therapy in patients with diabetes who are also overweight or obese due to their known effect of weight loss. However, in non-diabetic patients, the use of SGLT-2 inhibitors or GLP-1RA other than liraglutide with the purpose of weight loss is off-label.
In the treatment of obesity, liraglutide has approval at a higher dose than the recommended one for diabetes treatment. It is approved for obesity treatment in adults with BMI ≥30 kg/m or with BMI ≥27 kg/m if at least one weight-related comorbidity is present (e.g., hypertension, type 2 diabetes, dyslipidemia, osteoarthritis). The dose of liraglutide approved for obesity is 3 mg daily, but even an initial dose of 1.2 mg can provide weight loss and can be up titrated as tolerated (see below). Patients can often achieve weight loss with below the maximum dose of liraglutide with fewer side effects and adequate glucose control.
Randomized controlled trials have reported the efficacy of liraglutide for both diabetes control and weight loss. Several trials have shown sustained weight loss with other cardiovascular benefits in a maximum duration of 2 years.
In a 20-week study of 564 patients, liraglutide in four different daily doses (1.2, 1.8, 2.4, and 3 mg) showed dose-dependent weight loss compared to placebo or open-label orlistat, with 5.8 kg and 3.8 kg more weight loss than placebo and orlistat, respectively. In the 2-year extension study, the results were similar, and patients on the higher dose (2.4 and 3.0 mg) kept a weight loss of 7.8 kg at the end of the study (total n=92 patients for the higher dose combined). Liraglutide 3.0 mg also had the benefit of a decrease in body fat by 15.4% and lean tissue by only 2.0%. The prevalence of prediabetes and metabolic syndrome after two years was reduced by 52% and 59%, respectively, with simultaneous improvement of blood pressure and lipids.[22]
A 56-week trial compared liraglutide 3 mg with placebo in 3731 patients with BMI ≥30 kg/m or ≥27 kg/m with dyslipidemia and/or hypertension. Mean weight loss was -8.0 kg versus -2.6 kg in the placebo group, with the improvement of several cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life.[23]
The LEADER trial also showed that liraglutide reduced major cardiovascular events (death of cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in patients with type 2 diabetes in a lower dose than the dose recommended for obesity (1.8 mg versus 3 mg).[24] There is no cardiovascular outcome data in patients with obesity without diabetes.
Side effects of liraglutide are mainly gastrointestinal, including nausea and vomiting, which are usually worse at the beginning of therapy or after increment of dose. Nausea and vomiting have seemed to be dose-dependent. Sometimes an intermediate dose that patients can tolerate and that preserves the positive effects of the medication can be chosen. Pancreatitis has also been a finding, although there is no proven causal relationship. Gallbladder disease can predispose to cholelithiasis, and dehydration can occur secondary to persistent nausea and vomiting if the medication is not discontinued.[24] Liraglutide has also shown an association with malignant medullary carcinoma in rodents trial; however, this association remains unproven in humans.
Dosing and contraindications: Liraglutide is administered subcutaneously as an initial dose of 0.6 mg daily for one week, with 0.6 mg increments weekly until reaching the recommended dose of 3 mg. However, as explained before, many patients can not tolerate the higher dose but still can have benefits on the maximum tolerated dose. There are no data on longer than two years of use of liraglutide. Many other GLP-1RA have come onto the market with a similar response in glucose control, weight loss, and cardiovascular benefits; however, they have not received approval for the treatment of overweight or obese patients without diabetes. Researchers have not studied the medication in pregnancy, and it is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasias (MEN) 2A or 2B.
2) Orlistat inhibits pancreatic lipases leading to impairment of fat digestion in the gut. Fat is not completely hydrolyzed and, therefore, not absorbed. Weight loss is proportional to the calories lost as fecal fat excretion, which can represent a 30% calorie loss on an average diet.
Several studies have shown its efficacy, including randomized control trials and meta-analysis [25][26]. In a meta-analysis of 12 trials, the orlistat group had a mean weight loss of 8% versus 5% on the placebo group with similar behavioral intervention.[27] Subjects maintained weight loss with continuous therapy up to 24 to 36 months.
The Xendos study randomly assigned 3304 overweight patients to orlistat or placebo. Twenty-one percent of the patients had impaired glucose tolerance. During the first year, researchers observed a more significant difference between groups (11% versus 6% below baseline in the placebo group). This difference diminished during the next three years of the trial when the orlistat group was 6.9% below the baseline versus 4.1% in the placebo group. Despite a reduced difference by the end of the study, patients in the orlistat group had a lower incidence of diabetes compared to the placebo group (6.2 vs. 9%). In other trials in patients with diabetes, orlistat also provided more weight loss and lower glycated hemoglobin (A1C) at one year compared to placebo.[28]
Other benefits have also been seen in different studies. In a systematic review, orlistat revealed a reduction in systolic and diastolic blood pressure compared to placebo (weighted difference of -2.5 and -1.9 mm Hg, respectively).[29] Orlistat also improved serum lipid values in a multicenter trial, with low-density lipoprotein (LDL) cholesterol reduction by 5 to 10% in patients treated with orlistat and low-fat diet for 48 weeks from baseline[30].
Dosing and contraindications: Patients can use orlistat for up to 4 years in the treatment of obesity. If therapy is to continue for more than four years, a discussion with the patient is to inform then of the lack of more extended studies. The recommended dose is 120 mg three times daily, along with each meal. It is available over the counter in many countries, including the United States. It is a strong recommendation that patients get a daily multivitamin at bedtime due to the decreased absorption of fat-soluble vitamins related to chronic orlistat use.
The medication has not been studied in pregnancy and should not be a consideration in patients with chronic malabsorption, cholestasis, or calcium oxalate stones.
The most common side effects of orlistat are typically gastrointestinal, including abdominal cramps, increased flatulence, and fecal incontinence. These side effects tend to occur more frequently early during its use and to subside when patients adhere to a low-fat diet (less than 30%) without losing the weight loss effect.[31] FDA identified 13 reports of severe liver injury, although a causal relationship has not been established, since patients were also taking other drugs and had other medical conditions that could have contributed to that. Nevertheless, patients who take orlistat should understand that they need to contact their health care provider if signs or symptoms of liver injury occur. There was no increased frequency of cholelithiasis, cardiovascular, or psychiatric events.
Due to the fat fecal excretion, levels of fat-soluble vitamins (A, D, E, K) and beta-carotene become impaired by orlistat. Also, it can prolong the international normalized ratio (INR) and prothrombin time in patients taking warfarin by reducing vitamin K levels, requiring reduction of warfarin dose and close monitoring.[32]
Due to fat malabsorption, enteric calcium can bind to the fat excreted in the stools. As a consequence, intestinal oxalate becomes more available to be absorbed and then excreted in the urine. Excessive free oxalate can be deposited in the renal parenchyma causing acute nephrocalcinosis and acute kidney injury.[33]
3) Combination therapies: Due to the chronic aspect of the disease and the need for long term treatment, as well as the potential risk of side effects of different medications, it has been proposed that combination therapy can be more effective by using a lower dose of two medications with the advantage of one drug compensating potential side effects of the other drug and maximizing their efficacy.
3.1) FDA approved the phentermine-topiramate combination in 2012 for adults with BMI ≥30 kg/m or with a BMI ≥27 kg/m with at least one weight-related comorbidity (e.g., hypertension, diabetes, dyslipidemia) for use along with reduced dietary caloric intake for weight loss. It is not recommended for patients with high cardiovascular risk due to a potential increase in heart rate; however, a 2-year-duration trial has not shown an increase in mortality compared to placebo. Long term data in mortality is not available. It can be the first option in the treatment of obesity, or if the patient did not tolerate or failed liraglutide and/or orlistat, particularly in patients with binge eating disorder.
In the Conquer trial, which studied 2487 patients, there was a change in body weight of -1.4 kg in the placebo group versus -8.1 in the phentermine-topiramate (7.5/46 mg) after 56 weeks.[34] In an extension study of the initial trial (Sequel) that followed patients for extra 52 weeks, patients on the low dose of the phentermine-topiramate group achieved a mean weight loss of 9.6 kg versus 2.1 kg in the placebo group after 108 weeks from the original baseline.[35] It is evident that the weight loss in the second year was less prominent; however, most participants were able to maintain weight loss, whereas the placebo group had a slight increase in body weight. All individuals were participating in a lifestyle modification program at the same time.
Participants in the phentermine-topiramate group also showed improved cardiovascular and metabolic variables and lower incidence of diabetes in comparison to placebo. The combination was well tolerated over 108 weeks, with adverse events happening more frequently in the initial phase of the trial.
The most commonly reported side effects of the medication are paraesthesias, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Patients in the medication-treated groups observed a slight reduction in blood pressure at the expense of a slight increase in heart rate of 1.3 and 1.7 bpm for low and high doses, respectively, versus 0.4 in placebo. However, there were no reported adverse events related to the increase in heart rate.
In regards to psychiatric side effects, there was no increase in serious suicidal ideation or behavior in the participants during the 108 weeks of observation. There were reports of dose-dependent anxiety-related adverse events (3.1%, 6.5%, and 9.5% for placebo, 7.5/46 mg, and 15/92 mg arms, respectively). However, they were mostly mild in severity.
Dosing and contraindications: There are four different fixed drug combinations for the phentermine-topiramate combination. The starting dose is 3.75/23 mg for 14 days, which should then increase to the recommended dose of 7.5/46 mg. If, after 12 weeks of treatment, a 3 percent loss of baseline body weight does not occur, the recommendation is to increase the dose to 11.25/69 mg for another 14 days and then to 15/92 mg thereafter. If less than 5 percent of body weight is achieved after 12 weeks on the highest dose, the medication should be discontinued gradually to avoid withdrawal symptoms from topiramate.
The phentermine-topiramate combination is contraindicated during pregnancy due to teratogenicity (risk of orofacial clefts in infants exposed to the medication during the first trimester of pregnancy). It is mandatory to obtain a pregnancy test before starting the drug in childbearing age female and then monthly thereafter. It is also contraindicated in patients with hyperthyroidism or acute angle glaucoma and should not be started on patients who have taken monoamine oxidase inhibitors in the past 14 days. It should also be avoided in patients with a history of kidney stones due to the increased risk related to topiramate.
Recommended monitoring is as follows:
- Heart rate every visit
- Suicidal behavior and ideation screening and discontinuation of the drug if symptoms develop.
- Visual disturbances, especially acute myopia and signs of increased intraocular pressure
- Cognitive impairment since topiramate can cause disturbances in attention or memory
- Electrolytes and creatinine check-up before and during treatment, since topiramate inhibits carbonic anhydrase enzyme predisposing to acidosis, although no significant acidosis has been reported in the trials.
Phentermine can also be used as a monotherapy in the treatment of obesity. It is FDA-approved for a short term treatment (few weeks) in a regimen associated with exercise, behavioral modification, and caloric restriction for patients with BMI ≥ 30 kg/m, or ≥ 27 kg/m2 in the presence of additional risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).
Phentermine acts by suppressing appetite and causing early satiety. It is very often prescribed as monotherapy. The most extended study done with this medication was a 36-week trial dated back in 1968 that evaluated continuous and intermittent administration of phentermine, which led to more weight loss than placebo (-12.2 and -13.0 kg for continuous and intermittent use versus -4.8 kg in the placebo group).[36]
In the same group of sympathomimetic drugs, sibutramine was withdrawn from the US and European markets in 2010 after the study SCOUT showed a 16% increase in the incidence of cardiovascular events (a composite sum of nonfatal heart attack, nonfatal stroke, resuscitation after cardiac arrest and cardiovascular death) in patients receiving treatment with the drug versus the placebo group (more details on section "issues of concern").
3.2) Naltrexone-bupropion: Although there are no head-to-head studies available comparing this combination therapy with phentermine-topiramate, based on the results of published trials done with this combination, it is evident that it is less efficacious than the previously mentioned combination. Therefore it is not recommended as first-line pharmacologic therapy for obesity management.
A naltrexone-bupropion combination is a good option; however, for smokers who desire to pursue a combined therapy to quit smoking and mitigate the weight gain, usually following that. The exact mechanism of weight loss associated with this combination is not fully understood; however, they theoretically work synergistically in the hypothalamus and the mesolimbic dopamine circuit suppressing hunger centers.
Bupropion is a weak dopamine and norepinephrine reuptake inhibitor, which stimulates pro-opiomelanocortin (POMC) production and release of alpha-MSH and beta-endorphin that is an endogenous opioid, in vitro. The alpha-MSH activates the melanocortin-4 receptor (MC4R), which acts on reducing food intake, increasing energy expenditure, and causing weight loss. However, after continuous bupropion intake, as a down-regulatory mechanism, beta-endorphin reduces the activity of POMC cells by binding to the inhibitory mu-opioid receptor. Naltrexone that is an opioid antagonist works by blocking the mu-opioid receptor and disrupting the beta-endorphin inhibitory feedback on the POMC cells.[37][38]
The combination drug received FDA approval in September 2014 as a weight loss medication in addition to diet and exercise in those patients with BMI ≥30 kg/m or ≥27 kg/m in the presence of at least one weight-related comorbidity.
In a multicenter randomized trial, the combination caused a -6.1% reduction in body weight versus -1.3% in the placebo group. Only 50 percent of participants completed the 56 weeks of treatment.
Although mean weight loss was greater with combination therapy than with placebo, mean reductions in blood pressure and heart rate were significantly elevated in the placebo group (-2.1/2.8 versus 0.2/-0.4 mmHg and -0.1 versus 1.5 beats per minute).
The most common side effects of the naltrexone-bupropion combination are nausea, headache, and constipation.
FDA warns to monitor patients for suicidal behavior and ideation, risk of seizure due to bupropion lowering the seizure threshold, increase in blood pressure and heart rate, hepatotoxicity observed with naltrexone exposure, and angle-closure glaucoma.
Clinicians should avoid using the drug in patients with high cardiovascular risk due to the observed increase in heart rate and blood pressure; however, a cardiovascular safety trial was interrupted in the initial phase due to a breach in confidentiality, but preliminary data had shown a reduction in cardiovascular events, although controversial due to lack of completion of the study. The medication received approval with a warning for an increase in blood pressure and heart rate, but the cardiovascular risk was inconclusive.[39]
Dosing and contraindications: The initial dose is one tablet daily of 8 mg of naltrexone/90 mg of bupropion. The dose should increase, if tolerated, to one tablet twice daily after the first week, and to two tablets twice daily in the fourth week.
It is contraindicated during pregnancy as well as in patients with uncontrolled hypertension, seizure disorder, eating disorder, use of other bupropion-containing products, chronic opioid use, and use of monoamine oxidase inhibitors in the previous 14 days.
Pharmacologic Therapy for Obesity