Obesity is a chronic disease with significant health consequences, including increased risk of type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, and certain cancers. While lifestyle interventions are crucial, pharmacotherapy plays an important role in obesity management. Several medications are available, each with its mechanisms of action, efficacy, and side effect profiles. This article compares two such medications, Contrave and Metformin, providing an overview to aid in informed decision-making, always in consultation with a healthcare professional.
Obesity: A Growing Concern
The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has increased dramatically over the last four decades, reaching almost one third of the populations of developed countries of North America and Europe, and with overweight levels (BMI ≥ 25 kg/m2) of more than 40% of the population in Brazil. Studies have shown that even small weight losses of 5-10% of body weight, independently of how they were achieved, are associated with an improvement of the cardiovascular risk profile and a lower incidence of T2DM. In recent years, obesity has been considered a metabolic and neuroendocrine disease, which results from the interface between an obesogenic environment and an intrinsic genetic predisposition.
How Contrave and Metformin Work Differently
Contrave and Metformin employ distinct mechanisms to aid in weight loss. Contrave, a combination of naltrexone and bupropion, primarily works by reducing appetite and cravings. Bupropion is a reuptake inhibitor of dopamine and norepinephrine currently approved for the treatment of depression and as a supporting aid for smoking cessation, with effective yet modest results in weight loss. Naltrexone is an opioid receptor antagonist, initially approved as a treatment for opiate addiction, and later, for alcohol dependence. Despite these drugs having a modest efficacy when used in isolation, current understanding of the complex processes of central and peripheral appetite regulation enabled the hypothesis of a possible synergistic effect of their combination. The increase of dopamine and norepinephrine levels mediated by bupropion stimulates the neural activity of proopiomelanocortin (POMC). POMC neurons, which located in the arcuate nucleus of the hypothalamus, when stimulated leads to the formation of other peptides. POMC is cleaved into α-MSH and β-endorphin. Beta-endorphin exerts negative feedback inhibition on POMC activity and increases food intake. Naltrexone, by inihibiting opioid receptors, releases POMC neurons from the feedback inhibition exerted by beta-endorphin. Additionally, some studies on rats have demonstrated that the ingestion of palatable foods (e.g., candies) leads to increased β-endorphin levels in the hypothalamus. With this data, it is assumed that the release of opioids has a role in the expression of food palatability, and vice-versa. Some anecdotal reports in humans in the 1980s suggest that naltrexone, although not directly affecting hunger, decreases the feelings of pleasure associated with the act of eating, which culminates with reduced ingestion of food. It acts on the brain's reward system to lessen the urge to overeat.
Metformin, on the other hand, improves insulin sensitivity. This medication is an insulin-sensitizing drug known to modestly reduce weight in insulin resistant patients. By enhancing how your body uses insulin, Metformin can lead to weight loss, especially beneficial for individuals with insulin resistance or type 2 diabetes. This difference in their approach makes a crucial difference in how each might help you.
Weight Loss Effectiveness: What to Expect
Clinical trials suggest Contrave may lead to greater short-term weight loss (potentially 5-10% of body weight) compared to Metformin (possibly 3-5%). However, individual responses vary significantly. Neither medication guarantees weight loss, and a healthy diet and regular exercise remain essential components of any weight-loss strategy. Does this mean one is definitively superior? Not necessarily. Individual needs and response often determine the more effective option.
Read also: Comparing Contrave and Phentermine
A double-blind phase 2 randomized study with a 24-week duration, with 419 patients, compared three different doses of immediate release (IR) naltrexone (16, 32 and 48 mg/d), in combination with bupropion sustained release (SR), 400 mg/d, with placebo, bupropion SR, 400 mg/d, and naltrexone IR, 48 mg/d, in monotherapy. Patients receiving bupropion alone or the three doses of the combination were followed for an additional 24 week-extension. In 24 weeks the weight loss by intent-to-treat analysis (ITT) was 5.4%, 5.4% and 4.3% for the combination of bupropion with naltrexone, 16 mg (NB16), 32 mg (NB32) and 48 mg (NB48) respectively, against 2.7% for bupropion, 1.2% for naltrexone and 0.8% for placebo. The lower weight loss seen in the patients receiving NB48 was justified by the higher dropout rate (63%) due to side effects in this group. After 24 weeks, there was no sign of a plateau in any of the three combination groups, and in the final analysis of 48 weeks, the NB32 combination reached a higher success rate with an average weight loss of 6.6%. Based on these results, phase 3 studies were designed accordingly, using naltrexone SR in doses of 16 and 32 mg/d and bupropion SR, 360 mg/d, on a twice-daily basis (bid).
The COR-I trial randomized 1.742 patients for NB16, NB32 or placebo, with four weeks of titration of medication and a duration of 56 weeks. The placebo-subtracted weight loss (PSWL) by ITT analysis was 3.7 and 4.8% for NB16 and NB32, respectively. The COR-II trial tested NB32 in 1,001 patients, against 495 that received placebo. The results were similar to those of COR-I, with PSWL by ITT analysis of 5.2%. The proportion of patients with ≥ 5% reduction of initial weight compared to placebo was also similar in COR-I (48 vs. 16%) and in COR II (56 vs.
Side Effects: Understanding the Potential Risks
Both medications come with potential side effects. Contrave may cause nausea, dizziness, constipation, and increased heart rate. Metformin more commonly leads to gastrointestinal issues like diarrhea and upset stomach. A rare but serious risk associated with Metformin is lactic acidosis. Your doctor will thoroughly discuss these risks with you and assess your suitability for either treatment. Are these side effects manageable for you? This is a vital question to discuss with your doctor.
Dropout rates were high for both studies (46 and 51%, no difference compared to placebo), with around half of the cases being directly related to side effects. The most commonly observed side effect was nausea, around 30%, compared to 5 and 6% in the placebo group. The incidence occurred mainly in the initial weeks of treatment, still within the titration phase, with a tendency to fall after the fourth week. Other side effects significantly more common than placebo, in order of frequency were: Constipation, headache, dizziness, vomiting and dry mouth. There was no significantly higher incidence of adverse effects on the cardiovascular system, nor in relation to depressive disorders or suicidal ideation. BP of patients using the combination remained unchanged after 56 weeks, with a slight decrease of 2 mmHg in the placebo group, and a negligible increase of one beat per minute in the heart rate of the treated patients. Three serious events were reported, possibly related to the use of one component of the combination: seizure (one), paresthesias (one) and palpitations with dyspnea and anxiety (one).
Who is Each Medication For?
Contrave might be a better fit for individuals struggling with intense food cravings or emotional eating. Its appetite-suppressing effects can be particularly beneficial in these cases. However, for those with prediabetes or type 2 diabetes, Metformin's impact on insulin sensitivity often makes it a more suitable and sometimes medically necessary choice. It can simultaneously address weight management and blood sugar control. Only one study evaluated orlistat in combination with metformin, an insulin-sensitizing drug known to modestly reduce weight in insulin resistant patients. Fifty seven obese women without glucose intolerance were randomly assigned to receive orlistat, 360 mg/d, or orlistat, 360 mg/d, plus metformin, 1,700 mg/d. No differences were observed with respect to weight loss or insulin resistance indexes. At present, metformin for weight loss should only be used in patients with carbohydrate metabolism disturbances.
Read also: Weight Loss with Contrave and Topiramate
Contraindications
Bupropion is contraindicated in patients with a seizure disorder. Bupropion can cause seizure; the risk is dose-related. Bupropion is also contraindicated in patients with current/prior diagnosis of bulimia or anorexia nervosa (a higher incidence of seizures was observed in such patients treated with immediate-release bupropion) and in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Bupropion should be administered with caution in patients with conditions that increase the risk of seizure or who have other predisposing conditions including severe head injury; arteriovenous malformation; CNS infection or CNS tumor; severe stroke; metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, hypoxia); excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates; use of illicit drugs (e.g., cocaine); abuse/misuse of prescription drugs (e.g., CNS stimulants); diabetes mellitus treated with oral hypoglycemic agents or insulin; use of anorectic agents; and concomitant use of medications that lower the seizure threshold.
Metformin is contraindicated in patients with acute or chronic metabolic acidosis (including diabetic ketoacidosis) with or without coma. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Risk factors include renal dysfunction, age 65 years and older, hypoxic states, excessive alcohol intake, and liver dysfunction. Lactic acidosis has been associated with metformin accumulation in plasma at levels generally exceeding 5 mcg/mL.
Making an Informed Decision: The Importance of Consultation
Selecting the appropriate weight-loss medication is a collaborative process. A thorough discussion with your doctor is crucial. They will consider your medical history, current health conditions, and weight-loss goals to recommend the safest and most effective option tailored to your individual needs. Remember, a personalized approach is key for successful weight management.
Lifestyle Changes: The Foundation for Long-Term Success
Regardless of the medication chosen (or even if medication isn't chosen), lifestyle modifications are essential for enduring weight management. A balanced diet and regular exercise form the cornerstone of any successful weight-loss strategy. Medication can be a helpful tool, but it shouldn't replace these critical lifestyle habits. What's your commitment to a long-term healthy lifestyle?
Contrave vs Metformin: Long-Term Perspectives and Considerations
While Contrave demonstrates potentially greater short-term weight loss in some studies, long-term data comparing Contrave and Metformin remains limited. Metformin, with its extensive history in diabetes management, offers a broader base of long-term safety information. The choice between these medications necessitates careful consideration of your individual health, risk tolerance, and long-term goals. The rise of glucagon-like peptide 1 (GLP-1) receptor agonists for weight loss has encouraged many patients of Sriram Machineni, MBBS, to try medication for obesity. While the older drugs may not cause weight loss as quickly or dramatically as GLP-1s, they can still be effective in reducing excess body weight.
Read also: Comparing Contrave and Ozempic
Non‑GLP-1 medications include different combinations of phentermine, bupropion-naltrexone, topiramate, and metformin. Phentermine can be prescribed on its own or with topiramate. Bupropion and naltrexone can also be prescribed off-label as two separate scripts or as the single medication Contrave. Metformin is also prescribed off-label.
Other Anti-Obesity Drug Combinations
Considering that obesity is a multifactorial disease, with environmental factors linked to genetic factors, it is expected that drug monotherapy may result in unsatisfactory outcomes. Although little data exists for the use of combinations, in a questionnaire answered by obesity specialists in the US, 85% prescribed combinations of drugs, and 65% of them prescribed combinations not approved for obesity treatment. In this review, anti-obesity drug combinations in general will be discussed, covering those already studied, those still awaiting final results to be released and also those which are used empirically in clinical practice.
Some drug combinations have already been studied in the past and stopped being used. It is worth remembering that the suspension of the commercialization of these combinations was on account of side effects of one of their components and not due to any negative interaction between the drugs.
Phentermine and Fenfluramine
Phentermine is a catecholaminergic substance that increases the release of noradrenaline in the central nervous system (CNS), available for obesity treatment in the United States of America (USA) since 1959 (in doses of up to 37.5 mg/day). Fenfluramine raises the synaptic levels of serotonin in the CNS by stimulating the secretion and inhibiting the reuptake of serotonin. Dexfenfluramine is a highly selective D-isomer, which also leads to increased levels of serotonin and stimulates the hypothalamus. The combination of fenfluramine and phentermine resulted in a reduction of side effects and increased efficacy, even in lower doses, when compared to use of either medications by itself. This combination was widely used before fenfluramine was banned from the market in 1997 due to increased risk of valvulopathy and primary pulmonary hypertension.
Ephedrine, Caffeine and Acetylsalicylic Acid
Ephedrine is a nonspecific beta-adrenergic agonist which promotes weight loss through increasing thermogenesis. Cafeine and acetylsalicylic acid reduce the degradation of ephedrine, potentiating its action. The use of ephedrine combined with caffeine and/or acetylsalicylic acid is approved as a combination therapy for the treatment of weight loss in many countries. The combination of ephedrine and caffeine (20/200 mg) three times a day (tid) for 24 weeks proved to be more effective for weight loss than placebo or monotherapy with its components. Many studies however have raised concerns about the safety of ephedrine and its derivatives, and the commercialization of ephedra alkaloids was banned in the United States in 2004 due to adverse cardiovascular and cerebrovascular effects, although ephedrine is still commercialized for use under rigorous monitoring. Around 1.4% of specialist physicians in US still use ephedrine with caffeine for treatment of obesity.
Sibutramine and Orlistat
Orlistat is a synthetic hydrogenated derivative of lipstatin which partially inhibits the gastric lipase, pancreatic lipase and carboxyl ester lipase enzymes. These enzymes work hydrolyzing the dietary triglycerides into fatty acids and monoglycerides, which are subsequently absorbed by the mucosal cells of the gastrointestinal (GI) tract. Orlistat reduces the absorption of ingested fat by 30%, increasing its excretion in the feces. Since the mechanisms of action of these two medications are very distinct, their combined use was evaluated in some studies. In obese women who had already been using subutramine for one year, the combination of orlistat versus placebo for 16 weeks did not result in greater weight losses. Two studies were conducted at different centers in Turkey, with similar results. In a randomized open-label study of 12 weeks, treatment with diet alone (n = 19) was compared with diet combined with the use of sibutramine (n = 22), orlistat (n = 25) and sibutramine combined with orlistat (n = 20). The combination of sibutramine and orlistat proved more effective in the reduction of BMI in relation to monotherapy with orlistat (p < 0.001), but not significantly superior to sibutramine alone. Placebo-subtracted weight loss of the combined therapy was 6.5% (13.4% combination vs. 6.9% placebo). Another study involving 89 obese women, showed a mean weight loss of 5.5%, 10.2% and 10.6% with orlistat alone, sibutramine alone and combined therapy, respectively, once again with no statistical difference between the latter two groups. A large clinical series done by our group was developed to evaluate the efficacy of the combination of sibutramine and orlistat in 446 individuals for six months, with concomitant dietary counseling. Weight loss in three and six months was 9.9 and 13.4% for women and 8.7 and 12.3% for men. After six months, 88.7% of the patients that finished the study had lost more than 5% of baseline weight and 66% had lost more than 10%. The rate of discontinuation was 37%. Although an open-label study, we consider not only the number of patients enrolled to be expressive but also the proportion of patients with significant weight loss. In summary, studies of combinations that are safe and widely used in clinical practice worldwide are still very scarce. It is our belief that this combination appears to provide satisfactory results, although this was not confirmed in randomized controlled studies. In contrast with our opinion, some specialists in the obesity field believe that concomitant use of drugs acting on the gastrointestinal tract with centrally acting drugs does not result in additional weight compared to the latter by itself.
Bupropion and Zonisamide
Although in earlier stage of development, the combination of bupropion/zonisamide also seems promising as an anti-obesity drug. Zonisamide has been used as an antiepileptic drug in Japan since 1989, being approved for such use in the United States (USA) and in some European countries in the early 2000s. In some short-term studies of treatment of epileptic patients with zonisamide, weight loss was observed as a side effect. The mechanism of action for the antiepileptic activity of this medication is not totally clear, but it is believed that it is linked of sodium and calcium channels blockage. In vitro evidence has also shown that this drug leads t…