The ongoing pandemic of obesity is a chronic disease associated with a high risk of complications, including diabetes mellitus, heart disease, hypertension, dyslipidemia, osteoarthritis, sleep disorders, and multiple types of cancer. In Mexico, the prevalence of obesity in adults was 31% in 2012 and 33.6% in 2018, when defined as having a body mass index (BMI) of 30 kg/m2 or higher. It is projected that by 2050, 54% of men and 37% of women will be obese in Mexico, and obesity-related diseases, such as diabetes, hypertension, stroke, and knee osteoarthritis, among others, will have increased 2-fold.
While lifestyle interventions including diet and physical activity are the cornerstones of anti-obesity therapy, these strategies usually endure poor adherence and a low success rate. Hence, pharmacotherapy is recommended as an adjuvant for patients with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 if coexistent with obesity-related diseases such as hypertension or type 2 diabetes mellitus. A weight loss of at least 5 - 10% can significantly improve health-related outcomes in obese patients. Currently, a 5 - 10% weight loss over a 6-month period is considered a realistic goal with proven health benefit.
This article explores the individual roles of metformin and phentermine in weight management, and then considers their potential when used in combination, while also addressing safety considerations.
Understanding Metformin
Metformin is a medication primarily used to treat type 2 diabetes. Metformin improves how the body responds to insulin. It works by decreasing glucose production in the liver and improving insulin sensitivity in the body's tissues. Though not specifically designed as a weight-loss drug, some individuals experience weight loss as a side effect of metformin use.
Common side effects of metformin include taste disturbances, diarrhea, and other stomach-related issues.
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Important Safety Information Regarding Metformin:
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.
The risk of metformin-associated lactic acidosis increases with the patient's age because patients 65 years and older have a greater likelihood of having hepatic, renal, or cardiac impairment. Renal function should be assessed more frequently in older adult patients. Several postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure, especially when accompanied by hypoperfusion and hypoxemia; cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia (e.g., severe anemia, asphyxia) have been associated with lactic acidosis and may cause prerenal azotemia.
When such an event occurs, metformin should be discontinued. Dehydration (e.g., severe diarrhea or vomiting) may increase the risk for volume depletion, hypotension, and renal impairment; such patients may be at increased risk for lactic acidosis. Alcohol potentiates the effect of metformin on lactate metabolism; patients should be advised against excessive alcohol intake while receiving metformin. All patients treated with metformin should have renal function monitored regularly (at least annually or more frequently if necessary). If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, as well as immediate discontinuation of metformin. If lactic acidosis is diagnosed or strongly suspected, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.
Understanding Phentermine
Phentermine is an appetite suppressant that may be used short-term as an aid to weight loss. It is a sympathomimetic amine that acts by inhibiting appetite. Phentermine was first approved to aid weight loss in 1959, and it has since become one of the most commonly used weight-loss medications in Mexico and the United States. The current use of 15 mg or 30 mg phentermine for the treatment of obesity is recommended in the short-term (12 weeks), alongside exercise, lifestyle modifications, and caloric restriction.
Phentermine dose for adults is 15 mg or 30 mg once daily at physician’s discretion. Phentermine should be withdrawn if patient does not respond by 3 months.
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Efficacy and Safety of Phentermine: A Study in Mexican Patients
One study aimed to evaluate the long-term efficacy and safety of phentermine in the treatment of obesity in Mexican patients and to shed light on remaining questions of the optimal use of the drug. Efficacy and safety of oral administration of 15 mg or 30 mg of phentermine were assessed in a prospective, multi-center, uncontrolled phase IV, open-label study, which included 932 Mexican participants with ages > 18 years and a BMI ≥ 30 kg/m2.
Participants were recruited from 36 clinics located in 12 states of the Mexican Republic between August 2015 and December 2018. Patients were instructed to follow a diet of 1,500 kcal/day and to carry out physical activity for 20 minutes daily. Patients were allocated to receive 15 mg of phentermine or 30 mg of phentermine. Capsules of the drug (terfamex) containing the corresponding dose were prescribed to be taken orally, once every morning before breakfast, for 6 months.
The primary endpoint was the proportion of patients who experienced at least 5% weight loss with respect to baseline, since this is considered a relevant and achievable goal for patients under treatment with phentermine. Secondary endpoints were weight loss ≥ 10%, changes in BMI, body weight, waist circumference, hip circumference, body fat, visceral fat, systolic blood pressure (SBP), diastolic blood pressure (DBP), and plasma glucose with respect to their baseline values, and safety profile.
Key Findings:
- 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not after 6 months of treatment.
- An important number of subjects could benefit following the therapy from 3 to 6 months.
- 42% of 3-month non-responders had a reduction in body weight of at least 5% at 6 months.
- 77% of obese patients could benefit from extending phentermine treatment for 3 additional months.
- 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not at 6 months of treatment.
- Treatment with phentermine led to reductions in weight, which were proportional to the dose and duration of treatment.
- Of note, 30 mg phentermine was statistically superior to 15 mg phentermine in improving most of the anthropometric variables at 3-month follow-up, but not after completing the 6-month treatment.
- 15 mg and 30 mg phentermine also improved the rest of the cardiometabolic variables assessed, including body fat, visceral fat, SBP, DBP, and glucose. These parameters were similar in both groups, except for glucose, for which higher reductions were observed with inverse proportionality to the dose and time on drug administration. Phentermine did not increase heart rate or blood pressure with either of the two treatments.
Adverse Events:
A higher number of adverse events were reported in the 30-mg phentermine group, compared to the 15-mg phentermine group. The 10 most frequent adverse events were dry mouth, stress, increased appetite, pain in extremity, stretch marks, anxiety, constipation, back pain, polydipsia, and dizziness. Furthermore, dry mouth, stress, increased appetite, anxiety, acanthosis nigricans, polydipsia, and abdominal pain occurred significantly more frequently in patients treated with 30 mg phentermine, compared to 15 mg phentermine.
Important Considerations Regarding Phentermine:
Phentermine can be addictive and tolerance may develop to its weight-losing effects, rendering it less effective with time. CNS stimulants (especially amphetamines) have a high potential for abuse and misuse, which can lead to development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants can result in overdose and death; this risk is increased with higher doses or unapproved methods of administration (e.g., snorting, injection). Before prescribing a CNS stimulant, each patient's risk for abuse, misuse, and addiction should be assessed. Throughout therapy, it is recommended to reassess each patient's risk and frequently monitor for signs/symptoms of abuse, misuse, and addiction. Therapy with CNS stimulants should be administered cautiously, if at all, in patients with a history of alcohol or substance abuse.
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Some CNS stimulants are contraindicated in patients with marked agitation and/or anxiety since these symptoms may be aggravated. CNS stimulants may also exacerbate symptoms of behavior disturbance and thought disorder in psychotic patients, particularly children. Many amphetamines and amphetamine-like drugs are contraindicated in patients with advanced arteriosclerosis, symptomatic or unstable cardiac or cerebrovascular disease, moderate to severe hypertension, or hyperthyroidism. Like other sympathomimetic amines, amphetamines may cause cardiovascular adverse effects such as palpitation, tachycardia, cardiac arrhythmias, and elevation of blood pressure. Rarely, cardiomyopathy manifested as ventricular hypertrophy and/or congestive heart failure has been reported during chronic amphetamine use. In addition, sudden death has been reported in association with amphetamine therapy at usual dosages in children with structural cardiac abnormalities. In general, amphetamines should not be used in patients with structural cardiac abnormalities.
Potential Interactions and Considerations
When considering the combined use of metformin and phentermine for weight loss, it's crucial to be aware of potential interactions and specific considerations:
- Blood Sugar Monitoring: As you lose weight during treatment with phentermine, your dosage requirement of metFORMIN or any other diabetic medications you are receiving may change. You may need more frequent monitoring of your blood sugar and adjustment of your diabetic regimen both during and after treatment with phentermine. Let your doctor know if you experience hypoglycemia, or low blood sugar.
- Alcohol Consumption: MetFORMIN should be taken with meals, and excessive alcohol intake (either short-term binge drinking or frequent consumption) should be avoided during treatment. Taking metFORMIN with alcohol may increase the risk of lactic acidosis. Using phentermine with alcohol can increase the risk of cardiovascular side effects such as increased heart rate, chest pain, or blood pressure changes. In addition, you may also be more likely to experience nervous system side effects such as dizziness, drowsiness, depression, and difficulty concentrating. You should avoid or limit the use of alcohol while being treated with phentermine.
- Other Medications: It is important to tell your doctor about all other medications you use, including vitamins and herbs.