Gastroesophageal reflux disease (GERD) is a prevalent condition, often managed with long-term proton pump inhibitor (PPI) therapy. While PPIs are effective in controlling GERD symptoms, emerging research suggests a potential association between their long-term use and changes in body weight. This article delves into the evidence surrounding this relationship, exploring the potential mechanisms and implications for patient care.
GERD and the Role of PPIs
Gastroesophageal reflux disease (GERD) stands out as the most frequently diagnosed disorder of the esophagus, a condition regularly encountered within primary healthcare settings. The risk of experiencing reflux symptoms, the development of erosive esophagitis, or the onset of esophageal adenocarcinoma is known to increase in correlation with excessive weight and obesity. Accumulating evidence has confirmed the excellent efficacy and safety of proton pump inhibitor (PPI) therapy in patients with all grades of GERD, making these agents the mainstay of treatment. Consequently, PPIs comprise the largest outpatient pharmacy expenditure in the United States.
GERD is a chronic condition, necessitating continuous therapy for many patients to control symptoms and prevent complications. Long-term therapeutic options include PPI therapy and surgical or endoscopic procedures. The efficacy and safety of long-term PPI therapy have been extensively documented.
Long-Term PPI Use and Weight Gain: Evidence from a Clinical Study
One study evaluated 52 adult patients with GERD and 58 healthy controls. The study aimed to determine the possible impact of changes in body weight or body mass index (BMI) in reflux patients while on long-term PPI therapy. Patients undergoing daily maintenance therapy of PPI for at least 10 months were selected. Patients who had prior fundoplication or poor compliance with medication were excluded. The controls were sex- and age-matched subjects who visited the clinic for a yearly medical examination; they were free of reflux symptoms, and did not take PPIs or histamine receptor antagonists. They also did not receive advice on lifestyle modifications.
The diagnosis of GERD was made based only on the typical symptoms of troublesome heartburn and/or acid regurgitation. Initial therapy was a standard dose of PPI (omeprazole 20 mg, rabeprazole 20 mg, or lansoprazole 30 mg) once daily for 8 weeks followed by a daily maintenance half-dose therapy. The patients were followed-up at 4-week intervals in the clinics to assess symptom recurrence. Patients found to have recurring symptoms of heartburn or acid regurgitation were placed back on their initial PPI dose.
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The patients were educated on lifestyle modifications by their physicians in addition to the PPI treatment. Body weight, height, and blood pressure, as well as fasting serum levels of total protein, total cholesterol, and triglycerides were determined at baseline and at the last visit. The BMI was calculated as body weight (kg)/[height (m)]2.
The study revealed a significant association between long-term PPI treatment and weight gain in GERD patients. Patients with GERD showed increases in body weight (baseline: 56.4 ± 10.4 kg, end: 58.6 ± 10.8 kg, mean ± SD, P < 0.0001) and BMI (baseline: 23.1 ± 3.1 kg/m2, end: 24.0 ± 3.1 kg/m2, P < 0.001), but no such changes were noted in the control group. Twenty-four GERD patients were treated daily with 10 mg omeprazole, 12 with 20 mg omeprazole, 8 with 10 mg rabeprazole, 5 with 15 mg lansoprazole, and 3 patients with 30 mg lansoprazole. At baseline, there were no differences in BW and BMI between reflux patients and controls.
Categorical changes in body weight at the last visit compared to the baseline values showed that most of the control group (91%) remained stable, defined by a change of no more than 5% compared to baseline weight; however, only 60% of the PPI group remained stable. In addition, compared with 4% of the control group, 36% of patients had a more than 5% increase above the baseline in body weight (P < 0.0001).
Potential Mechanisms Linking PPIs and Weight Gain
The precise mechanisms underlying the observed weight gain in PPI users remain unclear, but several hypotheses have been proposed:
Impact on Gastric Emptying
Omeprazole and other PPIs delay gastric emptying, which induces postprandial fullness, dyspeptic symptoms, gastrointestinal bacterial overgrowth, and subsequent weight loss. Delayed gastric emptying can lead to postprandial fullness and dyspeptic symptoms.
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Appetite-Regulating Hormones
Numerous circulating peptides influence appetite. Ghrelin is produced in the stomach and acts as a meal initiator. A recent report revealed that long-term PPI therapy did not change the serum ghrelin level. Another peptide, leptin, is produced in the stomach and acts as an enteric signal involved in energy homeostasis. While some studies suggest PPIs may influence levels of appetite-regulating hormones like ghrelin and leptin, further research is needed to confirm these findings.
The Broader Context: Obesity and GERD
There is a growing body of literature regarding the association between BMI and GERD. A recent large meta-analysis of previous studies demonstrated a strong positive relationship between BMI and reflux symptoms. In addition, moderate weight gains, even among normal-weight persons, resulted in the development or exacerbation of symptoms in GERD patients.
It's crucial to acknowledge the established link between obesity and GERD. Excessive weight is associated with an increased risk of coronary heart disease, hypertension, angina, stroke, and diabetes, and constitutes an important cardiovascular health burden. Several studies have demonstrated a strong positive relationship between BMI and reflux symptoms. This bidirectional relationship underscores the importance of weight management in GERD patients.
Lifestyle Modifications: A Cornerstone of GERD Management
A practice guideline for patients with GERD recommends the use of lifestyle modifications such as elevation of the bed head, a decreased intake of fat, chocolate, alcohol, peppermint, coffee, onions and garlic, cessation of smoking, and avoiding recumbency for three hours postprandially, in addition to taking antireflux medications. However, the positive advantage of such lifestyle modifications on the patient’s condition is not well substantiated. Among these lifestyle interventions, elevation of the bed head, left lateral decubitus positioning, and weight loss are associated with improvement in reflux symptoms in case-control studies. These modifications alone, however, are unlikely to control symptoms in the majority of patients.
Given the potential for weight gain with long-term PPI use, coupled with the established link between obesity and GERD, lifestyle modifications remain a critical component of GERD management. Reflux patients treated with a daily maintenance therapy of PPI should be strongly encouraged to manage their body weight through lifestyle modifications such as proper diet and avoidance of overeating. This measure may reduce the overall medical costs associated with obesity-related illness as well as GERD.
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Emerging Therapeutic Avenues: Mitochondrial Protonophores
Emerging research explores novel therapeutic approaches targeting weight management and related metabolic disorders. Mitochondrial protonophores, which promote weight loss by increasing energy expenditure, have garnered attention.
OrsoBio is advancing a portfolio of protonophores for obesity, led by the liver-targeted oral agent TLC-6740. At ObesityWeek®, the Company will present Phase 1 data confirming the safety and PK of TLC-6740 when administered with acid suppressants, food, or in individuals with genetic variants that reduce the function of transporters that mediate its hepatic uptake. TLC-1180 is a novel, oral, second-generation protonophore with greater potency and systemic distribution than TLC-6740. In prior studies, TLC-1180 increased energy expenditure, reduced body weight, and improved glucose control in DIO mice.
These compounds, like TLC-6740 and TLC-1180, increase energy expenditure and promote fat-selective weight loss. Preclinical studies have shown promising results, with TLC-1180 demonstrating comparable or superior reductions in body weight and fat mass compared to semaglutide, and additive benefits when used in combination.
Implications for Clinical Practice
The evidence suggesting a link between long-term PPI use and weight gain has important implications for clinical practice:
Vigilant Monitoring
Clinicians should be aware of the potential for weight gain in patients on long-term PPI therapy and monitor their weight and BMI regularly.
Emphasize Lifestyle Modifications
Reinforce the importance of lifestyle modifications, including diet and exercise, for all GERD patients, particularly those on long-term PPIs.
Individualized Treatment Plans
Consider individual patient risk factors and tailor treatment plans accordingly. For patients at higher risk of weight gain or obesity-related complications, explore alternative GERD management strategies or closer monitoring.
Further Research
More research is needed to fully elucidate the mechanisms underlying PPI-associated weight gain and to identify strategies for mitigating this effect.