Regular metformin use slows knee osteoarthritis progression in patients with diabetes
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Patients with type 2 diabetes who report regular metformin use demonstrate a potential slowing of knee osteoarthritis progression, according to data published in Scientific Reports.
“In addition to its glucose-lowering effects in type 2 diabetes mellitus (DM), metformin also modulates inflammatory and metabolic factors, resulting in reduced inflammation and plasma lipids levels,” Francisco T. T. Lai, BSc, MPhil, PhD, of the University of Hong Kong, and co-authors wrote. “Metformin, a well-known adenosine monophosphate-activated kinase (AMPK) activator, can suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNA and protein expression in a dose-dependent pathway.
“Its mechanism on the reduction of pain intensity in many inflammatory disorders is explained by its inhibitory effects on the level of pro-inflammatory mediators, thus reducing the level of inflammatory cytokines including TNF-, IL-1, IL-6, IL-10 and adipokines,” they added. “The suppressed level of COX-2 and iNOS also reduces the levels of NO and PGE2 in cell culture media. The above anti-inflammatory and anti-oxidative effect of metformin on synovial joint tissue may reduce pain based on the metabolic regulation of inflammation in OA.”
To investigate the potential impact of metformin on the progression of knee OA in patients with type 2 diabetes, Lai and colleagues conducted a retrospective cohort study. The researchers extracted data from the Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority in Hong Kong, which collects information from all clinical consultations as part of routine practice.
The authors received access to routine records from all patients in the public sector aged 45 years or older. Researchers then created a closed cohort consisting of all patients with type 2 diabetes who visited any Hospital Authority-run clinic between Jan. 1, 2007, and Dec. 31, 2010. After enrollment, patients were followed until being admitted to a hospital for a total knee replacement (TKR), in-hospital death, or 4 years had passed from baseline.
Patients were defined as regular metformin users if they filled four or more prescriptions in the year leading up to enrollment. The primary outcome was the incidence of the first TKR undergone in a public hospital between Jan. 1, 2011, and Dec. 31, 2014. TKR revisions were not counted as an endpoint.
The analysis consisted of a matched cohort made up of 93,330 patients, of whom half (46,665) were regular metformin users. Among the regular metformin users, 184 patients were admitted for a TKR within 4 years. In the group that did not use metformin, 222 underwent TKRs within 4 years, according to the researchers. In the Cox regression, the HR for TKR among regular metformin users, compared with non-users, was 0.81 (95% CI, 0.67-0.98).
“Despite the low incidence of TKR and a relatively short 4 years follow-up period, we found a statistically significant 19% reduction in the rate of TKR in a diabetic population who are regular metformin users compared to non-users, with an apparent dose-response relationship,” Lai and colleagues wrote. “Future research should include longitudinal studies of longer follow-up period, more specific selection of patients with preexisting diagnoses of knee OA and its severity, and include dosage information of metformin.”
References:
Osteoarthritis: structural endpoints for the development of drugs, devices, and biological products for treatment guidance for industry. https://www.fda.gov/downloads/Drugs/GuidanceCmplianceRegulatoryInformation/Guidances/ucm071577.pdf. 2018. Accessed July 26, 2022.
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Metformin has been prescribed for more than 50 years and has shown effects not only in lowering blood glucose levels but also in moderating inflammatory and metabolic factors, leading to a decrease in inflammation and lipids. Its anti-oxidative and anti-inflammatory effects may impact inflammation in osteoarthritis and thereby help reduce pain. It has also been shown to aid in weight loss, which is beneficial for the type 2 diabetes population.
However, given its aid in weight loss and reducing pain it is no surprise that it may also help with reducing the incidence of knee replacements in patients with knee OA. Although more studies are needed to make this a recommendation, there is no doubt that it is a medication seen often in our rheumatologic patients and adherence is even more important.
According to the American College of Rheumatology, 790,000 total knee replacement surgeries are performed annually and can commonly be expected to last up to 20 years or more. Weight loss is mentioned on the ACR website as a way to slow the progression of OA, thereby decreasing the need for knee replacement surgery. If we have patients on metformin, this study shows all the more reasons why we should be speaking to our patients about adherence.
Approximately 1 out of 3 patients stop metformin within 3 months. Adherence is an issue for our patients, and we can help by setting expectations. It is cheap and the most common side effects — diarrhea and nausea — are of short duration. Here is where your nurses can play a big role — they spend more time speaking with the patients both during clinic visits and on the telephone answering questions. Equip your nurses with the information needed to help our patients stay on therapy — including metformin — because it is working in more ways than one to benefit our patients.
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David A. McLain, MD, MACR, FACP, FRCP
Metformin was discovered in 1922 and was investigated in France in the 1950s. It is considered the first-line treatment for type 2 diabetes mellitus throughout the world. It is on the WHO’s List of Essential Medicines. It was the fourth most prescribed medication in the United States, with more than 85 million prescriptions written for more than 17 million patients in 2019. An adenosine monophosphate-activated kinase (AMPK) activator, metformin can suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNA and protein expression in a dose-dependent pathway.
Its inhibitory effects on the level of pro-inflammatory mediators reduce the level of inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-10 and adipokines. These anti-inflammatory and anti-oxidative actions may explain its effects reported in this big data — each cohort was more than 46,000 patients — retrospective study. Osteoarthritis and type 2 diabetes share some pathogenic risk factors in common. Both are related to aging, obesity, and cytokine- and adipokine-mediated inflammation.
Metformin has been shown to facilitate weight loss, and that, coupled with its anti-inflammatory properties, could lead to slowing of the progression of knee OA. The results of this study are compatible with a smaller study that showed a 26% lower risk for total knee replacement in the group receiving metformin and COX-2 NSAIDs vs. the group receiving COX-2 NSAIDs alone over 10 years. Metformin is a fascinating drug and studies are underway with regard to prevention of cancer and Alzheimer’s, treatment of heart failure and rheumatologic conditions, and for improvement of longevity with its anti-aging properties. Stay tuned.
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