Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies

Abstract

Background. Asthma and diabetes are both diseases that affect a wide range of people worldwide. As a common treatment for diabetes, metformin has also been reported to be effective in improving asthma outcomes. We conducted a combined analysis to examine the efficacy of metformin in reducing asthma exacerbation in patients with concurrent asthma and diabetes. Methods. We searched the PubMed, Embase, and CENTRAL databases for articles published prior to April 2020 to find observational studies of individuals with concurrent asthma and diabetes that compared the risk of asthma exacerbation between metformin users and nonusers. Two researchers separately screened the studies, extracted data, and evaluated the risk of bias. The primary outcome was the adjusted risk of asthma exacerbation. The secondary outcomes were the adjusted risk of asthma-related hospitalization and emergency room visits. Review Manager was used for data analysis and plotting. I2 and χ2 tests were used to estimate heterogeneity. A random effects or fixed effects model was used depending on the heterogeneity. Odds ratios were calculated for dichotomous variables. Results. We included two studies with a total of 25252 patients. The pooled effect size showed that metformin was inversely associated with a risk of asthma exacerbation (OR = 0.65, 95% CI 0.28–1.48; χ2 = 5.42, P=0.02; I2 = 82%), asthma-related emergency department visits (OR = 0.81, 95% CI 0.74–0.89; χ2 = 0.36, P=0.55; I2 = 0%), and hospitalizations (OR = 0.43, 95% CI 0.14–1.29; χ2 = 4.01, P=0.05; I2 = 75%). Conclusion. This meta-analysis suggested that metformin decreased the risk of asthma-related emergency room visits for patients with concurrent asthma and diabetes. Metformin reduced the risk of asthma-related hospitalization and exacerbation but was not statistically significant. More randomized trials involving larger samples should be considered, and the mechanisms of these effects need to be fully elucidated.

Metformin and the Development of Asthma in Patients with Type 2 Diabetes

“…Persons who received metformin may have health-seeking behaviors, such as regular clinic visits, check-ups, and adherence to medications, and this healthy user effect may influence observed outcomes between metformin users and nonusers [23]. We matched the use of influenza vaccination, adult health examination, and the number of HbA1C tests per year to reduce the bias of the healthy user effect [24]. Additionally, this study showed that the longer cumulative duration of metformin use was associated with higher risk of asthma development.…”

“…Statin use was associated with lower asthma risk. Previous studies have shown that older adults, females, COPD, and rheumatoid arthritis showed a higher risk, and statin use had a lower risk of incident asthma [24,[27][28][29]. Reports suggest that asthma, cardiovascular disease, and chronic kidney disease are closely related, probably due to the contribution of chronic systemic inflammation [30].…”

“…Our previous study of metformin use in patients with COPD has disclosed that metformin was associated with a higher risk of hospitalization for COPD and invasive mechanical ventilation [34]. Physicians may choose to switch from metformin to other antidiabetic drugs in patients with advanced renal, liver, heart diseases, or frailty [24]. We excluded patients receiving dialysis or those with hepatic failure and matched patients with chronic kidney diseases, alcohol-related disorders, liver cirrhosis, and chronic obstructive pulmonary disease to decrease the bias of confounding by indication.…”

“…A prevalent user may be more tolerant or adherent to the medication under study than a new user and influence the investigated results. We used a new user design in this study to mitigate the bias of the healthy user effect [24]. Metformin can inhibit the complex I of the mitochondrial electron transport chain and reduce ATP production, leading to energy stress and diminished mitochondrial respiration in the skeletal muscle [35].…”

Association of dipeptidyl peptidase-4 inhibitor use and the risk of asthma development among type 2 diabetes patients

“…15 In addition, a meta-analysis indicated that metformin decreased the risk of asthmarelated emergency room visits for patients with concurrent asthma and diabetes but was not statistically significant for decreasing asthma-related hospitalization and exacerbation. 16 The benefits of second-line with treatment agents for type 2 DM, including sulfonylureas (SUs), sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase-4 inhibitors (DPP-4is), when treating asthma were limited and inconclusive, however. [17][18][19][20] DPP-4, also known as adenosine deaminase complexing protein 2 or cluster of differentiation 26 (CD 26), is encoded by the DPP-4 gene in humans.…”