Abstract
Aim
This study aimed to investigate the effects and safety of metformin in patients with concurrent diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD).
Methods
PubMed, Embase, Web of Science, the China National Knowledge, and Cochrane Database were searched to find studies that examined the effects and safety of metformin in patients with concurrent DM and COPD. We conducted a meta-analysis with a risk ratio (RR) and assessed the quality of included studies and pooled evidence.
Results
Eight studies were involved. Metformin was associated with lower risk of COPD-related hospitalizations (RR: 0.72, 95% CI: 0.53–0.98; I2= 89%) and all-cause mortality (RR: 0.60, 95% CI: 0.36–1.01, I2= 69%) in patients with concurrent DM and COPD, but did not increase the risk of hyperlactatemia (RR: 1.14, 95% CI: 0.92–1.41, I2 = 8%).
Conclusions
Metformin use is associated with lower risk of COPD-related hospitalizations and risk of all-cause mortality without increasing the risk of hyperlactatemia. Considerations should be given to conduct more high-quality randomized trials involving larger samples.
Introduction
Chronic obstructive pulmonary disease (COPD), a prevalent, preventable, and treatable disorder, is characterized by ongoing respiratory symptoms and incompletely reversible airfilow limitation (1). COPD may be linked to an increased risk of diabetes mellitus (DM) due to the sedentary lifestyle and adiposity of COPD patients, the inflammatory processes (2), and the treatment adverse effects associated with the use of high-dose corticosteroids (3). On the other hand, diabetes may aggravate the development and prognosis of COPD by affecting lung physiology, inflammation, and susceptibility to bacterial infection directly (4). The presence of diabetes among those with COPD is associated with worse outcomes including hospitalizations and mortality (5, 6). As a result, appropriate treatments are urgently needed for patients with concurrent DM and COPD.
Metformin, a typical oral biguanide, is still the first-line therapy for DM (7). Metformin can decrease plasma glucose levels significantly and is widely used due to its safety and low cost. Recently, more and more studies have indicated that metformin might exert positive effects on other diseases such as cancers (8), cardiovascular diseases (9), liver diseases (10), neurodegenerative diseases (11), and renal diseases (12, 13). In animal models, metformin could limit hyperglycemia-induced bacterial growth by reducing airway glucose permeability (14). Furthermore, metformin attenuates inflammatory responses by inhibiting the production of tumor necrosis factor-α, interleukin (IL)-6, and IL-1, as well as the inflammatory reaction of macrophages while increasing the synthesis of anti-inflammatory cytokines like IL-4 and IL-10 (15, 16). However, metformin has a potential risk of lactic acidosis (17). And hypoxia caused by COPD might aggravate lactic acidosis, which is fatal (18, 19). Although several published studies have reported the use of metformin on patients with concurrent DM and COPD, the results were inconsistent (20, 21, 22, 23, 24, 25). Herein, we conducted this meta-analysis and systematic review to assess the effects and safety of metformin in patients with concurrent DM and COPD.
Methods
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (26). The protocol for the meta‐analysis is registered with PROSPERO (CRD42021287378).
Search strategy
PubMed, Embase, Web of Science, the China National Knowledge, and Cochrane Database were searched from the date of their inception to October 2021. The following terms were used in the searches: (‘Chronic Obstructive Lung Disease’ OR ‘Chronic Obstructive Pulmonary Disease’ OR ‘COAD’ OR ‘COPD’ OR ‘Chronic Obstructive Airway Disease’ OR ‘Chronic Obstructive Pulmonary Disease’ OR ‘Airflow Obstruction, Chronic’ OR ‘Airflow Obstructions, Chronic’ OR ‘Chronic Airflow Obstructions’ OR ‘Chronic Airflow Obstruction’ OR ‘Pulmonary Disease, Chronic Obstructive’) AND (‘Dimethylbiguanidine’ OR ‘Dimethylguanylguanidine’ OR ‘Glucophage’ OR ‘Metformin Hydrochloride’ OR ‘Hydrochloride, Metformin’ OR ‘Metformin HCl’ OR ‘HCl, Metformin’ OR ‘Metformin’). We also scanned the references of included studies to avoid omissions in the search process.
Eligibility criteria and study selection
The inclusion criteria were as follows: (1) observational studies or randomized controlled trials (RCTs); (2) patients age ≥ 18 years; (3) examined the effects of metformin on patients with concurrent DM and COPD; (4) reported at least one clinical outcome among COPD-related hospitalizations, all-cause mortality, and hyperlactatemia. The exclusion criteria were as follows: (1) animal or in vitro research; (2) reviews, letters to the editor, or case reports with limited information; (3) duplicate articles.
Two investigators independently screened the titles, abstracts, and full texts of all articles obtained from the search strategy. The studies that met the inclusion criteria were eventually included. If there were any controversies among the reviewers, another author was consulted as the third investigator to achieve an agreement.
Data extracted
The data extraction table was predetermined for two researchers to independently extract data from each included study, including study characteristics (first author, year of publication, study design, sample size), participants’ characteristics (gender percentage, mean age), duration of follow-up, and clinical outcomes. Clinical outcomes including COPD-related hospitalizations, all-cause mortality, and hyperlactatemia were further investigated in our study. The ‘COPD-related hospitalizations’ included hospital admission for acute exacerbation of COPD or respiratory complications during the follow-up period among the participants. The ‘all-cause mortality’ was calculated as the total number of reported deaths among participants in all included researches. ‘Hyperlactatemia’ is defined as a serum lactate level of 2 mmol/L or greater (27).
Assessment of study quality and risk of bias
The Newcastle–Ottawa Scale (28) and Critical Appraisal Skills Programme (http://www.casp-uk.net/) were used to evaluate the quality of each observational study and randomized controlled trial, respectively.
Statistical analysis
Review Manager software (version 5.3) was used to estimate the risks of bias of the included studies, analyze data, and create plots. I2 statistics were also calculated to measure inconsistency across studies (29). I2 > 75% indicates ‘high’ heterogeneity, 51–75% ‘moderate’ heterogeneity, 26–50% ‘low’ heterogeneity, and 0–25% ‘nonsignificant’ heterogeneity. Risk ratios (RRs) were calculated for dichotomous variables. The fixed‐effects model was used for the meta‐analysis if there was low heterogeneity between the outcomes of each research. If the outcomes of each research showed high heterogeneity, the cause of the heterogeneity was investigated further to exclude the influence of obvious heterogeneity. Sensitivity analysis was performed by deleting one study at a time in order to determine the impact of the deleted study on the combined RR. The publication bias assessment and subgroup analysis were carried out using R language if enough original studies were included.
Results
Search results and description of studies
By executing the search strategy described earlier, a total of 590 articles were found after duplicated records were removed. After screening the title and abstracts, we downloaded the full texts of 29 records, and 8 studies were ultimately included in our analysis following the eligibility criteria, involving a total of 108,054 participants. Among them, seven were retrospective cohort studies, and one was randomized controlled trial. Four studies assessed the effect of metformin on COPD-related hospital admissions in patients with concurrent DM and COPD, three studies assessed the effect of metformin on all-cause mortality in patients with concurrent DM and COPD, and four studies assessed the influence of metformin on hyperlactatemia in patients with concurrent DM and COPD. The details of the study selection process are shown in Fig. 1, and the characteristics of the studies are shown in Tables 1 and 2. Meta-analysis was performed when same clinical outcomes were reported in more than one study. Overall, the methodological qualities of the researches were moderate.
Flowchart of study selection process.
Citation: Endocrine Connections 11, 9; 10.1530/EC-22-0289
Characteristics of the included studies.
| Study | Year | Region | Study design | Patients | Sample size (metformin users/metformin non-users) |
|---|---|---|---|---|---|
| Hitchings (20) | 2015 | UK | Retrospective cohort study | COPD with T2DM | 130 (51/79) |
| Dai (49) | 2017 | China | Randomized control study | COPD with T2DM | 140 (70/70) |
| Yen (22) | 2018 | Taiwan, China | Retrospective cohort study | COPD with T2DM | Stable COPD: 39,010 (19,505/19,505) exacerbated COPD: 15,442 (7721/7721) |
| Yen (25) | 2020 | Taiwan, China | Retrospective cohort study | COPD with T2DM | 41,288 (20,644/20,644) |
| Bishwakarma (23) | 2018 | America | Retrospective cohort study | COPD with DM | 11,260 (3193/8067) |
| Ho (24) | 2019 | Taiwan, China | Retrospective cohort study | COPD with T2DM | 511 (282/229) |
| Xu (50) | 2020 | China | Retrospective cohort study | COPD with T2DM | 84 (42/42) |
| Zhou (51) | 2017 | China | Retrospective cohort study | COPD with T2DM | 189 (97/92) |
Characteristics of the included studies.
| Study | Year | Male/total (%) | Age (years) | Duration (years) | Outcomes | NOS | ||
|---|---|---|---|---|---|---|---|---|
| Metformin users | Metformin non-users | Metformin users | Metformin non-users | |||||
| Hitchings (20) | 2015 | 33 (65) | 50 (63) | 70.5 ± 9.6 | 74.7 ± 9.6 | Not mentioned | All-cause mortality; metabolic acidosis |
8 |
| Dai (49) | 2017 | 51 (72.9) | 47 (67.1) | 67.45 ± 8.26 | 64.96± 10.24 | 1 | All-cause mortality | CASP18 |
| Yen (22) | 2018 | Stable COPD: 10,253 (52.6) Exacerbated COPD: 5159 (66.8) |
10,180 (52.2) 5101 (66.1) |
Stable COPD: 65.4 ± 10.7Exacerbated COPD: 71.8 ± 11.0 | 65.4 ± 11.471.8 ± 11.4 | Metformin users: 3.19; Metformin non-users: 3.17 |
All-cause mortality; metabolic acidosis; COPD-related hospitalizations |
9 |
| Yen (25) | 2020 | 11,151 (54.1) | 11,279 (54.6) | 63.9 ± 11.2 | 63.9 ± 11.2 | 5.1 | COPD-related hospitalizations | 9 |
| Bishwakarma (23) | 2018 | 1042 (32.63) | 2522 (32.63) | 66–74: 1501 (47.01) 75–84: 1400 (43.85) ≥85: 292 (9.15) |
2737 (33.93) 3958 (49.06) 1372 (17.01) |
2 | COPD-related hospitalizations | 8 |
| Ho (24) | 2019 | 232 (82) | 187 (82) | 72.1 ± 9.3 | 74.0 ± 9.3 | 2 | All-cause mortality | 7 |
| Xu (50) | 2020 | 21 (50) | 22 (52.4) | 60.51 ± 1.55 | 60.11 ± 1.64 | Not mentioned | COPD-related hospitalizations; hyperlactacemia |
8 |
| Zhou (51) | 2017 | 53 (54.6) | 49 (53.3) | 69.4 ± 7.2 | 69.7 ± 7.5 | 3 | All-cause mortality; hyperlactacemia |
8 |
CASP, Critical Appraisal Skills Programme; NOS, Newcastle-Ottawa scale.
Outcomes
COPD-related hospitalizations
Four studies reported COPD-related hospitalizations. Figure 2 shows the forest plots for the effect of metformin on hospital admissions in patients with concurrent DM and COPD. The risk of COPD-related hospitalizations was lower in patients with concurrent DM and COPD taking metformin compared with metformin non-users (RR: 0.72, 95% CI: 0.53–0.98; I2 = 89%).
Forest plot for the effect of metformin on hospital admissions of patients with concurrent DM and COPD.
Citation: Endocrine Connections 11, 9; 10.1530/EC-22-0289
All-cause mortality
Data of the all-cause mortality of patients with concurrent DM and COPD were extracted from three studies. Figure 3 shows the forest plots for the effects of using metformin on all-cause mortality in patients with concurrent DM and COPD. As shown in Fig. 3, all-cause mortality was marginally lower in patients with concurrent DM and COPD taking metformin compared with metformin non-users (RR: 0.60, 95% CI: 0.36–1.01, I2= 69%).
Forest plot for the effect of metformin on all-cause mortality of patients with concurrent DM and COPD.
Citation: Endocrine Connections 11, 9; 10.1530/EC-22-0289
Hyperlactacemia
Data of hyperlactatemia were extracted from four studies. As shown in Fig. 4, patients using metformin were not at an increased risk of hyperlactatemia compared with metformin non-users (RR: 1.14, 95% CI: 0.92–1.41, I2= 8%). There was no statistical significance, although a further sensitivity analysis has been performed.
Forest plot for the influence of metformin on hyperlactatemia of patients with concurrent DM and COPD.
Citation: Endocrine Connections 11, 9; 10.1530/EC-22-0289
Sensitivity analysis
Since the pooled results of COPD-related hospitalizations were of high heterogeneity, a sensitivity analysis was conducted for each outcome by excluding one study in return to evaluate the influence of each included study. After excluding the study (Fu-Shun Yen 2020), the heterogeneity turned out to be moderate (Fig. 5).
Discussion
Several prospective studies showed that COPD appeared to be an important risk factor for the development of type 2 diabetes mellitus (T2DM) after adjusting for possible confounders (2, 30, 31). Recent evidence suggests that hyperglycemia could exacerbate the progression and prognosis of diabetes and increases the mortality associated with COPD (5, 32, 33). Researches about metformin treatment on patients with concurrent DM and COPD have received more attention in recent years, but different trials showed inconsistent results. Zhu et al. performed a systematic review to examine the safety and efficacy of metformin in patients with COPD; however, they did not provide statistical evidence to support their findings (34). With eight included studies, our systematic review and meta-analysis first provides a comprehensive assessment of the effect and safety of metformin in patients with concurrent DM and COPD. The patients treated with metformin were associated with lower risk of COPD-related hospitalizations. And it seems that metformin marginally reduces all-cause mortality, although the result is not statistically significant.
Several biological plausibilities are likely related to the demonstrated protective effects of metformin for severe COPD exacerbation. First, COPD is related to increased inflammation and oxidative stress, whereas metformin is shown to exert an anti-inflammatory effect by activating AMP-activated protein kinase (AMPK) (35) and decrease airway remodeling by inducing the production of anti-inflammatory cytokines (36). Additionally, a prospective observational study showed 6-month metformin therapy substantially raised (11%) inspiratory muscle strength in patients with moderate-to-severe COPD (37), which indicated metformin might alleviate COPD symptoms worsening by improving respiratory muscle function. Third, insulin resistance is correlated with skeletal muscle dysfunction (38) and chronic systemic inflammation in COPD (39), which further exacerbate airway obstruction. Hence, an alternative reasonable hypothesis is that metformin might induce insulin resistance remission. Our meta-analysis indicated the risk of COPD-related hospitalizations was lower in patients with concurrent DM and COPD taking metformin compared with metformin non-users; however, significant heterogeneity existed. We hypothesized that heterogeneity may be associated with severity of COPD and the duration of metformin administration. Unfortunately, most original studies did not describe the severity of COPD in the patients and we were unable to perform a subgroup analysis of it. Regarding COPD-related hospitalizations, sensitivity analysis suggested that when the study by Fu-Shun Yen (2020) was excluded, heterogeneity decreased from 89% to 57% and RR changed from 0.72 to 0.57, with the results still being statistically significant. We suspect that because the study by Fu-Shun Yen (2020) had a longer follow-up (5.01 years) than the other three studies, the COPD-related hospitalizations were higher regardless of whether the patients were taking metformin or not, which might be one reason for the significant heterogeneity.
Our meta-analysis showed metformin seems to be associated with lower risk of all-cause mortality, although the effect was slight. As airflow restriction worsens, the degree of inflammation worsens in patients with COPD, who are more susceptible to multisystem diseases. Compared with those with mild disease, cardiovascular and other comorbidities are more common in patients with moderate and severe illness (6, 40). All comorbidities could increase mortality risk. Metformin could improve endothelial oxidative stress levels and attenuate hyperglycemia-induced inflammation, decreasing the incidence of cardiovascular comorbidities (41). Additionally, metformin decreases the occurrence of other comorbidities by activating AMPK (42, 43, 44, 45), eventually leading to lower all-cause mortality.
Metformin interferes with mitochondrial respiratory oxidation and inhibits gluconeogenesis of a variety of substrates, such as glycerol lactate pyruvate and amino acids (19). Metformin is thought to reduce gluconeogenesis from alanine, pyruvate, and lactate, and lactic acid levels may increase under certain conditions (46). Although metformin-associated lactic acidosis is an extremely rare condition, cases continue to be reported and its linked mortality rate is close to 50% (47). Metformin increases the risk of lactic acidosis when patients are in a hypoxic condition; type A tends to arise when tissue perfusion or blood oxygenation is lacking (47, 48). Patients with severe COPD are often accompanied by hypoxemia, which restricts the clinical use of metformin among patients with concurrent DM and COPD. However, our meta-analysis demonstrated that metformin use for COPD did not increase the risk of hyperlactatemia. Metformin is still the drug of choice for patients with concurrent DM and COPD when excluding other contraindications.
Our study first provides significant statistical evidence to assess the effect and safety of metformin on the patients with concurrent DM and COPD, which guides the medical treatments in patients with concurrent DM and COPD. Our meta-analysis demonstrates for the first time that the use of metformin in patients with concurrent DM and COPD is associated with lower COPD-related hospitalizations and the risk of all-cause mortality without increasing the risk of hyperlactatemia. These findings affirmed the metformin's active role in treatment for COPD. Subgroup studies could be carried out in the future to determine the appropriate dosing and duration of metformin therapy. However, several limitations should be acknowledged. First, the number of papers that were qualified for inclusion in our meta-analysis was limited and most of them were retrospective observational studies. Despite the fact that two included studies used propensity score matching to balance confounding factors and promote comparability, we were only able to obtain crude data from the original articles. Therefore, the influence of confounding factors on the results cannot be ruled out. Second, since the heterogeneity in the studies should not be overlooked when analyzing the results, a sensitivity analysis was done to ensure the reliability and stability of our findings. Finally, there may be publication bias since assessment and subgroup analysis could not be performed because not enough original studies were included.
Conclusions
In summary, this review and meta-analysis suggests that metformin use in patients with concurrent DM and COPD is associated with lower risk of COPD-related hospitalizations and all-cause mortality without increasing the risk of hyperlactatemia. Metformin is safe and well-tolerated in patients with concurrent DM and COPD. To prove and update the therapeutic efficacy of metformin in patients with concurrent DM and COPD, further high-quality RCTs and well-designed researches with larger sample populations are still needed.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by grants from the Key Research and Development Program of Shandong Province (2021SFGC0504), and Shandong Provincial Natural Science Foundation (ZR2021LSW015).
Data availability statement
All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.
Author contribution statement
Z T L, M G Y, C J X, and L D conceived and designed the study. M G Y, Z T L, and R Z contributed to acquisition of data, quality assessment, and design of statistical analyses. M G Y and Z T L interpreted the data and wrote the first draft of the study. Z T L, M G Y, C J X, and R Z performed significant revisions. All authors contributed to critical revision of the report for important intellectual content and approval of the final version to be published.
References
- 1↑
Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M & Fabbri LM et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. American Journal of Respiratory and Critical Care Medicine 2017 195 557–582. (https://doi.org/10.1164/rccm.201701-0218PP)
- 2↑
Rana JS, Mittleman MA, Sheikh J, Hu FB, Manson JE, Colditz GA, Speizer FE, Barr RG, Camargo CA. Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care 2004 27 2478–2484. (https://doi.org/10.2337/diacare.27.10.2478)
- 3↑
Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. American Journal of Medicine 2010 123 1001–1006. (https://doi.org/10.1016/j.amjmed.2010.06.019).
- 4↑
Gläser S, Krüger S, Merkel M, Bramlage P, Herth FJF. Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature. Respiration: International Review of Thoracic Diseases 2015 89 253–264. (https://doi.org/10.1159/000369863)
- 5↑
Parappil A, Depczynski B, Collett P, Marks GB. Effect of comorbid diabetes on length of stay and risk of death in patients admitted with acute exacerbations of COPD. Respirology 2010 15 918–922. (https://doi.org/10.1111/j.1440-1843.2010.01781.x)
- 6↑
Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. European Respiratory Journal 2008 32 962–969. (https://doi.org/10.1183/09031936.00012408)
- 7↑
American Diabetes Association. Standards of medical care in diabetes-2017 abridged for primary care providers. Clinical Diabetes 2017 35 5–26. (https://doi.org/10.2337/cd16-0067)
- 8↑
Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prevention Research 2014 7 867–885. (https://doi.org/10.1158/1940-6207.CAPR-13-0424)
- 9↑
Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes, Obesity and Metabolism 2011 13 221–228. (https://doi.org/10.1111/j.1463-1326.2010.01349.x)
- 10↑
Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, Ganne-Carrie N, Grando-Lemaire V, Vicaut E & Trinchet JC et al.Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. Journal of Clinical Endocrinology and Metabolism 2011 96 2601–2608. (https://doi.org/10.1210/jc.2010-2415)
- 11↑
Patrone C, Eriksson O, Lindholm D. Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet: Diabetes and Endocrinology 2014 2 256–262. (https://doi.org/10.1016/S2213-8587(1370125-6)
- 12↑
Neven E, Vervaet B, Brand K, Gottwald-Hostalek U, Opdebeeck B, De Maré A, Verhulst A, Lalau JD, Kamel S & De Broe ME et al.Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney International 2018 94 102–113. (https://doi.org/10.1016/j.kint.2018.01.027)
- 13↑
De Broe ME, Kajbaf F, Lalau JD. Renoprotective effects of metformin. Nephron 2018 138 261–274. (https://doi.org/10.1159/000481951)
- 14↑
Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, Tregoning JS, Baines DL. Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose. Thorax 2013 68 835–845. (https://doi.org/10.1136/thoraxjnl-2012-203178)
- 15↑
Hyun B, Shin S, Lee A, Lee S, Song Y, Ha NJ, Cho KH, Kim K. Metformin down-regulates TNF-α secretion via suppression of scavenger receptors in macrophages. Immune Network 2013 13 123–132. (https://doi.org/10.4110/in.2013.13.4.123)
- 16↑
Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJK, Savinko T & Wong AKF et al.Anti-inflammatory effects of metformin irrespective of diabetes status. Circulation Research 2016 119 652–665. (https://doi.org/10.1161/CIRCRESAHA.116.308445)
- 17↑
Flory J, Lipska K. Metformin in 2019. JAMA 2019 321 1926–1927. (https://doi.org/10.1001/jama.2019.3805)
- 18↑
Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Annals of Internal Medicine 2002 137 25–33. (https://doi.org/10.7326/0003-4819-137-1-200207020-00009)
- 19↑
Kreisberg RA Lactate homeostasis and lactic acidosis. Annals of Internal Medicine 1980 92 227–237. (https://doi.org/10.7326/0003-4819-92-2-227)
- 20↑
Hitchings AW, Lai D, Jones PW, Baker EH. Anti-hyperglycaemic effects of metformin in acute exacerbations of chronic obstructive pulmonary disease (COPD): a multi-centre, randomised, double-blind, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine 2015 191 A3967.
- 21↑
Hitchings AW, Lai D, Jones PW, Baker EH, CTT. Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial. Thorax 2016 71 587–593. (https://doi.org/10.1136/thoraxjnl-2015-208035)
- 22↑
Yen FS, Chen W, Wei JCC, Hsu CC, Hwu CM. Effects of metformin use on total mortality in patients with type 2 diabetes and chronic obstructive pulmonary disease: a matchedsubject design. PLoS ONE 2018 13 e0204859. (https://doi.org/10.1371/journal.pone.0204859).
- 23↑
Bishwakarma R, Zhang W, Lin YL, Kuo YF, Cardenas VJ, Sharma G. Metformin use and health care utilization in patients with coexisting chronic obstructive pulmonary disease and diabetes mellitus. International Journal of Chronic Obstructive Pulmonary Disease 2018 13 793–800. (https://doi.org/10.2147/COPD.S150047)
- 24↑
Ho TW, Huang CT, Tsai YJ, Lien ASY, Lai FP, Yu CJ. Metformin use mitigates the adverse prognostic effect of diabetes mellitus in chronic obstructive pulmonary disease. Respiratory Research 2019 20 69. (https://doi.org/10.1186/s12931-019-1035-9)
- 25↑
Yen FS, Wei JC, Yang YC, Hsu CC, Hwu CM. Respiratory outcomes of metformin use in patients with type 2 diabetes and chronic obstructive pulmonary disease. Scientific Reports 2020 10 10298. (https://doi.org/10.1038/s41598-020-67338-2)
- 26↑
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009 339 b2700. (https://doi.org/10.1136/bmj.b2700)
- 27↑
Suetrong B, Walley KR. Lactic acidosis in sepsis: it’s not all anaerobic: implications for diagnosis and management. Chest 2016 149 252–261. (https://doi.org/10.1378/chest.15-1703)
- 28↑
Margulis AV, Pladevall M, Riera-Guardia N, Varas-Lorenzo C, Hazell L, Berkman ND, Viswanathan M, Perez-Gutthann S. Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank. Clinical Epidemiology 2014 6 359–368. (https://doi.org/10.2147/CLEP.S66677)
- 29↑
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003 327 557–560. (https://doi.org/10.1136/bmj.327.7414.557)
- 30↑
Lee CT, Mao IC, Lin CH, Lin SH, Hsieh MC. Chronic obstructive pulmonary disease: a risk factor for type 2 diabetes: a nationwide population-based study. European Journal of Clinical Investigation 2013 43 1113–1119. (https://doi.org/10.1111/eci.12147)
- 31↑
Song Y, Klevak A, Manson JE, Buring JE, Liu S. Asthma, chronic obstructive pulmonary disease, and type 2 diabetes in the Women’s Health Study. Diabetes Research and Clinical Practice 2010 90 365–371. (https://doi.org/10.1016/j.diabres.2010.09.010)
- 32↑
Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM, Jones PW. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax 2006 61 284–289. (https://doi.org/10.1136/thx.2005.051029)
- 33↑
Castañ-Abad MT, Montserrat-Capdevila J, Godoy P, Marsal JR, Ortega M, Alsedà M, Barbé F. Diabetes as a risk factor for severe exacerbation and death in patients with COPD: a prospective cohort study. European Journal of Public Health 2020 30 822–827. (https://doi.org/10.1093/eurpub/ckz219)
- 34↑
Zhu A, Teng Y, Ge D, Zhang X, Hu M, Yao X. Role of metformin in treatment of patients with chronic obstructive pulmonary disease: a systematic review. Journal of Thoracic Disease 2019 11 4371–4378. (https://doi.org/10.21037/jtd.2019.09.84)
- 35↑
Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O & Efendic S et al.Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002 51 2074–2081. (https://doi.org/10.2337/diabetes.51.7.2074)
- 36↑
Park CS, Bang BR, Kwon HS, Moon KA, Kim TB, Lee KY, Moon HB, Cho YS. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochemical Pharmacology 2012 84 1660–1670. (https://doi.org/10.1016/j.bcp.2012.09.025)
- 37↑
Sexton P, Metcalf P, Kolbe J. Respiratory effects of insulin sensitisation with metformin: a prospective observational study. COPD 2014 11 133–142. (https://doi.org/10.3109/15412555.2013.808614)
- 38↑
Lazarus R, Sparrow D, Weiss ST. Handgrip strength and insulin levels: cross-sectional and prospective associations in the Normative Aging Study. Metabolism: Clinical and Experimental 1997 46 1266–1269. (https://doi.org/10.1016/s0026-0495(9790228-6)
- 39↑
Bolton CE, Evans M, Ionescu AA, Edwards SM, Morris RH, Dunseath G, Luzio SD, Owens DR, Shale DJ. Insulin resistance and inflammation – a further systemic complication of COPD. COPD 2007 4 121–126. (https://doi.org/10.1080/15412550701341053)
- 40↑
Sin DD, Man SF. Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease. Canadian Journal of Physiology and Pharmacology 2005 83 8–13. (https://doi.org/10.1139/y04-116)
- 41↑
Kheniser KG, Kashyap SR, Kasumov T. A systematic review: the appraisal of the effects of metformin on lipoprotein modification and function. Obesity Science and Practice 2019 5 36–45. (https://doi.org/10.1002/osp4.309)
- 42↑
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T & Fujii N et al.Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation 2001 108 1167–1174. (https://doi.org/10.1172/JCI13505)
- 43↑
Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008 57 696–705. (https://doi.org/10.2337/db07-1098)
- 44↑
He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013 62 1270–1281. (https://doi.org/10.2337/db12-0533)
- 45↑
Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prevention Research 2012 5 536–543. (https://doi.org/10.1158/1940-6207.CAPR-11-0536)
- 46↑
Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1999 22 925–927. (https://doi.org/10.2337/diacare.22.6.925)
- 47↑
Rajasurya V, Anjum H, Surani S. Metformin use and metformin-associated lactic acidosis in intensive care unit patients with diabetes. Cureus 2019 11 e4739. (https://doi.org/10.7759/cureus.4739)
- 48↑
Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. New England Journal of Medicine 1998 338 265–266. (https://doi.org/10.1056/NEJM199801223380415)
- 49
Dai H, Li X, Zhang L & & Wen Z. Safety and efficacy evaluation of metformin in treatment of patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus. Journal of Clinical Pulmonary Medicine 2017 22 1106–1108. (https://doi.org/10.3969/j.issn.1009-6663.2017.06.039)
- 50
Xu B. Effect of metformin on the prognosis of diabetes mellitus with chronic obstructive pulmonary disease and clinical analysis. Journal of Mathematical Medicine 2020 33 1034–1035. (https://doi.org/10.3969/j.issn.1004-4337.2020.07.039)
- 51
Zhou Q, Fan C & & Guo L. Influence of metformin on prognosis of concomitant diabetes and COPD. Zhejiang Medical Journal 2017 39 1782–1784. (https://doi.org/10.12056/j.issn.1006-2785.2017.39.20.2017-569)
