Non-metformin Group Research Articles

Metformin reduces serum CA199 levels in type 2 diabetes Chinese patients with time-effect and gender difference.

This study was designed to clarify the influence of metformin on serum carbohydrate antigen 199 (CA199) levels and its associated factors in Chinese type 2 diabetes mellitus (T2DM) patients. In total, 1,253 T2DM patients were enrolled, including a non-metformin group (n = 616), a short-term metformin group (at least 1 week to 2 years; n=325), and a long-term metformin group (≥ 2 years; n = 312). Their clinical and biochemical characteristics were collected and compared. After 1 year, the biochemical parameters were re-examined in 296 patients. Sex hormones were determined, and associations between CA199 and other variables were assessed. At baseline, the incidence of abnormal CA199 levels was 14.7%, 8.9%, and 4.7% in the non-metformin, short-term metformin, and long-term metformin groups, respectively. CA199 levels in females were significantly higher than in males (P < 0.01) and decreased significantly with the time of taking metformin (25.60 ± 13.68 U/mL in non-metformin controls vs. 17.62 ± 10.87 U/mL in the short-term group vs. 10.54 ± 8.14 U/mL in the long-term group; P = 0.000). The correlation and multiple stepwise regression analysis revealed that glycosylated hemoglobin, metformin, gender, total cholesterol, and follicle-stimulating hormone were independent impact factors on CA199 concentrations (all P < 0.05). Binary logistic regression revealed that the risk of abnormal CA199 concentrations of the total population with short-term metformin or long-term metformin treatment decreased 11% (odds ratio = 0.89; P = 0.001) and 30% (odds ratio = 0.70; P = 0.000), respectively, at baseline. After a 1-year follow-up, the incidence of high CA199 level decreased in both the short-term and the long-term metformin group compared with that of controls (P < 0.05). The extent of CA199 decrease in the long-term metformin group was the greatest (-17% vs. -4.9% in the short-term group vs. 3% in controls, P = 0.000), and the group's risk of high blood CA199 level was reduced 67% (odds ratio = 0.33; P = 0.023). The reduction in women was more apparent than that in men (-18% vs. -5%, P = 0.000). Metformin therapy reduced the CA199 level in Chinese T2DM patients, and its greatest decrease occurred in women with longer therapeutic time.

699P - Metformin Use is Associated with Improved Survival in Diabetic Pancreatic Cancer Patients

ABSTRACT Aim: Accumulating evidence suggests that metformin use is associated with better survival in cancer patients with diabetes mellitus. The aim of this study was to determine the effect of metformin exposure on survival in patients with pancreatic cancer. Methods: We conducted a retrospective cohort study of patients with diabetes and pancreatic cancer treated at Yonsei Cancer Center (Seoul, Korea) from 2005 to 2010. Clinical data on diabetes and pancreatic cancer were obtained from electronic medical record database and survival data were retrieved from the tumor registry at Yonsei Cancer Center. Survival analysis was carried out using a Kaplan-Meier plot, log-rank test, and Cox proportional hazards regression models were used. Results: The study included 428 patients with type 2 diabetes mellitus and pancreatic cancer. The median overall survival (OS) in metformin group (n = 111) was 12.6 months and 7.6 months in non-metformin group (n = 317; P = 0.001, log-rank test). Among metastatic patients (n = 220), median OS was greater in metformin group (6.7 months) than non-metformin group (5.4 months), but it was not statistically significant (P = 0.057, log-rank test). In multivariate model, adjusting for ECOG performance status, CA 19-9, stage (resectable/unresectable/metastatic), body mass index (BMI) and number of organ involvement, metformin use was independently associated with improved OS in all patients (HR = 0.78; 95% CI, 0.62-0.98; P = 0.032). Conclusions: Our finding suggests that metformin use might be associated with improved survival in pancreatic cancer patients with type 2 diabetes. Disclosure: All authors have declared no conflicts of interest.

Safety of Metformin in Patients with Chronic Obstructive Pulmonary Disease and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10–2.05) versus 1.10 mmol/L (0.80–1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5–5.8) versus 1.9 years (1.1–2.6), respectively (hazard ratio 0.57; 95% CI 0.35–0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

Effect of metformin on serum thyrotropin level in type 2 diabetic patients with subclinical hypothyroidism

Objective To examine the effect of metformin on serum thyrotropin (TSH) level in diabetic patients with subclinical hypothyroidism (SCH).Methods The long-term effects of metformin on thyroid axis hormones were assessed in 55 diabetic patients with primary SCH who were untreated with L-T4(study group),as well as in 31 diabetic patients with normal thyroid function (control group).According to using metformin or not,patients of study group were divided into the metformin group (group 1,n =28),and the non-metformin group(group 2,n =27).Serum TSH levels were compared between baseline and follow-up in patients receiving metformin treatment.Results After 30 weeks of metformin administration,a significant TSH decrease(t =2.91,P ＜ 0.05) was observed in group 1 [from(6.98 ± 1.92) to(2.44 ± 0.61) mIU/L].After stopping metformin therapy,the level of TSH at 52 weeks fol low-up was back to the baseline level [(6.99 ± 1.76) mIU/L,P ＞ 0.05].There was no significant difference in TSH level between baseline and after 30 weeks follow-up in group 2[(6.01 ± 1.63) mIU/L vs(6.21 ± 1.71) mIU/L,P ＞0.05].At the end of 30 weeks follow-up,no significant differences were found in body mass index and thyroid func tion in both metformin group and non-metformin group.In control group,metformin administration for 30 weeks had no effect on TSH level(P ＞ 0.05).Conclusion Metformin administration influences TSH without change of FT4 level in type 2 diabetic patients with primary SCH. Key words: Metformin; Subclinical hypothyroidism; Diabetes mellitus, type 2 ; Thyrotropin

Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus?

Background/AimsColorectal cancer (CRC) develops from colonic adenomas. Type 2 diabetes mellitus (DM) is associated with a higher risk of CRC and metformin decreases CRC risk. However, it is not certain if metformin affects the development of colorectal polyps and adenomas. This study aimed to elucidate if metforminaffects the incidence of colonic polyps and adenomas in patients with type 2 DM.MethodsOf 12,186 patients with type 2 DM, 3,775 underwent colonoscopy between May 2001 and March 2013. This study enrolled 3,105 of these patients, and divided them in two groups: 912 patients with metformin use and 2,193 patients without metformin use. Patient clinical characteristics, polyp and adenoma detection rate in the two groups were analyzed retrospectively.ResultsThe Colorectal polyp detection rate was lower in the metformin group than in the non-meformin group (39.4% vs. 62.4%, P<0.01). Colorectal adenoma detection rate was significantly lower in the metformin group than in the non-metformin group (15.2% vs. 20.5%, P<0.01). Fewer advanced adenomas were detected in the metformin group than in the non-metformin group (12.2% vs. 22%, P<0.01). Multivariate analysis identified age, sex, Body mass index and metformin use as factors associated with polyp incidence, whereas only metforminwas independently associated with decreased adenoma incidence (Odd ratio=0.738, 95% CI=0.554-0.983, P=0.03).ConclusionsIn patients with type 2 DM, metformin reduced the incidence of adenomas that may transform into CRC. Therefore, metformin may be useful for the prevention of CRC in patients with type 2 DM.

Effects of Metformin on CD133+ Colorectal Cancer Cells in Diabetic Patients

In diabetic patients complicated with colorectal cancer (CRC), metformin treatment was reported to have diverse correlation with CRC-specific mortality. In laboratory studies, metformin was reported to affect the survival of cancer stem cells (CSCs) in breast and pancreatic cancers and glioblastoma. Although cscs play a critical role in the resistance to 5-fluorouracil (5-FU) chemotherapy in CRC patients, the effect of metformin on cscs in CRC patients and the synergistic effect of metformin in combination with 5-FU on cscs are not reported. In the present study pathological examinations were performed in 86 CRC patients complicated with type 2 DM who had been divided into a metformin group and a non-metformin group. Comparisons regarding pathological type, incidence of metastasis, expression of CD133 and β-catenin were conducted between the two groups. We explored the synergistic effects of metformin in combination with 5-FU on the proliferation, cell cycle, apoptosis and the proportion of CD133+ cscs of SW620 human colorectal cancer cell lines. The results show that metformin treatment had reverse correlations with the proportion of patients with poorly differentiated adenocarcinoma, the proportion of CD133+ cscs in CRC patients with type 2 DM. Metformin enhanced the antiproliferative effects of 5-FU on CD133+ cscs in SW620 cells. These findings provide an important complement to previous study. Inhibition of the proliferation of CD133+ cscs may be a potential mechanism responsible for the association of metformin use with improved CRC outcomes in CRC patients with type 2 diabetes.

Elevated Hemoglobin A1c Levels Are Associated with Worse Survival in Advanced Pancreatic Cancer Patients with Diabetes

Background/AimsPre-existing diabetes mellitus (DM) has been identified as an adverse prognostic variable associated with increased mortality in various cancers. Although DM and hyperglycemia are considered risk factors for pancreatic cancer (PC), antidiabetic treatments for patients with advanced PC have been overlooked. This study aimed to evaluate the impact of hemoglobin A1c (HbA1c) levels on PC survival.MethodsWe retrospectively reviewed the medical records of first-diagnosed patients with advanced PC who were admitted to Konkuk University Medical Center from 2005 to 2011.ResultsA total of 127 patients were enrolled, and there were 111 deaths (87.4%) within the 7-year observational period. The most common etiology was disease progression (n=108). DM before PC diagnosis was observed in 65 patients (51.1%), including 28 patients with new-onset DM. The overall median survival times in patients with and without DM were 198 and 263 days, respectively (p=0.091). Survival time according to HbA1c was significantly different between the <7.0% and ≥7.0% groups (362 and 144 days, respectively; p=0.038). In the HbA1c ≥7.0% group, the median overall survival time was 273 days for the metformin group and 145 days for the nonmetformin oral agent group; however, there was no significant difference between the two groups (p=0.058).ConclusionsA high HbA1c level may be associated with worse survival in patients with advanced PC with DM. Antidiabetic treatment, metformin in particular, was associated with an improved outcome.

Clinical pathological characteristics and prognostic analysis of diabetic women with luminal subtype breast cancer

This study selected luminal-type breast cancer patients as the study subjects. The patients were divided into groups according to the presence of diabetes and the types of medication used, and the patients' clinicopathological characteristics and prognostic indicators were explored. A total of 5,785 patients with luminal-type breast cancer admitted to Tianjin Medical University Cancer Institute and Hospital between January 2002 and December 2006 were selected as the study subjects. The subjects included 680 breast cancer patients with diabetes and 5,105 breast cancer patients without diabetes. The patients were divided into Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subtypes. Each subtype was further divided into a metformin group, a non-metformin group, and a nondiabetic group. The research indicators included breast cancer mortality, age, body mass index (BMI), amenorrhea, the presence of cardiovascular and cerebrovascular disease, pathological stage, pathological type, lymph node involvement, vessel carcinoma embolus, and the chemotherapy and endocrine regimen. A Kaplan-Meier analysis was conducted to analyze the differences in breast cancer mortality rates among the groups. The Cox proportional hazard model was adopted to detect independent factors related to prognosis. Kaplan-Meier univariate analysis showed that for the Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subtypes, the cancer-specific mortality rates differed significantly among the metformin, non-metformin, and nondiabetic groups. The 5-year survival rates were 94%, 82%, and 91% (P = 0.002); 93.5%, 81%, and 89% (P < 0.001); and 84%, 77%, and 83% (P = 0.035) for the subtypes within each group, respectively. Cox regression multivariate analysis showed that compared with the metformin group, all three subtypes of the, the non-metformin group showed poorer prognosis (hazard ratio [HR], 3.579; 95% confidence interval [CI], 1.506-8.506 [P = 0.004]; HR, 3.232; 95% CI, 1.839-5.678 [P < 0.001]; HR, 2.034; 95% CI,1.019-4.059 [P = 0.044] for Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+, respectively). Compared with the metformin group, the diabetic group showed poorer prognosis only for the Luminal B (high ki67) subtype (HR, 1.762; 95% CI, 1.033-3.005 [P = 0.038]). In addition, for the Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subgroups, there was a higher proportion of elderly patients (P < 0.001) and postmenopausal patients (P < 0.001) in the metformin and non-metformin groups than in the nondiabetic group. Moreover, the probability of having cardiovascular and cerebrovascular disease was also higher (P < 0.001) in the metformin and non-metformin groups. For the Luminal B (high ki67) and Luminal B (her-2/neu +) subgroups, there was a higher proportion of obese patients in the metformin and non-metformin groups (P < 0.001). In terms of clinical characteristics, for the Luminal B (high ki67) subtype, the proportion of patients with invasive ductal carcinoma was lower in the non-metformin group than in the other two groups (P = 0.001). In both the metformin and non-metformin groups, the proportion of T3/4 patients was higher (P < 0.001), the proportion of patients with lymph node metastasis was higher (P = 0.001), and the proportion of patients with vessel carcinoma embolus was higher (P = 0.001) compared with the nondiabetic group. In conclusion, compared with the metformin group, the non-metformin group had a poorer prognosis for all subtypes of luminal breast cancer. In the diabetic group, only patients with the Luminal B (high ki67) subtype exhibited a poorer prognosis. Therefore, different diabetes medication may have a different impact on the prognosis of different subtypes of luminal breast cancer.

Metformin and Prostate Cancer: Reduced Development of Castration-resistant Disease and Prostate Cancer Mortality

BackgroundIn vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). ObjectiveTo determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. Design, setting, and participantsData from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. InterventionUse of metformin in localized prostate cancer. Outcome measurements and statistical analysisUnivariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer–specific mortality (PCSM), overall survival (OS), and development of CRPC. Results and limitationsWith a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24–3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78–7.62]; p<0.001), and PCSM (HR: 5.15 [1.53–17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83–119.89]; p=0.01). The retrospective study design was the primary limitation of the study. ConclusionsTo our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.

1450P - Effect of Prior Metformin Intake on First Diagnosis of Breast Cancer

ABSTRACT Introduction Metformin has been shown in pre clinical studies to have the ability to reduce tumor growth and exert anti cancer effects. It is being tested as a part of management of breast cancer (BC) in neoadjuvant and adjuvant settings and being entertained as a modality of chemoprevention in BC. We studied the effect of prior metformin intake on patients with first diagnosis of breast cancer. Methods All patients with a diagnosis of BC were identified from the Tumor Registry of our hospital, which serves the underserved population of Chicago, USA. All charts were retrospectively screened for age, tumor grade, node status at diagnosis, onset of diabetes mellitus (DM) prior to cancer diagnosis and intake of metformin including duration. Patients with a diagnosis of DM after cancer, intake of metformin less than 6 months or incomplete medical record were excluded. Difference in means was calculated using the student t-test. Results A total of 1569 patients were screened of which 133 patients were identified to have a diagnosis of DM before breast cancer and met the inclusion criteria. Of these, 95 patients were on metformin for an average 3.57 years (yrs) before BC diagnosis. Thirty-nine patients on metformin were younger than 60 yrs and 56 were older than 60 yrs age. Node positive disease was seen in 51.5% of metformin patients compared to 49% DM patients not on metformin (p = NS). However in patients younger than 60 yrs, node positive disease was seen in 66% of metformin patients compared to 86% non-metformin patients. The young patients on metformin had an average grade of 2.38 compared to non-metformin patients whose average grade was 2.83 (p = 0.02). More patients in young non-metformin group were Her2-neu positive (43%) compared to 23% in young metformin group. In older patients more non-metformin patients had triple negative disease (20%) compared to 9% in metformin group. Conclusions Prior metformin use may have a possible positive effect in patients with initial diagnosis of BC. This effect seems more pronounced in patients younger than 60 yrs of age where metformin intake was associated with a statistically significant reduction in tumor grade with a trend towards reduction in node positive disease and Her2 positivity. Further studies are needed to clarify the potential protective role of metformin in this younger group. Disclosure All authors have declared no conflicts of interest.

An observational study of the effect of metformin on B12 status and peripheral neuropathy

Aims Metformin is associated with lowering of vitamin B12 levels. We hypothesise that holotranscobalamin (holoTC) and methylmalonic acid (MMA) are more sensitive indicators of B12 deficiency in patients receiving metformin therapy, and that these correlate with declining peripheral neurological function. Methods Patients with type 2 diabetes were recruited and divided into those receiving metformin for greater than 6 months and a non-metformin group. Baseline characteristics were measured in both groups including vitamin B12, holoTC and MMA concentrations. Neurological function was assessed using neurothesiometry, monofilament, Neuropathy Total Symptom Score-6 questionnaire and the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs questionnaire. Results In total, 202 patients were recruited: 152 in the metformin group and 50 in the non-metformin group. Vitamin B12 levels were lower in the metformin group (219.1±105.4 ng/L, 281.4±95.1 ng/L, p&lt;0.001). HoloTC was significantly lower in the metformin group (54.8±30.5 pmol/L, 70.1±26.0 pmol/L, p=0.002). No significant difference in serum MMA was observed between the two groups (0.40±0.26 μmol/L, 0.35±0.22, p=0.23). No significant difference in neurological function was observed between the groups. Conclusion Although metformin therapy is associated with lower vitamin B12 status there does not appear to be any significant effect on peripheral neuropathy in those receiving metformin. We do not recommend changing current practice to routinely monitor or replace patients receiving metformin with vitamin B12 unless clinically indicated.

Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer

Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer. We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan-Meier plot, log-rank test, and Cox proportional hazards regression models. Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ(2) test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52-0.89) in a univariate model (P = 0.004), 0.64 (0.48-0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44-0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only. Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population.

The Gonadal Hormone Regulates the Plasma Lactate Levels in Type 2 Diabetes Treated With and Without Metformin

Our previous study showed there was a gender difference in plasma lactate concentrations in subjects with type 2 diabetes. This study investigated the effect of sex hormone levels on plasma lactic acid (LA) levels in type 2 diabetes with and without metformin therapy. Fasting whole blood specimens of 392 type 2 diabetes patients treated with metformin (n=199) or not (n=193) were collected. LA was measured with an enzyme-electrode assay. Levels of sex hormones, including testosterone (T) and estradiol (E(2)), were measured with a chemiluminescence microparticle immunoassay. Spearman's or Pearson's correlation and logistic regression analysis were performed for the factors associated with LA. The LA level in the metformin group was significantly higher than that in the non-metformin group (1.26±0.43 vs. 1.14±0.49 mmol/L, P<0.001), and LA levels of females were significantly higher than those of males (P<0.001). LA concentrations were positively correlated with E(2) level but negatively correlated with metformin and T levels (P<0.01). The logistic regression analysis showed that gender, creatinine, E(2), metformin, and T were independent factors influencing lactate levels. Analysis of subgroups demonstrated that the LA concentrations increased with the elevation of E(2) level (P<0.05) but decreased with the rising of T level (P<0.05). Sex hormones play an important role on regulating plasma lactate levels in diabetes patients treated with metformin. E(2) up-regulates but T tend to down-regulate lactate levels.

The Effect of Metformin on Responses to Chemotherapy and Survival in Stage IV Colorectal Cancer with Diabetes

Metformin is known to lower the risk of cancer and cancer mortality. However, the effect of metformin in stage IV colorectal cancer (CRC) patients with diabetes mellitus (DM) remains unknown. The aim of this study was to evaluate the effect of metformin on tumor response and survival in stage IV CRC patients with DM. We identified 106 patients who were diagnosed with both stage IV CRC and DM (81 patients who underwent palliative chemotherapy and 25 patients who underwent curative resection). Retrospective data of each patient's clinical characteristics, tumor response, and survival rate were compared between two groups of patients who either were or were not administered metformin. For the palliative chemotherapy group, tumor response, change in target lesion size, progression free survival rate, and overall survival rate were not significantly different between the metformin group and the non-metformin group on univariate and multivariate analysis. For the curative resection patient group, metformin use was associated with increased disease free survival on univariate analysis (p=0.012) and multivariate analysis (hazard ratio, 0.024; 95% CI 0.001-0.435; p=0.010), but not with overall survival. Metformin use in stage IV CRC patients with diabetes was shown to be associated with a lower risk of tumor recurrence after curative resection.

P259 Effects of metformin on clinical outcome in patients hospitalised for COPD exacerbations: a retrospective cohort study

BackgroundApproximately 10% of patients with chronic obstructive pulmonary disease (COPD) have co-existing diabetes mellitus, conferring an adverse prognosis. Metformin is a valuable first-line treatment for diabetes. However, its rare association...

Prognostic influence of metformin as first‐line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes

It has been reported that antidiabetic drugs affect the risk of cancer and the prognosis of patients with diabetes, but few studies have demonstrated the influence of different antidiabetic agents on outcomes after anticancer therapy among patients with cancer. The objective of this study was to evaluate the influence of the antidiabetic drugs metformin and insulin on the prognosis of patients with advanced nonsmall cell lung cancer (NSCLC) plus type 2 diabetes who received first-line chemotherapy. Data on patients with NSCLC who had diabetes from 5 hospitals in China during January 2004 to March 2009 were reviewed retrospectively. Ninety-nine patients were included in the final analysis. The influence of metformin and insulin on chemotherapy response rates and survival in these patients was evaluated. Chemotherapy with metformin (Group A) produced superior results compared with insulin (Group B) and compared with drugs other than metformin and insulin (Group C) in terms of both progression-free survival (PFS) (8.4 months vs 4.7 months vs 6.4 months, respectively; P = .002) and overall survival (OS) (20.0 months vs 13.1 months vs 13.0 months, respectively; P = .007). Although no significant differences in the response rate (RR) were observed between these 3 groups, when groups B and C (ie, the nonmetformin group) were combined, there was a tendency for better disease control in Group A than that in nonmetformin group. No significant difference in survival was observed between chemotherapy with insulin (Group B) versus other drugs (Group C). The current data suggested that metformin may improve chemotherapy outcomes and survival for patients who have NSCLC with diabetes.

Is it Time to Test Metformin in Breast Cancer Prevention Trials? a Reply to the Authors

To the Editor: We read with great interest the article by Cazzaniga et al. (1) on the potential use of the insulin sensitizing agent metformin for therapeutic and chemopreventive purposes in breast cancer. We found that the safety profile of metformin was inadequately elicited and poorly supported by the cited references. This was particularly striking with regard to lactic acidosis, defined by the authors as “the only potential adverse event in metformin therapy.” The authors further refer to this condition in terms of a rare event, which primarily occurs in patients with renal and hepatic disorders. The reported evidence was not exhaustive and the only cited reference was taken from an article published in 1996 (2). Given the current use of metformin in several common pathologic conditions associated with insulin resistance (e.g., type 2 diabetes and polycystic ovary syndrome) as well as the great potential of this drug in breast cancer therapy and prevention, the relation between metformin use and lactic acidosis in both diabetic and non diabetic patients is in urgent need of clarification particularly in light of much more recent and comprehensive scientific evidence.The Cochrane Collaboration has conducted a systematic review evaluating the risk of fatal and nonfatal acidosis attributed to metformin use compared with placebo and other agents in type 2 diabetes patients. Salpenter et al. (3) pooled data for a total of 59,321 patient-years of metformin use and 51,627 patient-years in the nonmetformin group. They found no evidence of the association between metformin use and risk of lactic acidosis.In nondiabetic patients, lactic acidosis occurs in association with pathologic conditions leading to tissue hypoxia, such as infections, heart failure, liver failure, and renal failure. In these cases, mortality is predicted by the severity of the underlying hypoxia and does not correlate with metformin accumulation (4, 5).In conclusion, when referring to the association between this drug use and lactic acidosis in an evaluation of the timeliness of testing metformin in breast cancer prevention trials, the following message should be clearly conveyed: although circumstantial evidence has linked metformin treatment with lactic acidosis, no causal relationship has been shown thus far, either in patients with type 2 diabetes or in nondiabetic patients. Conversely, this drug has been proven to reduce cardiovascular mortality in type 2 diabetes patients and, when considered in a preclinical setting, to possess anticarcinogenic properties on breast, colon, and prostate (1).No potential conflicts of interest were disclosed.

Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer

Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using chi(2) tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.

The Effect of Metformin on the Incidence of Type 2 Diabetes Mellitus and Cardiovascular Disease Risk Factors in Overweight and Obese Subjects – The Carmos Study

We investigated whether the addition of metformin to the treatment of overweight and obese individuals further reduces the incidence of type 2 diabetes mellitus (T (2)DM), prediabetes and metabolic syndrome (MetS) and improves cardiovascular disease (CVD) risk factors (RFs). We studied 366 adults (mean age 53.0+/-0.5 SE years, and mean BMI 32.3+/-0.2 SE Kg/m (2)) without CVD. All subjects received lifestyle recommendations and drug management of CVD-RFs, whilst 95 of them were additionally given metformin. The follow-up period lasted 12 months. At the end of the study the frequency of T (2)DM in the metformin and non-metformin group was 1.1 and 8.1%, respectively (risk difference=-7% with 95% CI from -12.7% to -1.4%, p=0.012). Participants with prediabetes displayed a greater reduction in the incidence of T (2)DM after taking metformin compared to those who had not received this drug (risk difference=-18.5% with 95%CI from -33.1% to -3.9%, p=0.010). Metformin had a similar beneficial impact on subjects with MetS (risk difference=-12.9% with 95% from -25% to -0.7%, p=0.040) and this was attributed to the greater increase in HDL-C (p=0.046) and decrease in fasting plasma glucose levels (p=0.024). Metformin also achieved a greater reduction in total cholesterol and LDL-C levels (metformin vs. non-metformin treated subjects: -31.9 vs. -17.3 mg/dl, p=0.001, and -26.2 vs. -15.9 mg/dl, p=0.006, respectively). Metformin reduces the occurrence of T (2)DM in overweight and obese non-diabetic adults and decreases the rate of MetS by improving the CVD risk factor profile.

Effects of lifestyle intervention and metformin on weight management and markers of metabolic syndrome in obese adolescents

The purposes of this study are threefold: to determine what components of the metabolic syndrome are present in obese adolescents, to determine what differences exist in the effects of lifestyle intervention versus lifestyle intervention plus metformin on weight management and select markers of metabolic syndrome in obese adolescents, and to determine which factors predict weight loss in obese adolescents treated with lifestyle changes and metformin. The study was a secondary data analysis utilizing a retrospective chart review of 63 obese adolescents aged 11 through 18 who were treated for obesity at the LeBonheur Youth Lifestyle Clinic from January 1, 2000, through June 30, 2005. Lifestyle interventions included diet, exercise, and counseling. The medication utilized was metformin. Outcomes evaluated included body mass index, relative body mass index (RBMI), weight, waist and hip circumference, blood pressure, serum lipid levels, fasting plasma glucose, 2-h oral glucose tolerance tests, and insulin levels. Changes in mean values between groups were evaluated using the General Linear Models procedure. Logistic regression was utilized to determine which factors might predict weight loss. The metformin group (N= 37) tended to be heavier, older, and had more components of the metabolic syndrome than the nonmetformin group (N= 26). All components of the metabolic syndrome were present in both groups (overall prevalence 55%). Both groups had a downward trend in RBMI, a surrogate marker for weight loss, but only the metformin group had a significant loss in RBMI points from baseline to end. There was a trend toward better diastolic blood pressure at 6 months in the metformin group (p= 0.06), which was not seen in the nonmetformin group. The only predictors of weight loss were higher RBMI (those who were heavier lost more) and the absence of type 2 diabetes mellitus (type 2 DM) (those with type 2 DM were less likely to lose 10 or more points in RBMI). All components of the metabolic syndrome are present in obese adolescents. The use of lifestyle changes and lifestyle changes plus metformin both produce some degree of weight loss, but subjects on metformin in this study lost significantly more RBMI points than those on lifestyle changes alone. Subjects with type 2 DM are less likely to lose weight than those without type 2 DM. Larger studies and studies with subjects more representative of the general population need to be carried out to assist in the development of evidence-based practice guidelines.