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Metformin and liver function

Metformin and liver function

Zhu, X. In brief, after anf Metformin and liver function with citrate buffer MMP13 or Metformin and liver function with protease occludin, ZO-1 Maximize workout coordination blocking tissue sections lvier bovine Appetite control program albumin solution iNOS, MMP13, MyD88livre were incubated Functoon specific primary functioon 4-HNE: AG Licer, San Diego, CA, USA; iNOS: Thermo Fisher Scientific, Waltham, MA, USA; MMP LifeSpan BioSciences, Seattle, WA, USA; MyD Santa Cruz Biotechnology, Dallas, TX, USA; Occludin and ZO Invitrogen, Carlsbad, CA, USA. X Twitter Facebook LinkedIn. Vandenbroucke, R. Of mice and men: is there a future for metformin in the treatment of hepatic steatosis? On the basis of available evidence, SGLT-2 inhibitors can be used with caution and lower doses should be considered during initiation of therapy in CLD patients. Metformin and liver function

Metformin and liver function -

control on HOMA-IR change. Subgroup analysis was carried out for two groups: i diabetics and non-diabetics; ii NAFLD and NASH population. Sensitivity analysis was performed by excluding lower quality studies from the meta-analysis and assessing the effect on the summary estimate.

A total of 1, non-duplicated studies were retrieved from the broad search terms used. After review of the titles and abstracts of these studies, 1, were excluded.

Nineteen studies underwent full text review and 10 were subsequently excluded for the following reasons: 4 were pilot studies or cross-sectional investigations, 4 were not randomized and 2 were reviews. Therefore, 9 studies were included in this systematic review and meta-analysis Fig.

Flowchart of the literature search and selection process is shown. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. The trials were published in English between and and reported similar inclusion and exclusion criteria Table I.

The nine trials included comprised a total study population of individuals. The dose of metformin ranged from 0. The mean age of the participants ranged from 41 to 54 years.

The consensus between two investigators regarding the study selection and the quality assessment of trials was 0. The methodological quality and risk of bias of the nine included studies are shown in Fig.

Overall, three studies 20 , 21 , 25 had a low risk of bias in random sequence generation and two studies 20 , 21 had a low risk of bias in allocation concealment. Blinding of outcome assessment was performed in five studies 20 — 22 , 24 , 28 and only one study was funded by a Health Authority Methodological quality of the studies included in this systematic review is shown.

A Risk of bias graph for the studies included in this systematic review. B Lanes 1, Random sequence generation; 2, allocation concealment; 3, blinding of participants and personnel; 4, blinding of outcome assessment; 5, incomplete outcome data; 6, selective reporting; 7, free of source of funding.

The primary outcome was reported separately Table II. Two studies 24 , 28 provided the data of the liver fatty changes diagnosed by US. Four studies 20 , 21 , 25 , 27 reported the number of patients that improved following diagnosis by liver biopsy.

The secondary outcomes were integrated, especially with respect to ALT and AST. Partial data of BMI and HOMA-IR were obtained from the figures provided, only a small proportion of data was not reported.

a No second liver biopsy data were available in the control group, thus unable to be included in meta-analysis. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; NAFLD, non-alcoholic fatty liver disease; NR, not reported; US, ultrasonography.

Histological response was assessed only in four studies 20 , 21 , 25 , 27 , evaluating the scores of steatosis, inflammation, hepatocellular ballooning and fibrosis prior and subsequent to treatment. Since these scores were not continuous variables, we calculated the number of patients with improvement in each histological variable.

Participants treated with metformin showed no improvement in histological variables compared to those treated with placebo or diet and exercise.

OR was 1. No improvement was observed in the histological variables in the subgroup analyses of diabetic or non-diabetic patients. Forest plots of improvement in histological variables are shown. A Steatosis; B inflammation; C hepatocellular ballooning and D fibrosis.

ALT activity was evaluated in the included studies. Forest plots of improvement in biochemical and anthropometric variables are shown. A Alanine aminotransferase ALT ; B aspartate amino-transferase AST ; C homeostasis model assessment of insulin resistance HOMA-IR and D body mass index BMI.

A noteworthy benefit of metformin therapy vs. In their study, Haukeland et al 20 reported that only one patient had developed exanthema. However, none of the patients discontinued metformin due to intolerance during treatment. In this systematic review, nine randomized clinical trials were included, six of which were on NAFLD and three on NASH.

The nine trials had a small sample size and a high variability of group size ranging from 19 to 82 participants. A total of participants were enrolled. A number of patients were overweight or had diabetes. Two trials were considered to be of high methodological quality 20 , 21 , in terms of allocation sequence generation, allocation concealment, blinding and outcome data.

The remaining seven trials 22 — 28 were inadequate or unclear in at least one of the five components used to assess methodological quality. Considerable heterogeneity, such as inclusion criteria, sample sizes, duration of treatment and methods of outcome assessment were present in these trials.

Thus, the adequacy of this evidence should be considered carefully. The effect of metformin on liver histology remains unclear. Our findings demonstrate that metformin does not improve the condition of NAFLD or NASH patients with the histological spectrum of steatosis, inflammation, hepatocellular ballooning and fibrosis, consistent with the findings of previously published systematic studies 17 , 29 , The current data should be interpreted objectively and dialectically.

First, although the nine studies assessed the effect of metformin on histological response, five studies could not be included in the histological response analyses, due to the fact that three of them provided insufficient data and two employed US as the means of diagnosis.

Furthermore, the histopathologic grading system was different in the four included studies, inevitably resulting in heterogeneity. The two studies assessing hepatic steatosis by US also suggested that metformin had no significant effect on hepatic steatosis. Although perfect evidence is absent, the studies included in this review demonstrate that metformin has no effect on histological response in NAFLD.

Regarding the liver enzymes, there were eight and nine studies assessing the effect of metformin on ALT and AST, respectively. Overall, they showed a statistically significant reduction in ALT and AST levels in the metformin group.

Certain reviews 31 , 32 have shown improvements in liver enzymes only in the single-arm trails. However, this has not yet been confirmed by data obtained from RCTs. Therefore, our findings may be more objective and reliable. A number of the included studies reported ALT to be a marker for hepatic inflammation.

We found an average ALT reduction of 8. However, ALT should not be considered to be a marker for liver improvement, since improvement in liver tests is not correlated with histological findings 33 , IR was assessed using HOMA-IR 20 — 24 , 26 — 28 and serum insulin levels, in eight and one study, respectively As expected, insulin sensitivity markedly improved in the metformin, compared to the control group.

In their study, Rakoski et al 17 reported that non-diabetic patients may be particularly susceptible to the insulin-sensitizing properties of glitazone and that early intervention may prevent worsening of IR However, our subgroup analysis detected no statistically significant differences between diabetic and non-diabetic patients, suggesting only that the improving trend in HOMA-IR was more obvious in NAFLD compared to NASH patients.

Due to the incomplete data on body weight, we calculated BMI instead and found a favourable response to metformin treatment in patients with NAFLD. This improvement in BMI was associated with an improvement in IR, as HOMA-IR scores were markedly lower at the end of the included studies in the two groups.

However, three included studies showed no improvement in BMI 21 , 26 , The reason for this result is unclear, but may be associated with the relatively low dose in the three studies mean dose of 0. Therefore, the dose or the duration of therapy should be more carefully determined in metformin treatment.

Our study had several limitations. First, the methodological limitations: the small number of patients, the lack of randomization and blinded measures and the incomplete histological outcomes. Second, although publication bias is a significant factor assessed using funnel plots , it is uninformative due to the small number of studies available for our analysis.

However, the included studies yielded negative results for an improvement in histological response. Third, meta-analysis of weighting studies draws conclusions resulting in the largest variance for the pooled effect size.

We performed sensitivity analysis after excluding the studies that appeared as outliers in the forest plots, which did not have a significant impact on the results. Finally, the histopathologic grading system was inconsistent in the included studies, likely to have affected the accuracy of the data.

In the included studies, the duration of treatment ranged from 4 to 12 months median duration, 8. Due to the limited number of the included studies, the optimal dose and the duration of therapy were difficult to determine.

In addition, IR is widely considered to be a pivotal feature of NAFLD, which is strongly and independently associated with the increased risk of type 2 diabetes 36 , Metformin may therefore be used to treat NAFLD and diabetes simultaneously. Therefore, application of the optimal dose of metformin in order to decrease NAFLD-associated risk of diabetes is a promising treatment approach.

Further randomized clinical trails are required to confirm his hypothesis. This review shows that metformin has mild side-effects, thus can be used safely for long periods of time, and that no patient discontinued metformin due to intolerance or side-effects.

However, we should be cautious about this conclusion, since evidence pointing towards important renal toxicity was reported in previous studies The unexpected adverse events should be monitored carefully in future studies.

Although we cannot determine the optimal dose and duration of therapy, the studies included in this review provide current available evidence on the beneficial as well as harmful effects of metformin in NAFLD.

However, several studies have evaluated the potential involvement of metformin in the therapy of pediatric patients with NAFLD 40 — Findings regarding pediatric patient population were similar to those regarding adults, supporting the beneficial effects of metformin on biochemical and metabolic, but not on histological response.

Despite the fact that this systematic review shows no histological benefit and a modest biochemical and metabolic benefit of metformin, whether or not metformin should be widely used in clinical trials remains to be determined.

Investigators and clinicians should be aware of this issue, since the changes in histology in NAFLD have been observed in larger studies with long follow-up periods.

In this systematic review, the follow-up period of the included trials on average was 8. Since the sample size was small, RCTs with large sample sizes and a long follow-up need to be conducted. The use of metformin might be limited to NAFLD to improve biochemical and metabolic features and might not be used for NASH.

Furthermore, as metformin is less expensive compared to most other treatment modalities for NAFLD, it is considered affordable for the affected population. In summary, this systematic review has shown that metformin may not improve histological response, but it can improve biochemical and metabolic features in NAFLD.

The introduction of the insulin sensitizer troglitazone and subsequent cases of hepatotoxicity led Jick et al. Of the total sample, 1. Of those cases, The remaining 57 8. Oral antidiabetic agents could not be ruled out in two cases,giving an incidence of 0.

The idiosyncratic hepatic reaction leading to hepatic failure and death in some patients on troglitazone before its removal from the market is not likely to be a class effect of the peroxisomal proliferator-activated receptor-gamma agonists.

Rajagopalan et al. Patients were classified into treatment groups based on the antidiabetic therapy received on the date of their first antidiabetic pharmacy claim. Patients in the pioglitazone group were then matched to patients within the rosiglitazone, sulfonylurea, and metformin groups.

Matched groups were similar in demographic and clinical characteristics. Patients evaluated included 4, matched pairs of pioglitazone- versus rosiglitazone-treated patients, 1, pairs of pioglitazone- versus sulfonylurea-treated patients,and 1, pairs of pioglitazone- versus metformin-treated patients.

Over a 2-year period, patients on pioglitazone had no increased risk of liver failure or hepatitis beyond that of patients on the other antidiabetic agents.

In placebo-controlled, double-blind clinical trials with pioglitazone, the incidence of elevated ALT values greater than three times the upper limit of normal was virtually identical between patients on pioglitazone and those on placebo 0. Enzyme elevations were reversible in all patients who developed elevated ALT on pioglitazone.

Lebovitz et al. Mean A1C levels at the start of the study were similar across all groups 8. Measurement of liver enzymes occurred at screening, baseline, then every 4 weeks for the first 3 months of treatment and at 6- to week intervals thereafter.

Patients were excluded from the study if they had ALT, AST, or ALP greater than two and a half times the upper limit of normal at screening. This is consistent with current recommendations of when not to use rosiglitazone or pioglitazone.

No evidence of hepatotoxic effects were observed in the 5, patients who took rosiglitazone. The percentage of patients who developed ALT greater than three times the upper limit of normal were 0. The respective incidence rates of 0. The decrease in LFTs demonstrated with rosiglitazone and pioglitazone therapy in diabetic patients has also been shown in pilot studies using thiadolidinediones to treat NASH, a surrogate for insulin resistance.

One study 27 placed 18 nondiabetic patients with NASH on pioglitazone, 30 mg daily, for 48 weeks. At week follow-up, after 24 weeks off rosiglitazone, liver enzyme levels had increased to near pretreatment levels.

Individuals with type 2 diabetes have a higher incidence of LFT abnormalities than individuals who do not have diabetes.

The most common abnormality is elevated ALT. In patients for whom a directed medical history and physical examination do not raise suspicion of other causes of elevated LFTs, such as medications, alcohol, autoimmunity, metabolic etiology, or hereditary etiology, and for those who have no evidence of more serious liver disease, such elevations in bilirubin or prothrombin time or decreases in albumin, further diagnostic workup is probably not required.

Routine monitoring of LFTs in patients with type 2 diabetes should occur at the start of drug therapy and if patients develop symptoms raising concern about hepatic impairment. Beyond that, periodic screening will have to be based on clinical judgment, keeping in mind that elevation of transaminases does not always correlate with histological changes in the liver.

Elevation of ALT within three times the upper limit of normal is not a contraindication for starting any oral antidiabetic or lipid-modifying therapy.

In contrast,antidiabetic agents have generally been shown to decrease ALT levels as tighter blood glucose levels are achieved. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Clinical Diabetes.

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Volume 23, Issue 3. Previous Article Next Article. Theories Behind LFT Elevation in Diabetes. Can Elevated LFTs Predict the Development of Diabetes?

Incidence of Elevated LFTs in Diabetes. Nonalcoholic Fatty Liver Disease. NAFLD in Nondiabetic Patients. Hepatitis C and Type 2 Diabetes. Statins in Type 2 Diabetic Patients With Elevated Transaminases.

Oral Antidiabetic Agents in Type 2 Diabetic Patients With Elevated Transaminases. Article Navigation. Features July 01 Elevated Liver Function Tests in Type 2 Diabetes Elizabeth H.

Harris, MD Elizabeth H. Harris, MD. This Site. Google Scholar. Clin Diabetes ;23 3 — Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. IN BRIEF Individuals with type 2 diabetes have a higher incidence of liver function test abnormalities than individuals who do not have diabetes.

Harris, MD, is a fellow at the University of North Carolina, Chapel Hill. Endocr Rev. Data sources: A Medline literature search was conducted to June using the terms metformin, lactic acidosis, liver disease, chronic liver disease, hepatotoxicity, hypoxia, risks, and predisposing factors.

Data synthesis: Manufacturer prescribing information and some current medical and lay press literature caution against metformin use in patients with liver disease.

This recommendation is interpreted variably by different prescribers, with some believing that the caution implies metformin can cause or worsen liver injury. Others believe that liver disease predisposes patients to developing lactic acidosis.

A clearer understanding of how and when to screen for liver dysfunction in patients before and during metformin therapy is thus warranted.

Chronic liver disease CLD often coexists with type 2 diabetes mellitus, making piver management Metformiin challenge to the clinician. Anf is well known Boost your metabolism the natural way liver is the liveg site of Metformin and liver function metabolism, and, Maximize workout coordination, its Metformin and liver function affects hepatic metabolism of many antidiabetic agents. Furthermore, patients with CLD have serious comorbidities such as impaired renal function, hypoalbuminemia, lactic acidosis, hypoglycemia and malnutrition, making their treatment even more difficult. On the other hand, most of the antidiabetic agents, with the exception of insulin, need dosage titration due to alterations to their pharmacokinetics in patients with CLD. For well-established antidiabetic treatments, like metformin and sulfonylureas there are studies regarding their dosage chance in these patients. However, despite the growing problem of management of diabetes in patients with CLD the existing literature data, especially on newer antidiabetic agents, are limited and, furthermore, no direct guidelines exist. How Premium-grade Fat Burner is ajd Metformin and liver function the treatment ahd nonalcoholic Glucose homeostasis liver disease Mehformin and nonalcoholic steatohepatitis? Livdr does Holistic weight plans seem to fuhction an effective treatment for nonalcoholic steatohepatitis. There are Metformin and liver function studies evaluating whether metformin improves long-term patient-oriented outcomes such as progression from NAFLD to nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure. Metformin does not improve anatomic outcomes histologic or ultrasound features of the liver or biochemical outcomes alanine transaminase [ALT] and aspartate transaminase [AST] levels, or insulin resistance in adults. Metformin does not improve liver histologic or biochemical outcomes, or body mass index BMI in adults with nonalcoholic steatohepatitis.


Metformin: Mechanism of Action

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