metformin

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Demystifying

“METFORMIN”

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Lactic acidosis "Metformin-associated lactic acidosis" or MALA Nine cases per 100,000 person-years. However, most of the reported cases have occurred in

patients with severe acute conditions Metformin got FDA approval in 1995

This raises the question of whether patients with type 2 diabetes mellitus have an increased risk for developing lactic acidosis with Metformin use compared with other glucose-lowering treatments.

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1. Metformin in Renal impairment

2. Metformin in pregnancy

3. Metformin in Cirrhosis

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KDOQI CLINICAL PRACTICE GUIDELINE FOR DIABETESAND CKD: 2012 UPDATE KDIGO

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What about Metformin in pregnancy?

Clinical experience and the evidence support Metformin use in pregnancy with respect to the immediate pregnancy outcomes.

However, does the use of Metformin in pregnancy ultimately have a beneficial, neutral, or deleterious effect on the offspring?

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So, what about Metformin in Cirrhosis!, then?

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Relevance to Clinical Practice 12th leading cause of mortality globally

The prevalence of type 2, five times greater than in those without cirrhosis.

Liver-related complications and death than patients with cirrhosis without diabetes.

The risk of death from cirrhosis among diabetic patients was greater than in the general population, with a standardized mortality ratio of 2.5, which is even higher than the mortality ratio of 1.3 conferred by cardiovascular disease in patients with diabetes.

Therefore, it is important to improve cirrhosis-related mortality in diabetic patients

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Nonalcoholic fatty liver disease (NAFLD) appears to partially mediate an increased risk of liver-related death among patients with diabetes. The presence of NAFLD increased deaths in diabetic patients, with a hazard ratio (HR) of 2.2, with 19% of deaths being liver related.

Metformin prevented and reversed steatosis and inflammation in a nondiabetic mouse model of nonalcoholic steatohepatitis (NASH) and improved liver histology and alanine minotransferase (ALT) levels in patients with NASH.

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Primary aim of the study

Assess the survival difference between diabetic patients who continued taking Metformin versus those who discontinued Metformin after cirrhosis diagnosis.

Find out other factors that would determine the survival outcomes in patients with cirrhosis with diabetes.

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Patients and Methods Diabetic patients diagnosed with cirrhosis

between January 1, 2000 and December 31, 2010 and who were on Metformin at cirrhosis diagnosis were included in this study (n = 250).

Patients were categorized into two groups, that is, those who continued Metformin after cirrhosis diagnosis and those who discontinued Metformin after cirrhosis diagnosis.

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Diagnosis of cirrhosis by histology (n = 124) by clinical features, namely,

portal hypertension (PH) morphologic characteristics consistent with cirrhosis in cross-sectional

radiologic images (small-sized nodular liver 6 caudate lobe hypertrophy

PH indicated by the presence of collateral vessels, varices, and/or splenomegaly), and/or thrombocytopenia (platelet count <150 K).

Diabetes was defined by a physician note, self-reported medical history, or the American Diabetes Association criteria

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Baseline characteristics of patients

Out of the 250 diabetic patients on Metformin at the time of cirrhosis diagnosis,

172 (68.8%) continued Metformin whereas 78 (31.2%) discontinued Metformin.

142 (56.8%) were male with a mean age of 61.2 years 181 (73.3%) had Child-Pugh class A cirrhosis. The etiologies of cirrhosis were NASH (56.8%), ALD (11.6%),

HCV (12.0%), HBV (2.4%), others (5.6%), and unknown (11.6%).

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Exclusion criteria

History of malignancy except for nonmelanoma skin cancer at cirrhosis diagnosis

Incomplete clinical information Age <18 years Discontinuation of metformin before cirrhosis

diagnosis Initiation of metformin after cirrhosis diagnosis

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Statistical Analysis Student t test for continuous variables and the chi-square test for

categorical variables

Survival of patients in both groups was estimated using Kaplan- Meier’s method and compared using the log-rank test

Associations between predictor variables and survival were determined by HR and 95% confidence interval (CI) calculated using Cox proportional hazards regression

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Reasons for discontinuation of METFORMIN

Diagnosis of cirrhosis (n = 61; 78% of patients who discontinued Metformin),

Uncontrolled plasma glucose (n = 55) Elevated serum creatinine (n = 53) Diarrhea (n = 2) Well-controlled plasma glucose level (n = 52) Switching to insulin therapy (n = 52) Unstated reasons during hospitalization (n = 52) Heart disease (n = 51).

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Selected MELD score in the multivariate analysis because MELD score better correlates with severity of liver impairment than the Child-Pugh classification

Thus, the potential effect of MELD score on outcome was assessed in subsequent analyses.

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Survival of Patients Who Continued Metformin Versus Those Who Discontinued Metformin After Cirrhosis Diagnosis.

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Strength of the study• Largest cohort of unselected patients with cirrhosis with

diabetes in which the effect of Metformin use has been investigated.

• Patients with cirrhosis with diabetes who have various causes of cirrhosis and a wide range of degrees of severity of liver impairment.

• Therefore, this study has contributed significantly to filling the knowledge gap in the debate on whether Metformin can be safely prescribed to patients with cirrhosis.

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Our study revealed the novel observation of an association between Metformin use and

improved survival in a cohort of patients with cirrhosis with diabetes.

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conclusion

• Continuation of Metformin after cirrhosis diagnosis reduced the risk of death by 57%.

• Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication.

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Limitations of the study Sample size of the study was not large enough to sustain the

multivariate model

Not able to take into consideration the effect of dose or duration of Metformin treatment on survival.

Not able to determine the minimum effective dose of Metformin that resulted in improved survival of patients with cirrhosis.

Prevalence of macrovasular and micro vascular diseases among diabetics has not taken in to consideration.

Retrospective study design, detailed information on use of antidiabetic agents was not always available

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Questions to be answered

A number of research questions should be further investigated.

It is worth examining the effect of Metformin on survival of patients with non-NASH cirrhosis in a larger cohort.

Whether initiating Metformin subsequent to diagnosis of cirrhosis

Does Metformin has an antifibrotic effect that would slow down progression or reverse the degree of liver fibrosis.

Metformin also improves the outcomes of patients with cirrhosis with impaired glucose tolerance.

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Take home message

These study results justify the continuation of Metformin therapy in patients with diabetes and cirrhosis from a safety standpoint and provide compelling evidence of a survival benefit, especially among patients with NASH-related cirrhosis.

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Future challenges

Validation of these results in a larger cohort would support continuation of Metformin use in NASH-related cirrhosis.

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Thank you!

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Kaplan–Meier estimator

Is an estimator for estimating the survival function from lifetime data.

In medical research, it is often used to measure the fraction of patients living for a certain amount of time after treatment.

Series of horizontal steps of declining magnitude which, when a large enough sample is taken, approaches the true survival function for that population

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Proportional hazards models Class of survival models in statistics

Can be viewed as consisting of two parts: the underlying hazard function and describing how the risk of event per time unit changes over time at baseline levels of covariates and the effect parameters, describing how the hazard varies in response to explanatory covariates.

A typical medical example would include covariates such as treatment assignment, as well as patient characteristics such as age at start of study, gender, and the presence of other diseases at start of study, in order to reduce variability and/or control for confounding.

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• A typical medical example would include covariates such as treatment assignment, as well as patient characteristics such as age at start of study, gender, and the presence of other diseases at start of study, in order to reduce variability and/or control for confounding.

metformin

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