Rationale for conducting a randomized trial to examine the efficacy of metformin in improving survival in cirrhosis: Pleiotropic effects hypothesis
Authors: Rohit Loomba
Journal: Hepatology (2014)

In recent years, major advances have been made in our understanding of the mechanisms underlying the progression of liver disease in patients with advanced fibrosis and cirrhosis.1 Many of these advances may lead to development of novel therapeutic strategies for reversal of hepatic fibrosis.1-3 However, limited progress has been made in improving transplant-free survival in patients with newly diagnosed cirrhosis. Emerging data from case-control and cohort studies have shown the beneficial association between statin or metformin use and reduction in the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis.4-6 In this issue, Zhang et al.7 report a retrospective study that provides novel data on the benefits of metformin in improving survival in diabetic patients with newly-diagnosed cirrhosis. The aim of the study was to examine whether continuation of metformin after the diagnosis of cirrhosis improves survival of patients with diabetes. The data were collected by retrospective medical chart review. The study included 250 patients with diabetes who were diagnosed with cirrhosis between 2000 and 2010, and were on metformin at the time of cirrhosis diagnosis. These patients were divided into two groups including 172 patients who continued metformin and 78 patients who discontinued metformin after the diagnosis of cirrhosis. Compared to patients who discontinued metformin, those patients who continued metformin had a significantly longer median survival (5.6 versus 11.6 years, P < 0.0001), and higher cumulative survival rate at 5 years (53.1% versus 77.5%). After adjustment of available key baseline variables, continuation of metformin was an independent predictor of improved survival with a hazard ratio of 0.43 (95% confidence interval [CI]: 0.24-0.78, P = 0.005). Metformin therapy was safe and did not result in lactic acidosis in those who continued metformin. These encouraging results suggest additional benefits of metformin beyond chemoprevention of HCC that may lead to survival benefit with long-term use of metformin in patients with cirrhosis. In context with previously published studies, the following three points are highlighted to have a more complete understanding of the results of this study: (1) Effect modification with other medications that may reduce the risk of HCC such as statins, aspirin, antiviral (against hepatitis B or C) therapy were not examined in this study. 2) If you increase the risk in the control group (by putting the patient on insulin instead of metformin), then the protective effect of metformin therapy may be accentuated in the treatment group. Patients with diabetes are generally placed on one or more antidiabetic medications. Those who had their metformin discontinued would have been placed on an alternative therapy for the management of diabetes. To further explain this phenomenon, it is noted that due to the retrospective nature of the study authors did not have data on other types of antidiabetic therapies and their association with survival in this study. It is known that insulin and sulfonylureas may increase HCC risk and thiozolidinediones may reduce HCC risk.5, 8-11 In order to better understand the effect of metformin, it is important to know the competing risks associated with alternative antidiabetic therapies. The risk in the group that discontinued metformin may be higher due to greater likelihood of exposure to insulin and other antidiabetic therapies that may potentially be more harmful in this population, accentuating the net benefit of metformin. 3) Another possibility is that worsening of glycemic control may have led to discontinuation of metformin. These issues could be handled if longitudinal data were available to capture changes in glycemic control and change in creatinine, and by using time-dependent Cox-proportional hazards analysis to account for changes in glycosylated hemoglobin and serum creatinine. Previous studies have suggested that metformin may be beneficial in the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).12 Although randomized controlled studies have not shown significant benefit of metformin in improving liver histology in patients with NASH, there are data to support that it may be beneficial, at least in some cases, in improving hepatic steatosis and ballooning degeneration, especially in those who lose weight.12-16 Due to the lack of significant benefits of metformin in the resolution of NASH, metformin is not recommended for treatment of NASH.17 However, in a subgroup analysis in this study, when patients were stratified according to the etiology of the cirrhosis, the beneficial effect of metformin was noted only in the NAFLD-related cirrhosis group. The authors did not find any significant benefit in the alcohol, hepatitis C, or hepatitis B-related cirrhosis group. It is possible that the study was underpowered to show benefits in other subgroups but it is also conceivable that the beneficial effect may be greater in NAFLD-related cirrhosis than other etiologies. Although the underlying mechanisms responsible for improving survival by continuation of metformin in diabetic patients with cirrhosis remain to be elucidated, a review of the published literature suggests a pleiotropic effects hypothesis. According to this hypothesis, metformin may have multiple effects across several interconnected metabolic pathways such as cell cycle, cell differentiation, cell growth, autophagy, apoptosis, fatty acid synthesis, glucose and insulin homeostasis, and inflammation that may explain these potentially interrelated mechanisms by which metformin may improve survival (Fig. 1). Briefly, metformin activates liver kinase B1 (LKB1), a serinethreonine kinase, which is often inactivated in human cancers, and leads to activation of adenine monophosphate-activated protein kinase (AMPK), a pleitropic master kinase, which has a multitude of effects on diverse metabolic pathways involving energy homeostasis and metabolism such as reducing hepatic gluconeogenesis, blocking fatty acid synthesis, and activating fatty acid oxidation, and thereby reducing hepatic steatosis.18, 19 In addition, AMPK acts by blocking cMyc, an oncogene, and phosphorylates p53, both of which play a role in tumor suppression, and blocks nuclear factor kappa B (NF-κB) activation and reduces interleukin (IL)−6 release (a progrowth cytokine), thereby decreasing inflammation. Furthermore, AMPK activates DICER, which is a key enzyme for the regulation of microRNAs as well as small interfering RNA. In addition, metformin acts by improving insulin sensitivity directly as well, as by an AMPK-mediated blockade of insulin receptor substrate 1 (IRS-1) and its downstream kinases such as the phosphatidylinositol 3'-kinase(PI3K)/AKT pathway, which in turn blocks the mammalian target of rapamycin (mTOR) pathway, reducing protein synthesis and potentiating autophagy. Furthermore, metformin may reduce oxidative stress by either direct activation of complex 1 in the mitochondria or by way of AMPK-mediated blockade of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, thereby reducing the production of reactive oxygen species. These are some of the potential antiproliferative, anticancer, antiaging, and antiinflammatory mechanisms of action of metformin that provide strong biological plausibility of the beneficial effects of metformin noted in this retrospective study. These cellular mechanisms translate into some of the already known and quantifiable clinical beneficial effects of metformin, including weight loss, reduction in gluconeogenesis, and reduction in serum glucose and insulin levels leading to improvement in insulin sensitivity. These clinical benefits of metformin improve the metabolic efficiency of the host and may also play a role in improving survival. Pleiotropic effects hypothesis: How does metformin improve survival in patients with cirrhosis and diabetes? Blue arrows represent activation or positive effect. Red arrows represent blockade or inhibition or negative effect. Metformin activates Liver Kinase B1 (LKB1), a serinethreonine kinase, which is often inactivated in human cancers, and leads to activation of adenine monophosphate-activated protein kinase (AMPK), a pleitropic master kinase, which acts via diverse metabolic pathways involving energy homeostasis and metabolism such as reducing hepatic gluconeogenesis, blocking fatty acid synthesis and activating fatty acid oxidation, and thereby reducing hepatic steatosis. In addition, AMPK acts by blocking cMyc, an oncogene, and phosphorylates p53, both of which play a role in tumor suppression, and blocks NFKB activation and reduces Interleukin-6 (IL-6) release (a progrowth cytokine), thereby decreasing inflammation. Furthermore, AMPK activates DICER, which is a key enzyme for the regulation of micoRNAs as well as small interfering RNA. In addition, metformin acts by improving insulin sensitivity directly as well as by an AMPK mediated blockade of Insulin receptor substrate 1 (IRS-1) and it's downstream kinases such as phosphatidylinositol 3'-kinase(PI3K)/AKT pathway, which in turn blocks the mammalian target of rapamycin (mTOR) pathway reducing protein synthesis and potentiating autophagy. Furthermore, metformin may reduce oxidative stress by either direct activation of complex 1 in the mitochondria or via AMPK mediated blockade of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and thereby reducing the production of reactive oxygen species. These are some of the potential antiproliferative, anticancer, antiaging, and anti-inflammatory mechanisms of action of metformin that provide strong biological plausibility of the beneficial effects of metformin. AMPK, adenine monophosphate-activated protein kinase; IL-6, interleukin-6; IRS-1, insulin receptor substrate 1; LKB1, Liver Kinase B1; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositol 3'-kinase. After reviewing the proposed pleiotropic-effects hypothesis; from a physician's perspective, a key question emerges: Should we start using metformin for improving survival in diabetic patients with cirrhosis? The answer to this question lies in understanding whether the quality of evidence is strong enough and whether the benefits of continuation of metformin far outweigh the risks associated with discontinuation to make a change in practice. Apart from physicians, other stake holders in this decision-making process include society and, most importantly, the patient. As the patient always come first, we need to think about the burden of such an intervention on our patients with cirrhosis. Hence, the potential adverse effects and tolerability of the intervention needs to be examined. Metformin is generally considered safe and well-tolerated. The most common adverse effects include nausea, vomiting, abdominal discomfort, diarrhea, and weight loss. Lactic acidosis is the most severe adverse effect but fortunately it is extremely rare. Furthermore, metformin should not be used in patients with elevated serum creatinine (≥1.7 mg/dL) due to increased risks of precipitating lactic acidosis. Therefore, monitoring of serum creatinine while on metformin would be needed to ensure patient safety, especially in a group of patients with cirrhosis who have diabetes, as they are at increased risk of developing both acute and chronic kidney disease. In addition, physicians are cautioned about the need to temporarily discontinue metformin at least 48 hours prior to any radiographic study that involves intravenous iodinated contrast administration (such as a contrast-enhanced computed tomography for HCC surveillance) due to the risks of contrast nephropathy resulting in lactic acidosis related to concurrent use of metformin. Despite these caveats, metformin is among the safest medications for the treatment of diabetes and would be an acceptable choice to most patients. From a societal perspective, the cost associated with a treatment is a key consideration. Based on the data from the Diabetes Prevention Program, the cumulative 10-year direct cost of metformin would be approximately $2,281 per patient.20 Hence, the potential economic burden of long-term use of metformin appears to be acceptable from a societal perspective. After having carefully considered both the patient and the societal perspective, we are now ready to circle back to solving the physician's dilemma of whether the evidence for continuation of metformin use for improving survival in patients with cirrhosis and diabetes is strong enough to change the practice. An approach founded on the principles of evidence-based medicine can help us examine the strength of the best available research literature to guide decision making in practice. The United States Preventive Task Force (USPTF) guideline for ranking evidence about the effectiveness of treatments is shown in Table 1. According to this ranking system, the current level of evidence for continuation of metformin for improving survival in this population is derived from a carefully conducted case-control analytic study from a single center, and therefore, would be classified as Level II-2. The gold standard in assessing the beneficial effect of a treatment is a large, multicenter, randomized-placebo controlled trial (RCT), which would be classified as a Level 1 on the USPTF ranking system. It is advisable to conduct RCTs in diverse biogeographic populations to assess the generalizability of the beneficial effects of an intervention before its widespread clinical application is recommended. I believe that this rigorous assessment by conducting an RCT is helpful in uncovering unanticipated risks (or benefits) of interventions that may not be seen or reported in previously published case-control or cohort studies. An example of a large RCT that provided evidence contrary to previously published case-control and cohort studies is the finding from the SELECT trial showing that vitamin E increased the risk of prostate cancer in healthy men rather than decreasing the risk, as suggested by previous studies.21 Therefore, we humbly appreciate the results of the case-control and cohort studies but rely on carefully conducted RCTs, when feasible, to inform changes in clinical practice. As a student of evidence-based medicine, I hope that this retrospective study sets the stage to launch a large, multicenter, RCT to examine the efficacy of metformin for improving survival in patients with cirrhosis who have diabetes. A well-designed and adequately powered RCT would help us quantify the benefits by knowing the number needed to treat to save one life and assess the cost-effectiveness of continuation of metformin in this patient population. The change in practice begins with the idea, which has now been impregnated by the findings of this study. Future studies will guide when we can translate these ideas into changing clinical practice. Rohit Loomba, M.D., M.H.Sc. NAFLD Translational Research Unit Division of Gastroenterology and Epidemiology University of California at San Diego La Jolla, CA