This is the first study showing that taking insulin sensitizers (like Metformin) to decrease INSULIN RESISTANCE, increases SVR. I have waited a long, long time for this study. Now we can use this study to get doctors to test people for insulin resistance and prescribe Metformin. Success rate is about to go up.....yes!
TRIC-1 Study: Metformin Added to Peginterferon alfa-2a and Ribavirin Improves RVR Rate in Treatment-Naive Genotype 1 HCV Patients With Insulin Resistance.
Treatment of Insulin Resistance in HCV Genotype 1 Patients (TRIC-1): prospective, multicenter, randomized, double-blind controlled study
Summary of Key Conclusions
• Metformin added to peginterferon alfa-2a/ribavirin in treatment-naive genotype 1 HCV patients with insulin resistance resulted in
....o Significantly increased RVR rate (Week 4 undetectable HCV RNA)
....o Similar rates of undetectable HCV RNA at Weeks 12 and 24 in either treatment arm
....o Significantly reduced insulin resistance at Week 24
• Metformin well tolerated
• Greater degree of insulin resistance reduces likelihood of achieving HCV sustained virologic response (SVR)
• Current study assessed impact of metformin added to HCV standard of care on SVR rates in genotype 1 HCV–infected patients with insulin resistance
• Metformin added to peginterferon alfa-2a and ribavirin significantly decreased HOMA index and increased rapid virologic response (RVR) rate vs placebo following 24 weeks of treatment in genotype 1 patients
Efficacy Outcome......................Treatment..Control ......P Value
................................................(n = 61).....(n = 63)
Week 24 mean decrease in
HOMA index (SD)......................-1.6 (2.1)...-0.87 (2.1)..< .01
Thanks for the article. This looks important. If I'm reading it correctly, the Meta group has over 4X the number of RVRs as the placebo group? Wow! Do you know what week the study is in now -- be great to see how it all translates into SVR. Do you have a link to the study? Thanks!
As you can see, oral antidiabetic agents were mentioned in this post. People may equate that with the Meta group. I have not seen any information that indicates metformin is a danger to the liver just in case anyone is suspicious of that particular group of oral diabetic meds. Thanks for the information Co, it is of particular interest to me. Trin
Female, 48 years
Member since Mar 2006
Mood: hippygem chillin out
Journal Entry: "The link below is for clinical trials you..." [Read]
, Sep 16, 2008 07:58AM
Welcome to the forums.
Many people with hepatitis C also suffer from other illnesses or disorders which require them to take medications. Many medications both prescription and over-the-counter drugs can be quite toxic to the liver (see list below).
The author notes that for example; taking paracetamol (acetaminophen in the USA) on an empty stomach or with alcohol can be harmful.
Eating regularly will help avoid this as well as help you absorb any other medications or supplements you are taking. But, if you are in pain, paracetamol is the best option with a safe dosage being 500mg four times a day or 2g daily (Riley, 2001 - part 1).
List of Toxic Medications:
• Muscle relaxants.
• Psychotropics (a drug which alters the mind) e.g. antidepressants.
• Anticonvulsants (a drug or agent that prevents or reduces the severity of convulsions).
• Lipid-lowering drugs.
• Oral antidiabetic agents (therapy for type 2 diabetes).
• Estrogens are any of various steroid hormones developing and maintaining female characteristics of the body; this hormone produced artificially for use in oral contraceptives etc.
• Anabolic steroids are any of a group of synthetic steroid hormones used to increase muscle size.
• Antituberculous agents (Riley, 2001 – part 1).
Hepatotoxic (toxic to the liver) Vitamins and Supplements:
Many vitamins and supplements can cause damage to the liver depending on the dose. One study in the USA found that up to one third of the patients in a liver clinic used herbal remedies. One of the most hepatotoxic vitamins is Vitamin A and anyone taking vitamin A supplements should be aware that doses higher than 25,000 IU (international units) per day may be dangerous. Most multivitamin preparations contain 4,000 IU vitamin A, which is well within the safety range. One of the few supplements which has been shown to be beneficial to the liver but without any toxic effects is Milk Thistle (Silybum Marianum) and there is no evidence of toxicity related to the pure form of milk thistle. It is known to protect cells in our liver that is not damaged (Riley, 2001 – part 1).
List of Toxic Vitamins, Supplements and Herbal Remedies:
• Amanita species – wild mushrooms.
• Asafetida – plant, comes in powder, tablet or oil form.
• “Bush” Herbal teas
• Chaparral – The active ingredient of chaparral is a potent antioxidant.
• Comfrey - is an important herb in organic gardening, having many medicinal and fertiliser uses.
• Echinacea - The above ground parts of the plant and roots of echinacea are used fresh or dried to make teas squeezed (expressed) juice, extracts, or preparations for external use. There are 9 known species. Used in various herbal remedies.
• Gentian - their roots were harvested for the manufacture of tonic liquor, also used as flavouring, for example in ‘bitters’.
• Germander or Teucrium – has garlic like aroma, is a genus of perennial plants, of the family lamiageae, used as a herb.
• Iron - Patients with chronic liver disease tend to accumulate excessive iron amounts in their liver parenchyma. 30% of patients with liver disease have high serum iron levels and 10% have excessive amounts of iron in their liver tissue.
• Jin bu huan tablets - is a traditional Chinese herbal product used as a sedative and analgesic.
• Mistletoe - for treating circulatory and respiratory system problems, and cancer.
• Nicotinic acid (niacin; Nicolar) - is a form of vitamin B. Niacin is available over the counter as vitamin B3.
• Pennyroyal oil – Comes in oil form or tea. Can cause serious liver and kidney problems.
• Senna fruit extracts - is used as a laxative.
• Valerian - has uses in herbal medicine as a sedative.
• Vitamin A - Consuming less than 25,000 IU is recommended and most multivitamins contain 4,000 IU which is within safety range. If you are taking multi vitamins, vitamin A might already be included in this, make sure that you are under the recommended limit (Riley, 2001 – part 1).
I'll make the same comment regarding liver toxic medications in the "HippyGem" post above, as I did for the web site recently posted. In short, the list is incorrect and/or outdated.
Liver specialists routinely prescribe many of the drugs listed in the above post therefore the label of "toxic" is highly misleading. Almost any drug can be toxic when taken to excess, but many of the drugs are safe when used as prescribe.
Statins and ADs are widely prescribed for those with Hepatitis C both on and off treatment, just to mention two of the drugs on the "toxic" list. I would therefore disregard this list and speak to your doctor regarding rx drug choices.
Dr D tested me for insulin resistance. He felt, going back 3 years ago, that insulin resistance hindered the effectiveness of SOC. Does anyone know what the incidence of insulin resistance was in this study? Did people with no insulin resistance experience any benefit?
The study is still ongoing. So there's no SVR data yet.
Here's the link....
And the commentary from several docs.....
Use of Metformin Plus Peginterferon alfa-2a/Ribavirin Among Treatment-Naive Genotype 1 HCV-Infected Patients With Insulin Resistance.
Paul Martin, MD:
Romero-Gomez and colleagues previously reported that insulin resistance is a predictor of nonresponse to therapy in patients with chronic hepatitis C. Because of these results, there has been growing momentum to treat this aspect of liver disease as part of a strategy to improve sustained virologic response (SVR) rates in hepatitis C.
At EASL 2008, Romero-Gomez and colleagues assessed the impact of adding metformin to standard HCV therapy with peginterferon alfa-2a 180 µg/week plus weight-based ribavirin 1000-1200 mg/day on SVR rates in 125 genotype 1 HCV–infected patients with insulin resistance (Capsule Summary). A total of 61 participants received metformin and 64 patients received standard HCV therapy alone. Metformin was dosed at 425 mg 3 times daily for the first 4 weeks and then subsequently increased to 850 mg 3 times daily for the remaining 44 weeks. The Week 24 interim analysis was presented, with the reported endpoints being the decrease in HOMA index at Week 24 and undetectable HCV RNA rates at Week 4 (rapid virologic response [RVR]), Week 12 (complete early virologic response), and Week 24.
The results of the study indicated that the addition of metformin to peginterferon and ribavirin significantly decreased HOMA index at Week 24 and was associated with higher RVR rates vs placebo in these genotype 1 patients. The mean decrease in HOMA index at Week 24 was -1.60 and -0.87 among the metformin and control groups, respectively (P < .01). The RVR rate among the patients who received metformin vs the control group was 28% and 6.3%, respectively (P 2 (a typical threshold for inclusion in the definition of insulin resistance). Patients in the metformin group received a dose-escalation schedule, on which the first dose increase occurred at Week 4.
The observation that metformin was associated with an improved rate of RVR but had no impact on virologic response at the later time points after Week 4 may suggest that improving insulin sensitivity allows the intracellular immune system to clear the virus in a subset of patients over the short term, but without any long-term benefits, raising the suspicion that there may be extrahepatic reservoirs of infection that may explain relapse in some patients. An RVR is often used to predict future therapy success, and as new interventions that improve RVR are introduced, clinicians quickly add these changes to the standard of care. However, we must await the SVR data to determine whether this triple combination also improves SVR rates and therefore might change our practice.
Also of note was a significantly higher incidence of diarrhea among patients who received metformin vs those who received standard therapy (34.1% vs 11.4%, respectively; P < .05). Other agents, such as acarbose, an alpha-glucosidase inhibitor, can also change insulin sensitivity and induce diarrhea. Therefore, diarrhea is an undesirable consequence of triple therapy with metformin in hepatitis C patients.
when getting tested for pituitary disease the subject of oral insulins were brought up, should eith the HGH treatment or the Interferon tx cause my sugars to go any higher.
Metforim was specifically mentioned by name as being unsafe and toxic to the liver by my endocrinologist, and it was confirmed by my GP, and is again confirmed in the article above that trinity just posted.
I was told that injectable insulin is much safer for liver patients.
Remember that people are trying to reach SVR but also to avoid further fibrosis and scaring so as to not lose normal blood flow. Any drug labeled toxic to the liver means it promoted more scaring and leads to more decompensation.
Just today I was looking over a pubmed list of drugs that do severe liver damage INDEPENDANT of dosage, meaning even one or 2 doses does great damage.
The list is long and disturbing.
I'd want to weigh the odds long and hard, before adding anything toxic to the cocktail all treaters are already on. It only takes one straw to break an already loaded camels back and in reading the literature, SOC already has many right on that precipice.
"could cause liver failure" is already in the list of possible outcomes of SOC.
Ergo, and especially for stage 3-4 patients or those with NASH as well, I'd be sticking to the safest form of insulin, not one that may do more harm than good.
Just my opinion, not trying to ruffle feather here, but to inform.
"Over 4x as many RVR, but %s pull even in week 12, and almost identical week 24. So in this case RVR means ...? I wonder what the SVR #s are/will be."
I bet you 10 carrots that the SVR will be higher for the Metformin group and the relapse rate lower.
You see....when you become insensitive to insulin (insulin resistance), your pancreas works faster and makes more and more insulin. But since you're insensitive to it, your body can't use it. So you end up with way too much insulin (hyperinsulinemia).
And high amounts of insulin.....block the effect of interferon. If you can get rid of the insulin resistance....you'll get rid of the high levels of insulin.....and interferon treatment will work better.
Here's a study that showed that insulin blocks the effect of interferon.....
Insulin resistance and hepatitis C.
Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARgamma receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, INTERFERON ALPHA BLOCKS HCV REPLICATION. However, WHEN INSULIN (at doses of 128 microU/mL, similar that seen in the hyperinsulinemic state) WAS ADDED TO INTERFERON, THE ABILITY TO BLOCK HCV REPLICATION DISAPPEARED.
From Insulin resistance and hepatitis C
World J Gastroenterol 2006 November 28; 12(44): 7075-7080
Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American.
Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin.
Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA ≤ 2 than patients with HOMA > 2. The actual rate was
60.5% for HOMA-IR 4
In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fi brosis progression.
Assuming RVR is RVR no matter how you get there the study posted by CoWriter shows that reducing IR has improved the on Tx response for those with a HOMA-IR of 2-4. In other words it has made those that were likely to EVR become RVR and thus easier to treat.
It hasn’t done much for the rest because even thou their IR score has dropped,
they are still Insulin Resistant.
Conjecture I know but the relapse rates will be lower in the Metformin arm.
"when getting tested for pituitary disease the subject of oral insulins were brought up, should eith the HGH treatment or the Interferon tx cause my sugars to go any higher."
The are NO "oral insulins". Metformin is an insulin SENSITIZER, meaning that it decreases insulin resistance. It does not provide insulin nor does it stimulate the pancreas to produce more.
"Metforim was specifically mentioned by name as being unsafe and toxic to the liver by my endocrinologist, and it was confirmed by my GP, and is again confirmed in the article above that trinity just posted. "
Lactic acidosis is a rare complication that can occur due to Metformin accumulation in patients with impaired kidney function since Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Obviously, you wouldn't want to give Metformin to somebody who's decompensated or has significant impaired hepatic function (or patients taking HIVmeds that can cause lactic acidosis).
The risk is from lactic acidosis if you have advanced liver disease and can't clear lactate, NOT from Metformin causing liver failure.
Many diabetics have some kidney damage and liver disease (yes, diabetes is considered liver disease too and it can raise liver enzymes) and they use Metformin without going into liver failure.
"I was told that injectable insulin is much safer for liver patients.
Remember that people are trying to reach SVR but also to avoid further fibrosis and scaring so as to not lose normal blood flow."
You mean like the fibrosis and scarring caused by insulin resistance and hyperinsulinemia on Hep C patients? LOL
Sulfanylureas (like Glyburide) used to lower blood sugar ON DIABETICS, stimulate the pancreas to produce more insulin...so they make the pancreas/beta cells work harder. Using insulin doesn't do that. That's the advantage.
"Any drug labeled toxic to the liver means it promoted more scaring and leads to more decompensation."
Actually, Metformin prevents liver damage from bacterial endotoxins....
"could cause liver failure" is already in the list of possible outcomes of SOC."
Show me where it says that Metformin can cause liver failure.
"Ergo, and especially for stage 3-4 patients or those with NASH as well, I'd be sticking to the safest form of insulin, not one that may do more harm than good. "
ROFL....so what you're saying is that insulin is safer for people with Stage 3-4 or NASH? So you're going to give insulin to people who are NOT DIABETIC, huh? LOL
We're talking about people who are INSULIN RESISTANT only, not DIABETIC!!! They don't need insulin!! They have hyperinsulinemia, remember?
BTW....your doctors may not use Metformin for HCV and NASH but hepatologists do.....
Dr Kugelmas says....
"if the liver biopsy of a hepatitis C patient shows features of steatohepatitis, I do measure HOMA and try to sensitize the patient to insulin by weight loss through diet and exercise, AND CONSIDER USE OF METFORMIN."
I agree with Jim, many of the drugs on that list are now being used safely and may in fact be beneficial for the liver. For example, a new study showed that simvastatin (Zocor) significantly reduced portal hypertension and improved liver perfusion in only 30 days....and compared to beta-blockers, the side effects were minimal.
Since insulin resistance/hyperinsulinemia increase fibrosis, perhaps Metformin can be used on insulin resistant non-responders or those who choose not to treat to slow down the liver damage, don't you think?
It's fine...but I don't like using things I have to download.
"Why are people with hcv more prone to Ir ? "
Because the hepatitis C virus causes it. The virus infection causes the liver to disgorge large amounts of sugar. Microbes tend to feed on sugar and iron. It's a very smart virus. It knows what to do to survive.
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