Pretreating with Metformin Lowers Viral Load & Increases SVR

[CoWriter]

Pre-treating with Metformin or Avandia for 3 months before tx lowered IR and viral load and resulted in an EVR of 71%....and the patients were co-infected (more difficult to clear) and some non-responders.


(from AASLD meeting Nov 2008).....


"In Chronic Hepatitis C (HCV), Pretreatment with Thiazolidinediones (TZDs) or Metformin Decreases Insulin Resistance (IR) and HCV Viral Load and Increases Early Virologic Response (EVR)."

M. Adler, J.L. Matloff, A.S. Boxer, H. Han, M. Vachon, D.C. Carriero, D.T. Dieterich, , Mount Sinai School of Medicine, New York, NY; M. Vachon, D.C. Carriero, D.T. Dieterich, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY;

Background: Chronic HCV is associated with increased incidence of insulin resistance (IR), which leads to a lower rate of sustained virologic response (SVR) following treatment with peginterferon plus ribavirin (IFN + RBV). Romero-Gomez et al. reported an SVR rate of 32.8% in genotype 1-infected patients with IR (HOMA-IR > 2) compared to 60.5% in those without IR. In addition, IR is associated with increased liver fibrosis and is characterized by a higher viral load, two other independent risk factors for decreased response to treatment. A recent study showed 0/5 EVR in patients with IR who were given a TZD at initiation of IFN + RBV. It is unknown if therapeutic intervention to improve insulin sensitivity prior to anti-viral treatment increases response to HCV treatment. Aim: To evaluate the effect of treatment with TZDs or metformin on IR and viral load prior to IFN + RBV and the impact on EVR. Methods: IRB-approved, we retrospectively reviewed charts of patients with chronic HCV from a liver clinic in our center. We included patients with IR treated with either metformin or a TZD for at least 3 months prior to initiating IFN+RBV. We compared HOMA-IR, HCV viral load, liver enzymes and BMI at baseline, after treatment with an insulin sensitizer (IS), and at week 12 of HCV treatment. Results: 17 patients met inclusion criteria. 10 were co-infected with HIV. The average age was 52.2 years, and 82% of patients were genotype 1. 11 patients were treatment-naïve to IFN+RBV. The mean stage of fibrosis was 2.7 on Metavir score in 12 patients. 11 patients received a TZD and 6 received metformin. The mean HOMA-IR decreased from 7.99 to 6.06 after treatment with an IS to 4.60 at 12 weeks of IFN + RBV. There was a significant mean decrease of 0.52 log in HCV viral load on each patient after treatment with an IS (p<0.01). An EVR was achieved in 12 patients (71%). The mean ALT value decreased from 86.2 at baseline to 72.5 (p=0.02) after treatment with an IS to 34.1 IU/L (p=0.01) after 12 weeks of IFN + RBV. BMI significantly decreased from 27.9 to 26.8 kg/m2 (p=0.02) following treatment with an IS. Conclusion: The use of a TZD or metformin improved insulin sensitivity prior to treatment with IFN + RBV. The baseline viral load, a risk factor for decreased response to treatment and until now referred to as an unmodifiable factor, was also significantly lowered. This intervention allowed a 71% rate of EVR in a population of mono and co-infected patients, the majority being genotype 1. This small pilot study suggests that targeting insulin resistance prior to treatment may enhance the chance of response to traditional treatment for chronic HCV.

http://aasld.scientificposters.com/epsAbstract.cfm?id=3

[mikesimon]

I don't think that's likely to happen. Apparently it's outside Paloma's realm.
Mike

[CockSparrow]

I do whats your problem.
It might be an idea if you actually posted something worthwhile instead of snide remarks.

CS

[CoWriter]

It's important that you discuss this with your doctor.

Having a fasting blood sugar higher than 100 lowers SVR....  

http://www.natap.org/2008/HCV/031008_01.htm



In genotype 1, studies have shown that the more insulin resistant you are, the lower the SVR....( a HOMA test measures insulin resistance.  2 is normal)

HOMA less than 2....  SVR 60.5%
HOMA between 2 and 4..... SVR 40%
HOMA greater than 4..... SVR 20%

http://www.ncbi.nlm.nih.gov/pubmed/1713 ... d_RVDocSum



Insulin resistance (being insensitive to insulin) causes the pancreas to make extra insulin....so you end up with hyperinsulinemia.

And high levels of insulin make the interferon (which is used to treat Hep C) ineffective.



"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"

http://www.ncbi.nlm.nih.gov/pubmed/1713 ... d_RVDocSum



This is a great article that explains insulin resistance and non-response....just in case you have to convince your doctor.

http://scielo.isciii.es/scielo.php?pid=S1130-01082006000800006&script=sci_arttext


Best of luck to you with treatment.  Let me know if you need more data to show your doctor.  

Co

[CoWriter]

"(1) For those that just scanned the article, the heading may be misleading. The pretreatment with Metaforim only appears helpful with SVR if you have pre-existing insulin resistance. "

That's correct.  Metformin is only prescribed for people who are IR.


"(2) The first line treatment for insulin resistance is exercise and weight loss which the study did not test against. In other words, the same results -- or perhaps better -- might have been achieved with lifestyle changes versus more drugs."

Total number of patients was 17.......10 were co-infected (and co-infected pts have a lower SVR), 6 were none responders, and they started with a mean HOMA of  7.99 (normal is 2).  

I really doubt that lifestyle changes alone would have given them an EVR of 71%. Studies have shown that when co-infected patients have a HOMA greater than 2, none of them obtain RVR or EVR.  

They also take HIV meds that cause IR.  So even if they lost weight the meds can continue causing IR.
  


"(3) As this study (as well as previous) suggests, if you have IR then you should address this with your doctor. This issue hasn't been addressed properly in the past by many treating physicians even with older studies so there's no reason to believe your doctor will necessarily address it now. It's up to you to take the lead and bring this up."


Great advice.  Unfortunately, many doctors aren't listening.  Some don't believe IR is a factor, and others are checking fasting blood sugar only.  So people will have to educate those docs.  


"(4) To "Co" -- I've always suspected insulin resistance in my case do to a number of factors including "apple" fat distribution, low hdl, high triglicerides and sluggish reaction after high carb meals. My docs, on the other hand, always point to my glucose level (don't have it handy) and say everything is fine."

I'm hearing that alot.....which is silly.  If somebody's blood sugar was 126 (considered diabetes), we wouldn't need a test to tell us they're insulin resistant.  We would know they are.  

Some hypoglycemics are insulin resistant.  As a matter of fact, many doctors believe that the hypoglycemic of today, is the diabetic of tomorrow.  

When you first start becoming insensitive to insulin, the pancreas makes extra insulin and is able to keep your blood sugar within normal limits (and it may do so for a long time).  And sometimes it makes too much insulin......which results in hypoglycemia.  But that doesn't mean that they're not insulin resistant.


"What readily available tests you would you run (or ask your doctor to run)  in my position, starting with acceptable blood glucose levels."

A HOMA which is a formula that uses results of a fasting glucose and fasting insulin.   Or as Bill said, a glucose tolerance test.  

Co

[jmjm530]

I addressed some of your thoughts in my last post here:
http://www.medhelp.org/posts/show/677145?post_id=post_3673517

Because of some of the responses I've gotten, it might seem I don't adhere to the fact that IR can affect SVR. Quite the opposite. Truth is I (and others) have been recommending here for years that people get down to an ideal BMI prior to treatment and/or address fatty liver findings with diet and/or exercise as a first line treatment. I also understand that IR and fatty liver can be found in thin folks and that still needs to be treated as well. So again, no arguments, and I'm not against Metaformin or other drugs for IR --  I was just offering a first line approach -- weight loss and lifestyle changes -- as a first line treatment in a thread dealing with IR. Still not sure what the problem with that is.

Lastly, while your study states that IR usually disappears after SVR -- some of us have found the opposite, i.e. no metabolic syndrome prior to treatment but metabolic syndrome post treatment. The reason here is the interferon. Sometimes I think we Hep C folks don't catch a break because if the Hep C doesn't get you, then treatment often will!

-- Jim

[CoWriter]

"My point is, HCV IR from what the studies show, is caused by hep c on a cellular/virus level.

Many heppers with a great bmi and in good shape are still IR.
Doesn't take much, IR >2 HOMA2 is enough to make you resistant to tx.

In the studies, after having a SVR, IR usually disappears, and no more IR meds are needed.

I have read so many studies in the last months my eyes are red."
________________________________


I'm impressed.  Keep up the good work....and don't stop talking about it,  Because what you say may help others clear.

Co  




J Hepatol. 2008 Jan;48(1):28-34.

Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3.

Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, George J.
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, NSW, Australia; Digestive Disease Research Centre, Shartati Hospital, Medical Science/University of Tehran, Iran.

BACKGROUND/AIMS: Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS: Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS: The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8muU/ml vs. 22.2+/-4.9; P=0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P=0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P=0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P<0.001) and fibrosis stage (P<0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of <2 were 6.5 times more likely to achieve SVR than those with HOMA-IR2.

CONCLUSIONS: Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.


http://www.ncbi.nlm.nih.gov/pubmed/17977612?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[scratchinghead]

I like it when you guys talk.

[apache1]

I agree that proper bmi and exercise are good and very important.

My point is, HCV IR from what the studies show, is caused by hep c on a cellular/virus level.

Many heppers with a great bmi and in good shape are still IR.
Doesn't take much, IR >2 HOMA2 is enough to make you resistant to tx.

In the studies, after having a SVR, IR usually disappears, and no more IR meds are needed.

I have read so many studies in the last months my eyes are red. Have to start cataloging them for future reference. I am looking for the  IR g2, g3 study Co gave me in another post of hers. It explains it well.

apache

[jmjm530]

Bill,

Thx. I'll print this out and go over. Probably end up getting one of those glucose meters one day and experiment a little just. I don't plan on using it long term -- unless I find something wrong -- so hopefully the strip costs will be neglible. Problem is now I'm eating very well (low carb) so I will probably have to challenge my system with a few higher carb meals to see what is going on.

Apache,

Whether HCV may be a factor or not, lowering BMI through exercise and diet seems like a more reasonable first line approach than going right to drugs. There are already studies that show lower BMI is associated with SVR. There are also other health reasons to lose weight, exercise and eat well.

CS,

Thx. I did the serum insulin tests on my own and they were normal but I'll go back and check the values.

All,

Dieterich, our resident expert and one of the authors, has been testing for IR prior to treatment for years -- according to a previous post by Andiamo, one of his patients. I assume he is not alone in this among the top-line hepatologists. Another reason to seek out the best liver specialist you can reasonably find prior to treating. IR is just one example where top-line liver specialists are ahead of the treatment curve. Many liver specialists, including mine,  were  double-dosing, using sensitive week 4 tests and agressively intervening with helper drugs many years before the "definitive" studies came out and those concepts started to become the standard.

-- Jim

[CockSparrow]

Jim - My docs, on the other hand, always point to my glucose level (don't have it handy) and say everything is fine.

Thing is Jim that IR is not just Glucose, You need your insulin level as well.
If insulin is above half the ULN or even just below then you are likely IR, at least from a Tx perspective.

With both you can then calculate your HOMA-IR
Insulin x Glusose / 405 if Glucose is measured in mg/dL
Divide by 22.5 if glucose is measured in mmol/L

You may want to look into Leptin resistance as well

CS

[apache1]

From CoWriter's past posts on this subject, my understanding is HCV IR can be caused by the hep c virus.
If I understood CoWriter correctly, in many hep c infected people, its not the usual factors such bmi and lack of exercise, overweight, etc. altgough these factors might contributue to IR.

The real culprit is the virus causing the IR by some type of cellular viralogical response to hep c.
Geno 1 seem to be very prone to this type of Hcv  IR, iirr. This has been documented in studies, and posted here by CoWriter.

here is one of her post on it
http://www.medhelp.org/posts/show/632937

Also, iirr, if you do not get a test that states your HOMA2 # you have not been tested for IR correctly.
Remember this is not the typical IR seen in pre-diabetes or diabetes...it is hep c induced insulin resistance (IR)

Here is a homa2 calculator.
http://www.dtu.ox.ac.uk/index.php?maindoc=/homa/index.php

apache

[bajawoman]

here is my stats which prove I am insulin resistant this was not even questioned by my GI but I went and had the tests anyway
I would have not had this test if not for my continuing contact with people on this site  and now I am going to discuss it with my GI
HOW TO CALCULATE HOMA IR
Your fasting blood sugar is 103 GLUCOSE.  That means you're pre-diabetic.  A fatsing blood sugar higher than 100 lowers your chances of treatment success.

Your insulin is 12 and your fasting blood sugar is 103.

The formula to see whether you're insulin resistant (is called HOMA) .....you multiply the insulin x fasting blood sugar and divide them by 405.


http://www.musc.edu/dfm/RCMAR/InsulinSens.html


So 12 x 103 = 1236 divided by 405 = 3

Your HOMA is 3

A HOMA greater than 2 means that you're insulin resistant.....and insulin resistance lowers your chances of treatment success.

There's a band new study that showed that for females who were insulin resistant, taking Metformin 850mg 3 times a day increased the SVR to 57.7%  vs 28.6% without Metformin.

(Metformin is a medication that makes you more sensitive to insulin).
they have these drugs in Mexico  I am on a low carb low fat low calorie diet and am excercising I will begin the meds and wait three months and take the test again

[justme53]

I find this very interesting since I am pre-diabetic and pre tx.  They would bump me up to diabetes II if I test over 125 mg/dL x 2 (BG) . Last FBG was holding at 120.

[Bill1954]

Hi Jim, I almost forgot to mention ranges;

I believe you’ll be looking for *fasting* BG results from 70-99 mg/dL; fasting results of 100 to 125 might indicate impaired condition (pre-diabetes), and fasting >125 mg/dL can be indicative of frank diabetes. A good overview is available at:

http://www.labtestsonline.org/understanding/analytes/glucose/test.html

Be well—

Bill

[Bill1954]

Hi Jim,

I’m sure CO will elaborate further, but here are some suggestions to monitor IR:

A glucose tolerance test requires a *fasting* baseline blood glucose (BG) reading; then an oral glucose solution (hummingbird syrup, lol) is administered and BG levels are then rechecked at specified intervals to see how the body metabolizes ‘sugar’.

If a doctor suspects diabetes, a hemoglobin A1c test is usually ordered. This measures glycosolated (sp?) hemoglobin, or the amount of ‘sugar’ that coats a red blood cell during its assumed life span. This test “looks back” at blood glucose averages ~90 days, giving the clinician a good snapshot of the patient’s recent BG history. Again, this test is abbreviated as the ‘A1c’.

As you mentioned, blood glucose meters for home use are readily available at grocery stores, pharmacies, etc. Many brands are available; the meters themselves cost approximately $US 60.00-100.00, but that’s the cheap part :o). The long-term costs involved are the test strips, lancet points and control solution. It might be a good idea to check accessory costs prior to purchasing a meter.

A good rule of thumb is to check fasting BG in the morning, then again 2 hours after meals (post prandial). Many diabetics will test several times daily to get a good average; this will help make accurate changes in medication.

It might be difficult to find a doctor that will order in-depth tests if the patients random BB is normal in serial testing; somewhat analogous to a doctor ordering PCR testing for a patient that is HCV antibody negative :o).

Again, I’m certain CO will contribute additional info, and correct any misinformation I might have provided; this will give you something to noodle until she does.

Good luck, my friend, and take care—

Bill

[jmjm530]

Thanks for posting. A couple of thoughts.

(1) For those that just scanned the article, the heading may be misleading. The pretreatment with Metaforim only appears helpful with SVR if you have pre-existing insulin resistance.

(2) The first line treatment for insulin resistance is exercise and weight loss which the study did not test against. In other words, the same results -- or perhaps better -- might have been achieved with lifestyle changes versus more drugs.

And in fact, the conclusion seems to suggest this although not clear when it ends with the more general statement of "targeting insulin resistance" versus simply treating with Metaformim. This is consistent with previous studies that show things like fatty liver and high BMI as negative predictors of SVR.

(3) As this study (as well as previous) suggests, if you have IR then you should address this with your doctor. This issue hasn't been addressed properly in the past by many treating physicians even with older studies so there's no reason to believe your doctor will necessarily address it now. It's up to you to take the lead and bring this up.

(4) To "Co" -- I've always suspected insulin resistance in my case do to a number of factors including "apple" fat distribution, low hdl, high triglicerides and sluggish reaction after high carb meals. My docs, on the other hand, always point to my glucose level (don't have it handy) and say everything is fine.

What readily available tests you would you run (or ask your doctor to run)  in my position, starting with acceptable blood glucose levels. And which doctors specialize in this area. I've also heard some have bought one of the those finger stick, blood glucose monitors for self testing. Something like eat a high carb meal and then test after a certain amount of time. Any comments appreciated.

-- Jim

-- Jim