Start With Three Drugs?

A new study says that people newly diagnosed with Type 2 can do better if they are immediately started on a three-drug combo. Does this make sense to you? Is it good science or bad medicine?


Muhammad A. Abdul-Ghani, MD, from the University of Texas Health Science Center at San Antonio, presented the findings at the ADA Scientific Sessions in Chicago. The study enrolled 155 people with Type 2 diabetes. The average time after diabetes diagnosis was five months. None of them were taking diabetes medications at the beginning of the trial. Their average HbA1c was 8.6%.

Half the subjects got “conventional therapy.” They were started on metformin. If their fasting plasma glucose (FPG) went above 100 or their A1C went above 6.5%, they were given glyburide. That’s a sulfonylurea, a drug that pushes the pancreas to produce more insulin. Over a three-month period, if FPG or A1C crept up anyway, a basal insulin was added.

The other group started three drugs (“triple therapy”) right away. The drugs used were metformin, pioglitazone (brand name Actos), and exenatide (Byetta).

Subjects were seen in the clinic every three months, where their FPG, A1C, weight, and home glucose monitoring logs were recorded. Medications could be adjusted down for blood glucose levels of less than 60 mg in a day or symptoms of hypoglycemia (low blood glucose).

On the triple therapy drugs, most people were able to attain an average A1C of 6% and keep it there for two years or more. People in the conventional therapy were averaging an A1C of 6.6% after two years.

There were other advantages to the multi-drug approach. People receiving triple therapy lost an average of 2.6 pounds of weight, while those receiving conventional therapy gained weight. Hypoglycemia occurred in 46% of those in conventional treatment compared with 15% in triple therapy.

Dr. Abdul-Ghani hopes that a larger study might show a lower risk of microvascular complications in people on triple therapy. If it does, he said, starting those who are newly diagnosed on multiple drugs could become the new standard of practice.

Many experts find this report exciting news. Quoted on the Web site Diabetes in Control, Carol Wysham, MD, clinical associate professor of medicine at the University of Washington School of Medicine, Seattle, stated, “I’m very excited by this, by any concept that will help to spare beta cells and…will keep patients stable for longer.”

I’m not as enthusiastic. The long-term negative effects of triple therapy cannot be known yet. Actos has already been shown to increase the risk of heart failure.

Indeed, edema (swelling, often a sign of heart or kidney failure) has already occurred in 5.3% of the triple-therapy group in the first two years. Gastrointestinal side effects such as diarrhea occurred in 33% of the triple therapy group, compared to 21% in the conventional group.

I also wonder how researchers can know that starting three drugs at once made the A1C difference. They weren’t the same drugs the conventional group got. Of course the people receiving glyburide and insulin would get more hypoglycemia. Of course they gained weight. That’s what those drugs do. Of course people on Byetta would have slightly lower A1C levels. It’s just a better drug. That doesn’t mean people necessarily needed metformin, Actos, and Byetta all at once.

It also remains to be seen if lowering A1C through drugs makes a difference in people’s overall long-term health. It may just be improving lab numbers. We won’t know for years if this therapy makes a difference in rates of complications or death.

Radical change
Giving newly diagnosed people three drugs would certainly be a radical change. Current practice is usually to try diet and lifestyle before drugs, or sometimes diet and exercise after immediate short-term treatment to get a high A1C down.

If diet and exercise “don’t work,” defined as keeping the A1C below some number, usually 7% or 6.5% depending on the doctor, people usually are given metformin. Typically, that “works” for a while. When it no longer does, when numbers move up, this is called “treatment failure.” Doctors may add a sulfonylurea drug like glyburide, or some other pill, or insulin.

Some diabetes specialists have long been unhappy with this approach. Dr. Ralph De Fronzo, lead author on the Texas study, uses the analogy of breast cancer. Doctors don’t treat cancer with one drug and wait for it to fail, and then try something else. Diabetes should also be treated more aggressively, in his opinion.

But aggressive drug therapy can bring up another problem: People taking multiple drugs might be less likely to take life changes seriously. Some recommended diets may not be healthy for people with diabetes. And even if they are, people may not stay with them for various reasons. That’s why treatment “fails.”

If people receive more support in finding and maintaining the foods and physical activity (and sometimes medications, and sometimes relaxation) that are right for them, their diabetes can stabilize and even improve dramatically (see below). On the other hand, if they don’t eat foods that work for them, it’s doubtful that even three good drugs will make much long-term difference.

My new book, cowritten with Jim Healthy is out. Diabetes Heroes is about ordinary people reversing their Type 2 diabetes. (“Reverse” doesn’t mean cure, but it does mean being off medications with normal numbers.) A lot of inspiring stories like the ones we read here all the time.

You can get a free copy and see a moving video interview with one of the “heroes” here.

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33 thoughts on “Start With Three Drugs?

  1. I think it’s a lousy idea for everyone but the drug manufacturers.
    I started out on diet and exercise and was successful for years. Then I went on metformin and as long as I eat right, I have good numbers. The other drugs have a boatload of side effects, and with allergies to other drugs I couldn’t take any of them anyway. My husband was doing well on metformin until his kidneys were damaged by Celebrex; since then he’s been on a succession of drugs, being taken off Actos because of the bladder cancer risk.

  2. Interesting comments. From the cheap seats, my sense on type 2 diabetes is generally medical science is currently trapped on a mix of Type 1 thinking and a view that type 2 diabetes is a single orthagonal disease all trapped around the pancreas and insulin.

    Current thinking does not display any clue about glucose flow control from blood stream forward to the fat and skeletal cells and what happens when the muscle/fat cells get loaded.

    next, the system is a complex chemical plant, multi organ, multi hormone involving stomach, intestines, liver, kidneys, thyroid, gall bladder et all. The sooner we stop the search for the unified field theory and holy grail answers and research properly how the whole system interacts/works and how it stumbles, the sooner we can resolve the problems and tune it rationally.

  3. My personal opinion is the sooner type 2’s start on insulin once diet and exercise can’t manage and metformin can’t manage the diabetes, the better everyone will be. The side effects of the rest of the diabetes medications tend to do more harm than good.

    Being diagnosed late prevented me from being on the oral medications for any period of time and I was moved to insulin and haven’t looked back. I am happy for those that are able to manage with diet and exercise and I encourage them to go this route as long as they are able.

  4. Deb:

    Excellent feedback and comments. Am on metformin, small amounts of insulin and 1200 calorie diet and 1.5 to 2 miles walking and getting good numbers.

    Off actos – that i sreal pain as my kidneys were going down hill till I got off it.

    Glyburide, glimperide, starlix et all royal pain and off that stuff.

    Best wishes and thank you for sharing!

  5. Actos was worst drug I was ever given.. it caused extreme weight gain, fat pockets all over, shortness of breath, tiredness, and other side effects..There a is a great website where folks talk about their neg. experiences with this drug…very bad for many…others say it works great for them

    Some other drugs cause bottoming out too easily..Have been happy with metformin so far along with Onglyza..

    I am not a med professional but it appears that if meds are needed in addition to dietary vigilance & excercise, each person is diff so treatments should be customized.

  6. I took Byetta for a few years and it almost killed me. Luckily I stopped it before my Pancreas got too bad. I thought it was a wonder drug, lost weight, lowered my blood sugar, but almost losing my life over it wasn’t worth it.
    Trying the Metformin first I think is still the way to go and add more as it’s needed.

  7. Let’s see…Actos…banned in France and Germany…hmmmm… It seems to me all we have here is insufficient research, denial, and a possibility of more profits for Big Pharma.

    It’s a shabby and slipshod approach to treatment (you’re right: we don’t do this with cancer) and it may also be missing many diagnoses of LADA–my variety of diabetes–in supposed type twos because the physician is playing around with new drug “ideas” instead of testing antibodies.

    The gold standard for me (and I admit it’s still an imperfect one) is a low-carb diet, physical activity, frequent testing, insulin, and a bit of old tried-and-true Metformin. The latter, of course, isn’t making any money for the drug companies any more: so I’m sure the “three-drug-therapy” suits them to a t.

    How about putting research money into finding ways to understand, prevent, and cure, diabetes instead of funding new drugs?

    Oh. I forgot. That wouldn’t increase any corporate bottom lines, would it?

  8. My clinic has flat out stopped prescribing Actos even though my insurance company recommends it.

    I’ve been doing very well with the combo of Metformin and Bydurion (once a week Byetta.) I’m one of those people who digests food extremely fast, resulting in glucose spikes. Bydureon has helped a lot with this, but now I have to stop taking it. The insurance will no longer cover it, saying I need to switch to (you guessed it) Actos, which doesn’t even follow the same mechanism.

  9. I am on Metformin, Byetta and Lantus. I started this program last Nov. 2012 and I have loss 33 lbs and my A1C is 6.4 right now. I feel good and am hoping to lose about 20 more lbs. I Live in Atlanta and my Doctor put me on this program out of WASHINGTON DC. If we are doing what we need to do to stay healthy I am hopeful we can have a long life.

    Best Regards to all

  10. My concern is taking all these drugs could damage your pancreas. It seems like pancreatic cancer is increasing . I don’t know what causes it but what do all of you think???

  11. I find, as a type 2 diabetic, that diet is important, but just a small part of the problem. My numbers are the highest upon rising in the morning. I haven’t eaten all night obviously, so why is this happening. No one seems to have an answer. Controlling blood sugar levels 24 hours a day seems to be impossible, at lest for me.

    I take metformin,2000, plus glimepiride 2mg

  12. I have not taken any medication for diabetes and have always maintained an A1C below 7.0, and have no diabetic retinopathy or neuropathy. Several months ago, I started taking vitamin D, 2000 mg twice a day and have noted a huge improvement in my fasting levels. I’m due for another A1C in three months, and I’m eager to see the results.
    I avoid drugs because I’ve had bad experiences with various prescription medication and I’m allergic to aspirin and other meds using similar ingredients, so I prefer to try a natural method first.

  13. Interesting information but I don’t see any comments regarding compliance with the treatment for either group. I would think the average person would really be hesitant to start 3 new medications and many would have trouble with paying for 3 new medications even with insurance. Many peoplefind it difficult to adjust to taking even one new medication and it’s side effects. I would certainly think the compliance with starting 3 at once would be poor. There are so many side effects! All of them seem to make you more hungry too. I strongly believe that once I started insulin I was in trouble- really gained weight rapidly and had no control of my appetite.

  14. I have used all three of the drugs in this article have had very little effect. Started on exenatide in Sept after it was released in June.
    Did okay but stayed sick all the time. Saw a specialist and was put on Victoza for 28 days prior to being placed in hospital with pancreatis. Now on insulin only. Doing okay not great. But think this is due to not exercising as I should.

  15. I am currently on metformin, glyburide and Victoza. I do experience occasional episodes of low blood sugar, but the Victoza really helps to control and balance my blood sugar. Ideally I would like to just be able to control my blood sugar with diet, (low glycemic, low-carb) works best for me. However, at this point in my life I would just like to take less medications and still lose the excess weight. I started out with just the metformin, but slowly had to add the others because just the one didn’t work. Would I have done better if I had started on 3 meds? Who knows.

  16. It is a no brainer that Byetta is a superb injectable incretin mimetics, and it works beautifully. However, are the researchers aware of the pricing of this class of treatment alternative?? It is really out of reach and most of insurance companies discourage patients from using. If it ever gets covered, patients may higher prescription copay. If the big pharma comapanies can lower the profit margin and make the pricing affordable, trust me, many patients will get prescribed with that. Also in my experience, more dramatic A1c decrease comes with the combined use of some type of insulin and the incretin mimetics. Research is research, but the research findings cannot be translated to the real world practice, particularly in light of many working poor diabetic folks who can barely afford their generic medications. CP

  17. Because I was in my 50’s when first diagnosed, I was diagnosed as Type 2. Diet and exercise didn’t work. Then I tried metformin to no effect. I tested negative for anti-bodies so they increased the metformin. The doctor finally decided I have LADA with no anti-bodies and started me on insulin. What a difference! If they had put me on a 3 drug combo, who knows what it would have done to me since I don’t have Type 2 after all. I also think the diet and exercise program at the beginning was good to get me in the right frame of mind on carb counting and the huge benefits of regular exercise. I did spend too much time trying different doses of metformin and wish I had been put on insulin sooner.

  18. This is a comment for Christine V. whose glucose is highest in the morning. Ask your MD about the “Dawn” effect. Carol

  19. I have had type 2 diabetes for about 12 years. I I have gone through the actos and glyburide routine for periods and decided that with the poor info coming out about Actos, I decided on my own to use only glyburide. My A1c at the time was 5.2. Go figure. It is obvious that each case is different. The only major side effect I have id peripheral neuropathy. I don’t ever read anything meaningful about what to do about that particular aspect of diabetes. Two Drs. have said there is nothing can be done about it

  20. Carol, What will the dr. tell you about Dawn effect? I have it and there is nothing the dr. could tell me that has changed anything. At least he knows that I believe Lipitor caused my
    diabetes, and I told him before the FDA made the
    drug companies list it as a side effect.

  21. Interesting…
    START treatment with THREE drugs…

    Well, the drug companies have found another way to clear their inventories and make a profit! Most doctors are well meaning but some don’t have a clue as to how to help us diabetics! This recommendation gives them “green” light for potential over-medication. They would have to increase their follow-up care to make sure there are no detrimental effects…ah! More co-pays…
    Have your doctor check your insulin levels, not just your glucose levels. If your levels are low or non-existent, then it makes sense to start insulin.
    But,if your insulin levels are O.K., I found great results from restricting carbs, especially avoiding high fructose corn syrup, getting plenty of rest, exercising regularly, drinking plenty of fluids–not sodas or diet sodas–and eating a low glycemic diet–the internet has many lists you can refer to. The point is to try not to “overwhelm” the insulin you are still making or “increase” the need for insulin in the first place. This has worked wonders for me as I am no longer on any medications…used to be on Januvia and metformin. My last A1c was 5.8.
    This approach may not work for everyone, but it’s worth a try. It does take commitment…at first you need to test your BG often to find out what causes your BG to spike after meals…then eliminate these from your diet. Then, if your BG is still too high, add metformin (which addresses insulin resistance) at the lowest amount that works and if you can tolerate it.
    These other drugs mentioned increase your insulin by squeezing it out of your poor pancreas and adding even more insulin to your system that may already be loaded with insulin it can’t use…they can cause weight gain. Just what a diabetic needs!!! They also expose you to pancreatitis and pancreatic cancer. Eventually, the pancreas will wear out and you will then need to go on insulin.
    This search for a “one size fits all” approach by researchers is wrong headed and simplistic and a disservice to us diabetics. I am very grateful to this blog that shares ideas so that we can learn from each other. Ultimately, we are in charge of our own destinies…not the doctors, researchers, or the drug companies.

  22. I must say, that all of this pushing of MD’s (more drugs) is just incredulous to say the least. My mother was a T2 diabetic back in the day when there was not much ‘other’ known about it except as ‘sugar’. Now with advances in the great pool of knowledge, I cannot fathom the reason ANY full life loving individual would allow their doctor ‘know all about it’ prescribe any drugs while conscious!

    There are other ways to beat this and turn it back, it does require some discipline, forward thinking, and most importantly, support! You want to know what that is???? Diet and exercise… I fought it for over 15 years and now have accepted that I must take this as the basis of helping myself and not take drugs. We all, at some point, were/are looking for that magic bullet and it was in our mouths all the while, for the most part. All I can add is, my running average fasting bgs’ was 256 with A1C’s at 13.2%.. I go for follow up testing in four (4) weeks to find out if, in fact, my lifestyle change has lowered all these numbers. I urge you to consider it, your health and health care depends on it, as your family depends on you..

  23. I was diagnosed with type 2 in 2005. started taking 500mg of metformin 2 times a day I lost 75 lbs. the first year. My A1C has been between 5.5 to 6.0 ever since. I have been very satisfied with the results of this medicine and hope the same dose continues to work.

  24. Any time you treat people like herd animals, there is a problem. No two people are alike, so how can you just prescribe 3 medications for everyone and have it work? I was on metformin and actos along with a couple of other drugs. My iron got so low that I had to have a blood transfusion and then iron infusions. It was a very scary time. They were sure I had a bleed somewhere, but when I went through all the tests, it showed nothing. Them my Diabetes Self-Management magazine arrived with an article about iron and the metformin connection. I immediately decided to get off metformin. I went on the Nutri System D diet and lost 37 pounds. My last Ferrin level was 120 and I haven’t had an infusion in a year and a half! I’m off the metformin, actos and one of my blood pressure meds! My AIC is 6.7 and I’m feeling so much better. I think the 3 drug regimen is a recipe for disaster in the long term. We are not herd animals, we are human beings and doctors are not always right.

  25. An interesting study. I have been a diabetic
    for 38 years. I was started on glyburide and twenty years later I started to take insulin. currently I take two insulins per day. Thirty
    units of Lantus and a sliding scaled of 8 to
    20 units of Humalog. My A1C averages 6.5 to
    7.0. Exercise is important and a good diet
    us also important. I have been trained in
    nutrition and I attribute my success to the
    knowledge I have of what to eat to be healthy.
    The only health problem I have had is a stent
    in my left coronary artery about seven years
    ago. I just had a stress test and passed it and the nuclear test showed no problems with the

  26. How come nobody mention supplements instead of meds? Supplements such as Berberine, Cinnamin,
    Alpha Lipoic, Carnitine along with diet and exercise do wonders without the numerous side effects from multiple medications. Has hekped me greatly with my sugar numbers.

  27. comment about supplements is most interesting.

    I offer they help but do not see them as replacement for meds like metformin and insulin.

  28. I’ve experimented with a variety of supplements. Some help. None are as effective as prescriptions, all of them have their own side effects.

    And some that are imported from foreign countries actually contain prescription ingredients without properly acknowledging them on the label. For examplem Diexi, imported from India and sold as a “natural formula” contains Metformin.

  29. I have been a type 2 diabetic since 1991. I have been through every pill on the market and the results were minimal. I have been diagnosed as insulin resistant so I have been put on Lantus Solostar and Novolog Flexpen. Because I have high sugar count in the morning, I find that I must split my Lantus by taking half at night before bed and the balance after breakfast. Novolog must be adjusted to each meal or your insulin will be either too high or too low. Eat a healthy diet but adjust the amount of insulin based on the portion size.
    I have been able to reduce by insulin injections by 50 % by taking a drink imported from India called Amla (aka Gooseberry) I take one cap in the morning on an empty stomach and one cap in the evening one hour after my dinner. I also take a supplement called Salacia Oblonga daily.
    The biggest problem with diabetics is weight. The prescription pills and any insulin injections will always result in weight gain-sometimes as much as 30(thirty) pounds! I implore you to read and buy a book written by William Davis, MD entitled “Wheat Belly” I, personally, followed his suggestions and have lost 22 pounds since October 2012. It is not a diet. You won’t be able to put the book down util it’s finished!

  30. I have eaten what I thought was a healthy diet for years. After reading this blog decided to cut out most of the carbs in my diet and exercise more. Before cutting down on the carbs I did not want to more anymore than I had to.
    In order to change my diet I thought about what tastes and textures I like to eat, with a balance of fruit (berries)vegetables and protein. I am so happy with what I eat, I don’t feel hungry like I have on diets. Better still I have lost almost 20lbs (for someone who is 4’11”) that is a good amount and my A1C has gone from 7.2 to 6.2. I really enjoy exercising now I feel that I will be able to get off more of my medications. I am no longer taking Januvia and have been able to drop 5 units of my once a day insulin. I am still taking Metformin, but am thinking I will be able to decrease or stop that as well.
    I am thankful for drugs but know that if I can control this with food and exercise it will be much better. Thanks to all who share.

  31. My daughter has had diabetes Type 1 for 21 years, grandson is 4 and had it since 4 months old. I got diabetes 8 years ago. I had a 7 a1c when I started with metformin. I soon discovered I could not control it with that alone, …so I asked to go on insulin. I began a vegan diet and dropped to an a1c of 6.0. Then I went on Dr Richard Bernstein’s diet of low carbs, …6 carbs morning, ..12 at lunch, 12 at dinner. I am not in the ballpark Bernstein wants me to be, …I have an a1c of 5.4 now. I have easily adopted the lifestyle!!! Small doses of insulin, with small amounts of carbs means less lows, ….and good numbers. No doctor has yet suggested low carbs like Bernstein. I think the profession is out for money …and Bernstein is 79 years old, ….a Type 1 diabetic, …with an a1c of 4.8 and wonderful numbers for cholesterol etc. We are carb intolerant…period. And there are wonderful substitutes for potatoes, rice and noodles, ….Read Dana Carpendar’s 500 Low Carb Recipes to find out.

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