Drug Combo Linked to Increased Health Risks

According to an evaluation of multiple studies, taking a combination of two common types of Type 2 diabetes drugs may be linked to an increased risk of dying or ending up in the hospital due to cardiovascular disease.


The new study, published in the August issue of Diabetes Care, pooled data from nine large studies with more than 101,000 total participants with Type 2 diabetes. These participants had been treated with diet alone, metformin (Glucophage and other brand names), a sulfonylurea drug, or a combination of metformin and a sulfonylurea.

The researchers found that people who had been treated with metformin and a sulfonylurea had a significantly higher risk of dying or being hospitalized due to cardiovascular disease than any of the other groups.

However, people on the combination drug therapy did not have a higher risk of dying from cardiovascular disease or from any cause when risk of death was considered on its own. Only when risk of death was combined with risk of hospitalization did the researchers see a higher risk with combination drug therapy.

Trying to explain their findings, the researchers offered the following thoughts:

  • People who need combination therapy to control their blood glucose levels are likely to have more rapidly-progressing diabetes or have had diabetes for a longer period of time (or both); it may be the more advanced diabetes, rather than the treatment, that raises risks.
  • Weight gain (which is associated with sulfonylureas) may increase some risks, even when the drug is used in combination with metformin, which is not associated with weight gain.
  • Sulfonylureas can cause hypoglycemia, and using them in combination with metformin may make hypoglycemic episodes harder to recover from because metformin prevents the liver from making extra glucose. Hypoglycemia may increase cardiovascular risk.

An analysis of several observational studies like this one doesn’t carry as much weight as a full-scale clinical trial, and the researchers point out that its results should not be used as a basis for treatment decisions. Instead, they propose further studies in this area to determine the safest and most effective ways to manage diabetes.

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  • Bob Hawkinson

    It’s always hard to tell what to do. This kills you and that wipes out your heart, or this and that together destroy your blah blah blah…
    It seems that we must be ever on alert for negative impacts from the things we ingest…be it food or pharmacy..
    Keep going……Peace, Bob

  • CalgaryDiabetic

    Dear Tara. In my particular case I found sulfonylurea to be really bad stuff: causes low’s, makes you fat and contrary to insulin you have no control of blood sugar whatsoever. But I remember Pete’s wife who was very slightly diabetic did very well on it. Metformin is good stuff for most people but not for me. Still you wonder if it would be best to start insulin very early to preserve your own pancreas as long as possible.

  • pjnmickey

    Thanks, Ken, for pointing me in a possible direction. I have been taking metformin for several years. First in combination with Avandia, the glymepiride, then Byetta. I have the stomach disorder, Barrett’s Syndrome, so I am now off met and Byetta. But, I am also very fatigued, having memory problems and aches and pains. When I see the doctor tomorrow, I will ask him about this.

  • patricias

    Hello, I really am about over this medication stuff. It’s hard enough to worry about your diet, then you find out the medication you’re taking may cause a risk also. I’ve been on 3 different kinds of medication, by 2 different doctors. The first was metformin alone. It actually helped my sugar, A1c and my weight. I felt great. Within 6 months my A1c dropped to a 7 from an 11 But my doctor didn’t think it was working fast enough. Then she put me on avandamet. Gained back the 40lbs I had lost and became very depressed and tired all the time. I expressed my concerns and was asked if I wanted antidepressants. NO, I take enough stuff now. After chest pains started I dedcided I needed a new doctor. Now I take glucovance and januvia, my sugar has leveled and the pains have stopped, But what can you do to find what works for you without having to sample the whole market and risk heart health in the mean time. All these changes have happened in less then 3 years. Tired now!

  • L. Bright

    A diabetic for a decade, my new doctor took me off Metformin and Enalapril, telling me in combination they caused my kidney failure. Now I’m saddled with dialysis three times a week. He did not say which drug was to blame — just the combination.

  • Ken Buchmann

    Dear Tara: I took metformin for over ten years with relatively good results but then the blood glucose became more difficult to control and kidney function became affected and I am now vitamin b12 deficent. I am now taking glimepiride with good results also vitamin B12 injections which has made me feel as if I have found the
    “fountain-of-youth” Ken buchmann

  • Muzings

    Wow! I have been diagnosed with type 2 diabetes for over 1 1/2 years. I was on Avantia and switched to Actoplus Met after the “heart attack scare” I have been put on Lisonpril Simvastatin to protect my kidneys… I have managed to keep my A1C scores below 6.8 (from 12.4) … Now what?

  • Q

    The problem that everyone is citing here with drugs and side effects has a deep root in our health care system. Do you know that drug manufacturer companies pay doctors (GPs and specialists) to attend their seminars/conferences just to teach them how to prescribe? Do you know that we (scientists) are doing research more on drug discovery (creating drugs faster and faster) than on cell signaling/metabolic pathways (the actual communications among cells/organs/systems?) Do you know that Phase IIII of clinical trials is almost obsolete (virtual) and drugs enter the market after the Phase III? Do you know that on the FDA’s website there are drugs that are not approved by FDA yet they are available to the population in the market. No wonder that all of us (patients) are just laboratory rats/mice for the increasing failure and few successes of drugs!

  • clement shepard

    I have been on glipizide for over fifteen years up to about two years I was taken cozzar which I got off of when the bad new about it,now I am novolin70/30 and glipizide

  • Airborne Mom

    I took Metformin alone and while my A1C was always between 5.5 to 5.8 my family doctor felt I had good control just based upon my numbers. I would have several lows in between meals. Since I had been on Metformin for several years I went to an internist to get a second opinion regarding all my medications and he put me on a combo of Byetta and Actos. The new combination kept my sugar levels very consistent. We have recently located to a small town and I had to find a new doctor and she has diagnosed my chronic pain as fibromyalgia and I am on Lyrica, which states you should not take Actos. So I am now just using Byetta and watching my diet. As with any change I recorded my sugars several times a day to be sure that my numbers stayed in check. I have now lost a over 10 pounds, I have no ups and downs and the best thing is I am more active! I can actually move without pain and open food jars, I can tolerate long drives better. I have not felt this good in many years. It has only taken 10 years of misdiagnosis of osteo arthritis and depression along with taking the meds for those conditions that were incorrect. It makes me wonder if all the meds we take for conditions we don’t have that set us up later for additional complications. It is always a fine balancing act and a tough one to get control over. My last A1C was 5.7. At least now I feel like I am moving in the right direction.

  • Tara Dairman, Web Editor

    Hi everyone,

    Thanks to everyone for all the comments. As the blog entry states above, this study is preliminary and isn’t meant to be used as a basis for treatment decisions. So try not to be too alarmed. All drugs come with certain risks, and taking drugs in combination can compound risk; but not managing your blood glucose levels is also very risky.

    If you are concerned about the diabetes drugs you take, talk to your health-care provider about the risks and benefits of your regimen so that you can decide together what is best for you.

  • jomo64

    I started out taking just Metformin twice a day. But that wasn’t enough to contro my glucose levels so my doctor prescribed Byetta. I started out with the 5 pen and then went to the 10 pen. I take 2 shots a day along with 2 metformin a day and my levels have evened out considerably, mostly normal readings. I have lost over 20 pounds and feel great. The combination of the two drugs seem to work really well for me. As the Byetta pen is also a appetite suppressant, I don’t eat more than 3 meals per day and rarely snack in between. I’m loving it! I recommend Byetta to anyone with type 2.

  • Gloria

    Over a period of 34 years physicians have prescribed various drugs/exercise/diets. At this time my experience has been similar to “jomo64” above. Over the years I have experienced low levels, normal to high-normal levels. Nearly one and a half years ago the results moved to over 200, and on to 300. Combinations were tried and failed. At this time I use 750mg Metformin HCL ER tabs twice a day in addition to Byetta 5mcg pen injections twice a day. My weight started slowly going down, then I found that I wanted less food and have started closely watching what I eat. Since 9/07 I have now lost 36lbs. This is the first time in my adult life that I have consistently lost weight. My A1c was 5.6 at a Diabetes meeting this week.

  • ladybromel

    I was on metformin for 6 years along with glyburide and byetta. My creatine level went up to 1.7 and my doctor took me off of metformin. It was damaging my kidneys. It was the only med that was keeping my numbers down.
    Now I take glyburide, actos, byetta and lantus and my sugars are out of signt: anywhere from 200 to 4050. No matter what I eat, or exercise, I can no longer keep my numbers down.
    Along the way I read an article from Dr. Witticker and he says all diabetic meds are bad for us and do us more harm than good and the doctors know this and that all we need do is diet and exercise.
    I’m now so confused I don’t know where to turn to at all.

  • acampbell

    Hi ladybromel,
    I can understand your frustration, especially since you are taking several medications for your diabetes. A healthy eating plan and regular physical activity are, for most people, the first step in managing type 2 diabetes. While both can be very effective, there is usually a point at which diet and exercise alone just aren’t enough, and medication is needed. This is because type 2 diabetes is progressive. Over time,your beta cells in your pancreas can’t continue to produce enough insulin, and your body may not be able to use what insulin it does make all that effectively. Not all diabetes medicines work for everyone, and it often takes time and effort to find the right combination. The medicines that are available are very effective, however, and have enabled people with diabetes to live longer, healthier lives. I’d suggest talking with your physician, and perhaps suggesting that you work with an endocrinologist to help you get on the right medication regimen.

  • KT556

    I see a lot of info about metformin alone and in combination with other drugs — but no one has mentioned one of the really common daily side effects of metformin.

    That side effect being the constant, explosive diarrhea from which so many have suffered — and I do mean suffered.

    This in turn causes an artificial “starvation” reaction within the body — which in turn causes constant weight GAIN — an oxymoron if there ever was one.

    The “output” rapidly equals the “input” but the body believes it is starving because food does not stay in the system long enough to be processed for its nutritional values. OIY!

    Does anyone have a doctor who addressed this situation and found a solution?

    PS NO longer on Metformin.


  • annie

    I take a combination of glimepiride and metforbin,
    am I at risk of heart failure?