Diabetes Medication and Weight Gain

As we continue to study various diabetes medications and patient experiences, I am struck by the number of oral medications that cause weight gain. Patients reported weight gain with 12 of the 18 drugs we studied. And 6 drugs had weight gain incidences of 12.9% (Amaryl) to 31.5% (Actoplus Met). This means that of all of the reports of side effects, weight gain reports comprised 31.5% for Actoplus Met, for example.

Many type 2 patients are trying to lose weight. So the fact that their medication makes that close to impossible and actually has them gaining what could be significant amounts of weight is unacceptable to them.

However, many physicians seem to dismiss patient complaints of weight gain. And today I read an article that sparked this post. I was reviewing information about Takeda releasing new data this week to the FDA on their DPP IV inhibitor, alogliptin. Alogliptin and Actos+alogliptin were originally rejected by FDA because Takeda did not have enough cardiovascular safety data. Takeda is running more studies to specifically look at cardio issues, which is a good thing.

In my research, I found an article from 2010 where researchers favorable to the Actos+alogliptin combo stated that the greater the increase in weight a patient experienced, the greater the decrease in HbA1c. He therefore concluded that the weight gain was purely cosmetic and not a metabolic issue. This was a peer-reviewed article on the NIH website published in Vascular Health Risk Management. In our study, Actos had an incidence of weight gain of 22.5% with some patients report as gaining as much as 50-60 pounds in a manner of a few months.

Significant weight gain has to further stress the already stressed system of a patient with diabetes. More weight has to be a bigger problem that simply cosmetic.

So not only are patients faced with physicians who do not disclose the weigh gain potential of their medications but those evaluating new drugs may not take this side effect seriously. There are several studies that show that even a 5-10% reduction in weight, say 10 to 20 pounds in someone who weight 200, reduces blood glucose levels and reduces the need for medications.

Patients find weight gain caused by diabetes medication to be important and want physicians and researchers to feel the same way.

AZ & BMS's new diabetes drug, dapagliflozin, not approved by FDA

Two weeks ago, I wrote about AZ & BMS's new diabetes drug, dapaglifizon. Looking at the data, I had my concerns about the drug and its links to cancer, increased infections, and increased renal stress and liver stress.

The drug had it review on July 19. By 9 to 6 votes, the panel rejected the drug over liver and cancer concerns. This was to be the first drug in this new class of SGLT2 inhibitors that removes glucose by moving it through the kidneys and then through urine.

It will be interesting to see what happens with similar drugs from Lilly, J&J, Astellas and Boehringer Ingelheim. Will they have time to ensure they have different data? Can they have different data?

I have to say I was not excited about this new class when I first read about it. I understand it would be once a day dosing and doesn't seem to impede weight loss - these are big positive for patients especially the weight loss.

But the risks of some of the newest classes of drugs are high. And we have just begun to see problems with DPP IV's which I predict will increase.

The FDA may send dapagliflozin back for more trials. But for me, efficacy would have to be tremendous and physicians would have to really screen who gets the drug, for the risks to be worth it.

Proactive Product Safety and Efficacy Surveillance Through Observational Research

I just read an article in PharmaVoice on the value of proactive pharmacoviligance . It was dated February 2011; I'm a bit behind on my reading.

However, I couldn't agree more. Manufacturers need to study their products closely post commercialization in order to understand how those products perform once they are used outside of the clinical setting. It is unrealistic to assume that patients and physicians will always have the exact same experiences observed in clinical trials. The world outside of the clinical trial is filled with comordities, concomitant medication, variable adherence, and more. Post-marketing surveillance studies can also serve as a way to catch concerns and address them before they become real issues like lawsuits and loss of approval.

Manufacturers should also want to preserve their products for potential future indications and to ensure that the right patients get the right treatment. I expect executives to would want to know how physician and patient experiences are going to impact the company's bottom line.

Let's face it, all safety and efficacy issues bubble to the surface eventually. We assume that executives would want to proactively manage their portfolios not just because it is good patient care, but because it is good business too.

We spend a good deal of time analyzing patient and physician experiences with pharmaceutical products. We get a real look at how patients and physicians use drugs and devices in real-world settings. We see safety and efficacy issues that definitely can pose potential problems for brands and for companies. We see misunderstandings that offer companies the opportunity to fix things at the source.

When we did our 10-year retrospective study on Avandia, we learned that problems were evident as early as 2004. GSK would have had time to change their label and marketing, instruct physicians, and educate patients. Maybe then in 2008 lawsuits would not have been the recourse patients/caregivers felt that they had to take. Maybe it didn't have to cost GSK so much in legal fees and consumer trust.

When we studied Actos earlier this year, we learned that Takeda faces some real problems with Actos that could impact approvals for future indications. Bladder cancer, bone fractures, and cardiovascular risks are not going away. We believe that Takeda needs to address these risks now for both their current diabetes patients as well as for new trials in different disease states..

So why isn't pharma being more proactive in pharmacoviligance as well as efficacy studies?

We believe that observational research and surveillance studies need to start as soon as a drug or device is in market. It is not only in the best interest of the patient but it is also ultimately in the best interest of the company and the industry. The contributors to the article I read were mostly from non-manufacturers like we are at Wool Labs.

How do we get more of the manufacturers on board?

Too Many Diabetes Drugs Simultaneously and Drug Interactions

I have been working on the analysis of a new study we just completed focused on 18 oral diabetes medications.

Part of the analysis is looking at the medications that patients are taking and the potential impact on the performance of their diabetes drugs.

First, I am struck by the fact that many patients are on many drugs simultaneously. It seems that if one drug is not working, then they are prescribed another to add on top without any analysis of why that initial drug didn't produce the desired results. Yes, some patients are on a more obviously structured approach of shorter-acting combined with longer-acting products. Others, though, seem to have the kitchen sink thrown at them. This approach seems unique to diabetes type II. I can't say that I see this in anyother disease state; even cancer with its cocktails and combination therapy is quite disciplined.

Ok, so what are we seeing. First, patients get prescribed a drug at diagnosis, not uncommonly, Metformin. So patients' initial physical response is supposed to be (1) reduction in blood glucose, (2) reduction in hA1c, and/or (3) side effects or not. If the patient's numbers don't improve, I typically don't see evidence that the patient and the physician sit together and ask why. (We'll skip the fact that physicians tend to ignore patient complaints of side effects with Metformin and therefore, patients are not taking the drug as prescribed in many, many cases - which would be why).

What we do see is that patients will be prescribed another drug to put on top of Metformin, not always switched, just added to. And sometimes that happens again and again. Drugs don't always get removed from the regimen, just added to. And dosing schedules get complicated.

Each time a drug is added, several things can happen. First complicated regimens are hard for patients to keep up with. Second, these drugs can have interactions both with each other and with other non-diabetes drugs. Some diabetes drugs interfere with one another creating hypoglycemia and/or unstabled blood glucose numbers, which is maddening for patients who can't seem to get their numbers under control. Next, physicians see the lack of control and more often than not, blame the patient without always scrutinizing the whole process.

At some point, sometimes quite confusingly for patients, the drugs all get swamped out for a new set. Sometimes patients just start on one new drug. But the pattern starts again of adding but not subtracting until the next critical mass happens.

The pattern doesn't necessarily change if the patient starts on insulin. At first, insulin seemsused alone but that doesn't always last and oral meds are added back.

At the same time, patients are working changing their diet and exercise patterns, which also impacts drug performance at the original dosing regimen many times resulting in hypoglycemia. And with patients on multiple drugs at one time, the non-diabetes drug interactions grow - birth control and blood pressure meds, NSAIDS, thyroid drugs, some antibiotics, asthma meds - all increase risk for both hypoglycemia and hyperglycemia simultaneously. No wonder so many people can't get their numbers under control.

The whole process doesn't seem the best way to tackle what is called an epidemic. Many patients do figure it out with hard work and lots of research. But a lot more don't.

So more drugs on the market is not going to make this better. Diabetes needs a better approach that figures out why some medications work and others don't, how diet and exercise really impact medication needs, and how to reliably stop the advance of the disease. The kitchen sink approach is not a long-term strategy.

Our predictions for Actos are coming true and the future of the drug is at risk.

With the demise of Avandia, Actos is now the world's leading type II diabetes medication.

However, Actos has lost support just recently in France and Germany over bladder cancer concerns.

And new information on macular edema concerns add more risks. The US has increased warnings but has not moved to rescind approval.

In our March 2011 report, we made a few predictions about the future of Actos. The first prediction was that increased risk for bladder cancer, macular edema, bone fractures, and heart risks for younger patients would surface and cause problems for the brand, including its removal from the market. The removal has started in the EU.

The second prediction was that any further movement to restrict or rescrind support for Avandia would also cause problems for Actos since we do not believe the brand is strong enough to be the last TZD standing. The FDA is removing Avandia from US retail availability in November of this year. Therefore, we see even more increased scrutiny of Actos as the brand had never really been able to separate itself completely from comparisons to Avandia.

Now Actos goes off patent at the end of this year but Takeda needs Actos to survive well past patent expiration. Takeda has Actos in clinical trials for future indications including MS. So, if the product gets pulled completely, it will not be able to expand.

But patients with MS as well as other autoimmune diseases that Takeda is eyeing for Actos are at risk for bone fractures. So our third prediction is that if increases in bone fractures surface in enough numbers to catch the FDA's attention, it could end future trials and indications. Also MS patients are younger (the average age of diagnosis is 33). We may seen increases in heart-related problems in MS trials with Actos further complicating things.

Actos is a huge part of the Takeda portfolio and revenue. It's future seems at risk and those risks have accumulated quickly in the last 6 months or so. So does Actos in jeopardy mean Takeda is in jeopardy too?

Why are there differences in FDA and EU regulatory viewpoints?

Last week the FDA reviewed and rescinded support for Avastin for breast cancer. At the same time, the EU regulators expanded support by approving Avastin's use first line with the chemotherapy agent Xeloda. Interestingly, there are quite few US patients on this same combination who report success.

In June of this year, France and Germany rescinded support for Actos and the EU version of Actoplus Met based on the reports of increased risk for bladder cancer. The US regulators added a warning for increased risk for bladder cancer for those taking Actos, Actoplus Met and Duetact for more than 1 year. But the FDA has not moved to rescind support of Actos or its combos here in the US, yet. That might change now that the ADA reported in San Diego last week that Actos and Avandia both show an increased occurance of macular edema.

And the EU pulled Avandia while the FDA restricted its use but did not ban it.

J&J's blood thinner Xarelto just won FDA approval in a pretty long battle while the drug has been used in the EU since 2008.

There are plenty more differences in both biologics and devices. In our data, we see patients experiencing the same benefits and concerns regardless of geography. Patients stories paint a more global viewpoint than it seems the regulators do and are typically confused as to why a drug is banned on one continent but available in another.

I certainly want the FDA to take its time and use solid data when they approve or ban products but it seems that perhaps data, experiences, and criteria could be shared more across regulatory bodies. The manufacturers are global as are patient experiences.






So, why do these regulators differ.

Is the new diabetes drug Dapagliflozon safe and effective?

On June 24, 2011, Bloomberg reports that the BMS and AZ diabetes drug, dapagliflozon, is safe and effective based on a study comparing the drug with metformin against metformin+glipizide. The article did acknowledge that dapagliflozon was associated with more urinary and genital infections.

On June 27, 2011, Yahoo health reports that dapagliflozon is effective but in addition to patients having more infections, it seems that an increase in bladder and breast cancer may also be associated with the drug.

Dapagliflozon is in a new class of drugs that blocks glucose from being absorbed into the bloodstream through the kidneys and allowing more sugar to be released in the urine. Therefore, sugar spends more time in the urinary tract, which could explain the increases in infections as bacteria would have more time to grow. Diabetes patients are already at increased risks for these types of infections so this drug increases that risk even more.

However, cancer increases should be met with some concern. Actos is also being linked to increases in bladder cancer by those who take it more than a year. Januvia and other DPP-IV drugs are linked to suppressing the body's able to fight cancer. As most patients diagnosed with diabetes remain on some medication for perhaps the rest of their lives, the increased cancer risks are serious.

And the label will already carry the risk for renal impairment or failure which would make sense as the kidneys would have to work harder on this drug.

That is not to say that the drug doesn't do some good things. It can lower blood pressure and seems to help patients make it easier to lose weight. Patients only need to take it once a day. These are real positives.

Lilly, J&J, Boehringer Ingelheim, and Astellas are all developing drugs in this new class. So, the risk-benefit profile needs to be carefully watched. If in a two year study the cancer and infection rates are already significant, what happens after 10 years.

The Bloomberg article reports that physicians will begin using the drug immediately upon approval. The FDA is scheduled their review for July 19.

If I were a patient and I looked at this data, I'm not sure I would be ready to take it so fast.

It is rare in the data we have (and we have an enormouse amount of diabetes data), do I see phyicians and patients talking about that patient's personal risks before taking a drug. So for example, for dapagliflozon, I would think it wise to find out if the patient already had frequent URI or genital infections, compromised kidneys and/or if there is a family history of certain cancers. To me, immediately if any of these things were true, then the patient would not be a candidate for this drug or any in its class. That way, perhaps this drug can be useful and valuable while mitigating the risks in the wrong patients.

However, since we do not see this happening much today, I am not convinced it will happen with this drug either. Therefore, my prediction is that is the FDA approves the drug, we will see serious problems reported by patients within 2 or 3 years post approval that perhaps could have been avoided.