Combination therapy, in which doctors prescribe more than one drug to treat type 2 diabetes, is a fairly common practice. However, most newly diagnosed type 2 patients start off with metformin or a sulfonylurea and don’t go on a two-drug therapy until their first drug begins to lose its effectiveness. But combination therapy could soon become an earlier option for people with type 2.
Merck reports that Janumet, a combination of metformin and the company’s DPP-4 inhibitor, Januvia. has had substantial success in lowering A1Cs in clinical trials of type 2s who were just starting treatment. At the recent ADA conference in San Diego, I spoke about Janumet and combination therapy with Sethu K. Reddy, MD, the Philadelphia-based Vice President of US Medical Affairs for Merck and the former Chairman of Endocrinology, Diabetes and Metabolism, at Cleveland Clinic in Ohio.
Nadia: You’ve released a study that found Janumet, a combination of metformin and Januvia, better at achieving blood glucose control than metformin alone in people with type 2 diabetes.
Dr. Reddy: So many type 2 patients in the US still are not at the A1C targets recommended by the American Diabetes Association or the American Association of Clinical Endocrinologists. So we think Janumet is how can we get more patients to achieve their A1C targets and make it easier for physicians to help them get there. We studied more than 1,000 patients with poorly controlled diabetes. Their A1Cs averaged around 9.8 or 9.9%. We know that when most doctors see patients with levels like that, their first instinct is to prescribe insulin. Our question was whether prescribing a combination therapy right from the start would work better than a standard metformin-alone therapy, as well as delay any resort to insulin.
Nadia: How long was the study?
Dr. Reddy: Eighteen weeks. By the end, more people got to the target with Janumet compared to metformin alone. Forty-six percent got to the ADA target of a 7% A1C using Janumet, compared to 23 percent using metformin alone. Tolerability for the Janumet was the same as for metformin alone.
Nadia: What motivated Merck to test this combination?
Dr. Reddy: We in the diabetes field have been slower to adopt early combination therapy than our friends in cardiology or hypertension treatment. For example, blood pressure specialists often put people on two blood pressure medications simultaneously. Once they know what patients’ baseline blood pressure is, they can predict which ones will need two medications. Similarly, based on baseline hemoglobin A1C, we can make an educated guess that some patients will do better on early combination therapy. This is based on the principle of treating success rather than failure. The old approach has been to start a patient on a single drug, wait until it’s no longer effective, and then think about adding the next drug. What we’re doing is starting the patient right away on combination therapy with the goal of achieving quick control and getting that A1C down-and then, hopefully, keeping it down.
Nadia: Often when patients start on a type 2 medication and it doesn’t work, their physicians put them on insulin. But many people are fearful of injecting, so it seems that your combination therapy would be very attractive to them. And because the drugs are already combined, the patients wouldn’t have to remember to take one and then the other.
Dr. Reddy: We’re pretty hopeful that a patient who is already used to taking metformin twice daily will have no problem taking Janumet twice daily. Same routine, different drug. In the very near future, if the FDA approves it, we hope to have a once-daily version that would make it even easier for somebody to be on this therapy. As far as people’s reluctance to go on insulin, we know that many doctors themselves are resistant to prescribing it because of patients’ concerns about injections and the complexities of insulin therapy. But here you have the possibility of taking patients whom you might have put on insulin a few years ago and offering them a 50 percent chance of getting to their A1C target simply by taking an oral medication.
Nadia: I can understand how years ago doctors may have been inclined to put type 2s on insulin fairly quickly, just to avoid the anxiety involved as type 2s worked toward what was seen as an inevitable point in their disease. I think that most type 2s would prefer pills over insulin injections. But isn’t adherence a big issue here, namely taking pills on time and in the right quantity?
Dr. Reddy: Yes, compliance and adherence to a regimen is always a major issue. We’re all thinking of ways to help patients more closely follow their regimens. But, generally speaking, oral agents have an advantage over injectibles, especially when you consider the number of times per day a patient has to take one versus the other.
Nadia: Are there any restrictions on combining Janumet with other common diabetes medications therapies, and are there concerns about renal issues?
Dr. Reddy: It can be used following the recommendations for Januvia itself. Januvia has been approved for use with metformin, pioglitazone, sulfonylureas, and insulin, so Janumet can be combined with those same drugs. In fact, of all the agents in this particular class, DPP-4 inhibitors have the broadest indications for use and the least number of limitations. In terms of adverse events, whatever restrictions apply to metformin have to apply to Janumet as well, of course, so that’s a baseline. The Janumet release has some of the recent Januvia label changes that were made with regard to postmarketing reports of pancreatitis and renal dysfunction associated with Januvia. I want to reiterate that postmarketing reports do not imply causality and are made as a means of reminding patients with diabetes that pancreatic and kidney problems occur in many cases, regardless of which drugs they’re taking. They need to be aware of those possibilities and take necessary precautions.
Nadia: One of our writers is a type 1 who really wanted to try something in combination with her insulin, so she asked her physician to prescribe metformin. He resisted at first, but when he finally did prescribe it, her A1C went down almost immediately. Have you considered metformin and insulin as a combination therapy for type 1?
Dr. Reddy: Officially speaking, metformin and Janumet would be off-label use for treating type 1 diabetes since both are intended for type 2. However, I can understand a rationale for off-label treatment of type 1. Let’s say somebody unfortunately develops type 1 diabetes at age three. As a small child, they’re lean, but as they get older, they fall into the same habits as the rest of us. They put on weight, eat a little bit too much, exercise less, and by the time they’re 35, may have a high body mass index and be overweight or even obese. When you are overweight or obese, you develop insulin resistance, so some doctors think that metformin can be helpful for addressing that particular part of the syndrome.
Nadia: There are other DPP-4 inhibitors on the market, some of them newer. How do you differentiate Januvia/Janumet from them?
Dr. Reddy: How is Januvia different from the other medications that are available in its class? Well, doctors can put a lot of faith in the breadth of the studies and clinical experiences covering it. We’ve had close to five years of its use in the US [Januvia was approved in October 2006], so there have been millions and millions of prescriptions written for it. I compare it to my father: He has always been older than me and I will never quite catch up to him as long as we’re both living. So I think that Januvia having that five-year lead in clinical experience, users’ comfort levels, and acceptance by physicians and specialists make it different than newer medications.
Nadia: What happens when a patient thinks a therapy isn’t delivering?
Dr. Reddy: That’s always a possibility. Let’s say a patient has heard that a certain therapy often leads to extensive weight loss. Maybe that patient was expecting to lose 30 pounds and ends up only losing five pounds. He might say, “I’m not getting all the benefit from this that I expected.” So along with the actual effects of a drug, you always have to deal with patients’ expectations.
Nadia: So the therapy itself is only one part of the picture. Adherence is another, and the individuality of each patient is yet another.
Dr. Reddy: That’s right. In fact, those variables are one of the reasons why Merck US and Merck globally are putting a lot of resources behind adherence. We have done a lot of adherence research trying to identify how to predict whether someone will or will not adhere to a certain therapy
Nadia: Do you have data that you can share?
Dr. Reddy: We have a copyrighted tool developed by our US outcomes research group called an “adherence estimator” for healthcare professionals. Many institutions and practices have incorporated it into their practice. The idea is if you can identify which patients might later have problems with adherence, you can come along with helpful interventions at the right time.
Nadia: What’s the next step for Merck, especially when it comes to adherence?
Dr. Reddy: In our study, Janumet lowered A1Cs by 2.4%, compared to 1.8% with metformin alone. But that was in a clinical trial, where patients were tracked by a physician, a nurse coordinator, and a research nurse, all of whom contributed to a high rate of compliance. Our challenge now is, how can we replicate that adherence and those results in the real world, in real life? That’s what we would like to be able to do, to have the same outcome in the real world that we had in the study. We have to come up with innovative ways to do that because you can’t do it exactly the way you did it in the study. It would be expensive to duplicate the conditions of a clinical trial, but if we were to work through pharmacists, public forums, and patient champions, as well as health professionals, I think we could find all sorts of new ways to engage the patient.