Type 2 Diabetes Management: Choosing the Best Therapies

An Explosion of New Diabetes Treatments

Anne L. Peters, MD: Hi. I'm Dr Anne Peters. I'm here today with Dr Ele Ferrannini, who is a professor of medicine at the University of Pisa. Today we are going to tackle the difficult question of how to synthesize all that is new in the treatment of diabetes and how to make it practicable.

Why don't you tell us what your perspective is, an overview of what we have for treating diabetes that has come up in the past few years?

Eleuterio Ferrannini, MD, PhD: I think what is really striking about diabetes is that over a relatively short period of time, a number of new drugs and approaches have become available, whereas previously, the treatment and management of diabetes was essentially in a phase of stagnation. This is in contrast to what has been seen with hypertension, where there has been a steady development of new drugs over the course of time.

The other thing that is interesting is that there are multiple targets. It's not just the glucose or the glycated hemoglobin (A1c), but it's also the weight, the prevention of hypoglycemia, and correction of the basic pathophysiologic defects in diabetes. On the one hand, this should not be too surprising because we know that diabetes is a systemic, multifactorial, and polygenic disease. It makes all the sense in the world that there should be multiple therapeutic targets.

The difficulty for physicians is that all of these approaches have become available over a relatively short period of time. Although I believe that, in the long term, it will turn out to be an advantage and an asset, it may initially be confusing because doctors may have some difficulty finding the best treatment for the individual patient with so many options open.

Dr Peters: Yes. I think another thing that makes it confusing is that not only are there all the classes of drugs, but there are different names within the classes for each agent. Then, there are all of these combinations that all have their own names. Everything varies from once a day to once a week to oral to injected. I think it's very important for practitioners to start to understand the classes themselves and then how they will mesh together.

Choosing a First and Second Agent

What is your primary goal? When you have a patient with type 2 diabetes whose A1c is 9% or 10% and he is 45 years old, what do you think of when you start therapy?

Dr Ferrannini: The first thing that I do is gather as much information about this patient as I possibly can:

• How did he learn about his diabetes?

• How long has he been diabetic?

• Is there a family history of diabetes?

• What is his blood pressure?

• What is his serum lipid profile?

• What is his renal function?

• Is there any history of allergy or intolerance to other drugs?

• What is his family situation, not just the socioeconomic level, but the family?

Once I have compiled all of this information, I start thinking about informing the patient about diabetes. He may already know a lot but have prejudices or false ideas about it. Maybe he has been on the Internet and has found some strange things about this drug or that drug, etc. I think it's crucial these days that the information that is available is accurate, supported by evidence, and given at the very first contact with the patient before getting into the conversation about possible therapeutic options and what best fits his stage of diabetes.

Dr Peters: Do you tend to always start with metformin?

Dr Ferrannini: I think I would do that if it hasn't already been given to the patient. You cannot expect anything bad from metformin except for intolerance, in which case you stop it. Otherwise, according to reasonable recommendations, you are going to see this patient again within 3 months at most, and if metformin was not sufficient, then you have a number of options. I think that is quite reasonable.

Dr Peters: We talk about all of the choices at the second step. It's the step where everybody seems to get confused, partly because the guidelines make it clear that there is not one specific way to choose. Everybody is practicing in a different setting. Patients have different preferences. When you are treating somebody and choosing the second step—let's just say that cost isn't an issue, you can use any step that you want, and renal function is normal—what kind of next step do you tend to follow?

Dr Ferrannini: I think that there is sufficient power in terms of efficacy and safety in the different classes of oral agents such that I wouldn't mind trying an oral combination, either on top of metformin or in triple combination, because we know that the dipeptidyl peptidase-4 (DPP-4) inhibitors are very well-tolerated drugs. We know what to expect from them. We know that they're weight-neutral. They by themselves don't cause hypoglycemia, so we can go for those.

The glucagon-like peptide-1 (GLP-1) receptor agonists have pretty much the same profile, but they are injectable, so it may not go along with the preferences of the patient.

Now we have the sodium glucose cotransporter 2 (SGLT2) inhibitors, which can be combined with anything and everything simply because of the completely different mechanism of action. We have a good chance of benefiting on the side of weight control, avoiding hypoglycemia, and lowering blood pressure, which is in the range of the effect that you would see with an antihypertensive drug. Again, it depends on whether the patient is hypertensive or not. I don't think it would be unreasonable to try an oral approach first.

Dr Peters: That makes sense. There is often pushback in terms of injections, although with the once-weekly GLP-1 receptor agonists, my patients don't seem to mind them. Some of the techniques where you don't actually have to see the needle make it a lot easier.

Dr Ferrannini: Yes. I forgot to mention, Anne, that one thing that is new and that has happened because of this increased availability of tools is that the therapeutic armamentarium for type 1 diabetes is expanding. I find that of special interest because type 1 diabetes treatment has been insulin, insulin, insulin, insulin, and now we have better insulins and different insulins. The insulin treatment as a science and as a concept is being revisited and rediscovered.

There are also emerging data that some of the new drugs that were developed for type 2 diabetes may show benefit in association with insulin in type 1 diabetes. For the diabetic population at large, this is definitely progress.

Dr Peters: Yes. For everybody with diabetes, this explosion of new technology and treatments is making life easier and better, although maybe more complicated.

Is it sufficient to say that your choice of an agent—going back to type 2 diabetes—would be something that doesn't cause hypoglycemia, doesn't cause weight gain and ideally causes weight loss, and is relatively simple such as a pill once a day or an injection once a day or once weekly?

Dr Ferrannini: Yes.

Don't Fear the Insulin

Dr Peters: When you move on to insulin in a type 2 diabetic, how do you start treatment?

Dr Ferrannini: I think the experience and data that I have accumulated over the past 5 years do show quite convincingly that basal insulin is an advancement over whatever we had previously. This obviously explains why there are similar basal insulins being developed at a faster rate, which would be confusing to some colleagues but will be an advantage because there will be more options available. Again, I think the science of insulin treatment has improved.

Dr Peters: I tell practitioners to never be afraid of the next step. Each time I see patients, it's often because somebody—they or the practitioner—didn't want to start the insulin or advance the therapy. I think that we need to really encourage people to not wait because if you have an A1c of 8%, it's much easier to get it to target if your target is less than 7% than if you wait until the A1c is 9%.

Dr Ferrannini: Yes.

Dr Peters: For many of the practitioners that I know, even though they theoretically understand how to use insulin, there is a big barrier there. To me, insulin is just one of any of these tools. It shouldn't be this big to-do. "Oh my gosh, it's going to be insulin." I find insulin easy to teach, easy to use, and most patients that I have are capable of self-adjusting. I teach them how to go up on the dose, and it seems to work very well, at least in my clinic.

Dr Ferrannini: And there are lines of investigation into even better insulins. One day, we may have intelligent insulins that respond to glucose levels almost in a physiologic way, so I agree with you.

Forming a Partnership Pact

As I see it, the whole process is crucially important at the very beginning, the first time you see the patient, because you want to leave some imprint. It has to take the form of a negotiation, a treaty that you sign with the patient so that he is fully informed about the goals and agrees with the strategy that you eventually propose. I think this is the best way of gaining that patient's compliance.

We know that in the whole of medicine, the number one problem for undertreatment of a disease is compliance, just taking the pill or the injection. If you, from the very beginning, imprint the patient into this collaborative mood, you can gain in compliance. I think that's one very good reason for expecting success.

Dr Peters: I would add two things. One is talking about side effects with patients. I always go through what the patient is going to read because a lot of my patients are going to go out there and look at blogs that say, "This thing can cause cancer. It can cause this problem." I always discuss the side effects.

I also try to never make my patients feel judged because if their contract with me is for X, Y, and Z, and they don't meet those targets, I still want them to come back. I always tell people that I can create goals with them, but I also don't want them to not come back and see me.

They have to take ownership. I'm not the one taking the pill or changing my lifestyle because bad habits can trump almost any medicine. But I do agree entirely that working with the patient, becoming partners, and creating that pact is incredibly helpful because they have to actually do what we say. We have to work together.

Dr Ferrannini: Another thing is that many patients these days are curious about the mechanism of action of the drug that you are going to be suggesting. A question that I frequently get asked is, "You're giving me this pill, so what is wrong? What aspect of diabetes, what defect is this drug going to be targeting?"

I think that simple but accurate information is crucial, and it doesn't correlate with the education level of the patient. Even a patient with a relatively lower level of education will ask the question. One must be prepared to answer this question, as well as explaining that the list of side effects and safety concerns are part of the way drug development and medicine are practiced these days. If every one of those listed adverse events were to occur, we would have no drugs for any disease. It's important to put those side effects into context, particularly the ones that are relatively frequent and avoidable.

Dr Peters: Right. It's avoiding those side effects, saying, "I will check your creatinine. We'll make sure your kidney function is fine." It helps people feel safe.

Dr Ferrannini: And for the SGLT2s, for example, ask whether the patient has ever had a genital infection, and, if so, warn that this may recur during treatment.

Dr Peters: Is there a tool or a resource that you refer primary care providers to, for them to learn more about all of the drug choices and treatments?

Dr Ferrannini: No. I think that face-to-face contact with the doctor is still an essential element of medicine. Actually, I have the opposite concern that being flooded with guidelines obfuscates clinical judgment from the physician and weakens the unique relationship. When you are a patient—even as a doctor, if you become a patient because you're taken ill somehow—you know that you look at the face of the doctor that is in front of you with different eyes. There is immediately a reaction of delivering yourself into the hands of your colleague and wanting to be confident.

Dr Peters: That's a fascinating approach. I actually like it. I think that tends to be what I do in my own practice. Sometimes I wish I had simpler tools to teach or to give a patient when I'm trying to explain the choices that they have, but it is difficult to simplify. And it is about trust. If you don't have trust in the physician or the provider, you're never going to get anywhere, so I completely agree. Trust me, I'm a hand-holder with the best of them.

New Developments on the Horizon

Is there any new development that you think is most exciting, something on the horizon that isn't on the market? What have you learned or heard about that you think might further change the way we treat people with diabetes?

Dr Ferrannini: There is going to be the first report of the results from a cardiovascular outcomes trial using a member of the SGLT2 inhibitor class.^[1] It is going to be very interesting to see what sort of cardiovascular protection was achieved in what category of patients and whether it will be possible to dissect out which of the effects of the drugs might have contributed to the cardiovascular protection, if that's what the study shows.

I expect that this will be a topic for long-lasting discussions among drug developers, academics, physicians, and patients because this would be the first modern randomized controlled trial to show a reduction in cardiovascular risk in patients who were recruited because they had a high cardiovascular risk. It will flip over the paradigm that if cardiovascular damage is too advanced, it's too late to intervene or reverse it, that the residual risk would still be overwhelming for the patient. I think this is good news.

Dr Peters: Yes. Anything that we can do to take this complex disease, which involves macrovascular and microvascular risks, and improve it and use as few pills or treatments as possible makes everybody happy. It makes our job easier as clinicians because we don't have to tell patients about as many drugs. It'll make life easier.

The Bottom Line

What we've said is that there are all of these choices, and physicians have to understand the choices that are available. They have to engage patients in understanding the options, the side effects, the benefits, and the goal of treating diabetes, which is minimizing weight gain and hypoglycemia and maximizing A1c reduction and the ability to lose weight.

We have a lot that we can do that we didn't have before. Clinicians shouldn't be afraid to try the new treatments, but they also need to be cautious to make sure that they are aware of side effects and emerging side effects. I can't know for sure that any drug won't come up with some side effect in the future, but I really feel that my patients trust that I'll tell them or be aware of it. They trust that I am aware of what is going on.

Dr Ferrannini: Certainly, yes. It's probably worth telling your patient that diabetic people have been faring much better.

Dr Peters: That's what I tell them, yes.

Dr Ferrannini: For example, an article from the United States that was published recently showed that the incidence of major vascular complications from diabetes has dropped by 50%.^[2] We learned the other day that in Europe, diabetes is no longer the number one cause of blindness,^[3] and this is the first time in many, many years.

So on the one hand, we cannot have the patient underestimate his condition, but we do not want to inject pessimism and lack of hope because there has been progress.

Dr Peters: Tremendous progress, and I think we all have to keep that in mind. When I saw the data from the United States that were published last year,^[3,4] I felt so validated. Over the course of my career, the outcomes in our patients have only gotten better. We are making a real dent in this very complicated disease.

I want to thank you for joining me today. This has been Dr Anne Peters for Medscape.