COMMENTARY

How to Use New Type 2 Diabetes Guidelines

ADA/EASD Position Statement 'Translated' for Clinicians

Anne L. Peters, MD, CDE

Disclosures

September 21, 2012

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The Cornerstone of Care

Hi. I am Dr. Anne Peters, Director of the Clinical Diabetes Programs at the University of Southern California. Today I am going to answer some questions that many people have raised about using the new position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) on the treatment of type 2 diabetes.[1,2]

I was on the committee that wrote the position statement, so I am well versed in what we wrote, why we wrote it, and what we were thinking as we were writing the position statement. However, I am also a clinician, and many of you are clinicians, so I wanted to address what I think about when I see a patient with type 2 diabetes, with the new position statement in mind, and how I track through it.

Let's start with lifestyle. I can't tell you how important lifestyle is, and I never give up. I discuss lifestyle with each patient at each and every visit. I try to create a plan for exercise, and I talk about approaches to weight loss. I always discuss it, and I never stop believing that patients can lose weight. Even when they gain weight, I know that they can lose weight. So, I work with that, but I'm enough of a realist to know that most of my patients will need medication.

Metformin

In the position statement, the first medical treatment is the use of metformin. Metformin is a drug that has endlessly positive results. I have discussed the use of metformin before, but suffice it to say that it helps nearly every facet of the type 2 diabetes syndrome. It lowers blood sugar levels, it helps reduce cardiovascular risk; it may even help reduce risk for cancer and Alzheimer's disease

The problem with metformin is that many patients experience gastrointestinal side effects that limit its use. In the United States, the 500-mg tablets are available. I am not sure if 250-mg tablets are available, but if I have a patient who can't tolerate the lowest available dose, I send them to a compounding pharmacy to have an elixir of metformin prepared, so they can start with a teaspoonful (50 mg). I generally find that if I start a patient on a low enough dose and advance slowly enough -- say, 50 mg for 2 weeks, 100 mg for the next 2 weeks, and so on -- I can work them up to a reasonable dose. I want to get most patients to 1 g twice daily, but for some patients, even 500 mg twice daily will suffice and I will see benefit.

I tend to be dogged when it comes to getting patients to tolerate metformin. When it is made into an elixir, it is much easier to titrate in patients who don't tolerate the standard starting dose.

Let's say that metformin isn't enough -- that a patient's hemoglobin A1c remains above your target for the patient (and not everybody should have the same target; it depends on comorbidities, age, duration of disease, etc.) Let's say that your target for a patient is an A1c below 7%, a fairly standard target. According to the algorithm, you have infinite choices. You can start a sulfonylurea agent, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a glucagon-like peptide-1 (GLP-1) receptor agonist, insulin, or a thiazolidinedione On some level, that doesn't help you very much, so let's look clinically at an individual patient.

Let's throw aside cost considerations for now (we will get back to that in a minute). In most cases, I add an agent that does not cause weight gain -- one that hopefully will cause weight loss -- and does not cause hypoglycemia. That is the ideal agent. For those benefits, we have a DPP-4 inhibitor or a GLP-1 receptor agonist.

DPP-4 or GLP-1?

How do I choose between those 2 agents? I tend to use 2 different criteria. If I have a patient whose main goal is to lose weight (for example a patient who is working hard but remains significantly over his or her target weight and wants to lose another 5-10 lb) I will choose a GLP-1 receptor agonist because it is the only agent that is associated with weight loss in most people. It may not be a lot of weight, but for many patients, losing even a couple of pounds is beneficial and may motivate them to lose more weight.

In the setting of a patient who wants to lose weight, I will choose the GLP-1 receptor agonist. When it comes to maintaining weight and avoiding hypoglycemia, either the DPP-4 inhibitor or the GLP-1 receptor agonist will be effective. A DPP-4 inhibitor is a little easier because it is a pill rather than an injection, and it has very few side effects. In my patients, I tend to see a somewhat more robust A1c reduction with the GLP-1 receptor agonist than with a DPP-4 inhibitor.

Say that I have a patient whose A1c is 8% and I want to get them down below 7%. For that patient, I will choose a GLP-1 receptor agonist vs a DPP-4 inhibitor. If a patient's A1c is 7.5% or 7.4% and I want to get it below 7%, then adding a DPP-4 inhibitor makes a lot of sense. I don't sweat too much over this choice because if a patient wants to try a DPP-4 inhibitor to avoid an injection, I will try that, and if it doesn't work, I switch them. I try to work with the patient's wishes and desires.

The beauty of these 2 drug classes -- DPP-4 inhibitors and GLP-1 receptor agonists -- is that they don't cause hypoglycemia and can cause either weight neutrality or weight loss. With respect to cost, both are expensive drugs and both classes of drugs have been on the market a relatively short time, 5-6 years rather than 10-20 years. We don't have data on long-term follow-up.

Sulfonylurea Agents

With respect to sulfonylurea agents, a whole world of people seem to hate these drugs, but I am not one of them. It is not my favorite class of drug -- my favorite agents are those that don't cause hypoglycemia and weight gain. However, the sulfonylurea agents work. They have been around a very long time. In the United Kingdom Prospective Diabetes Study -- a very good, long-term diabetes study -- sulfonylurea agents were helpful. They were part of the mix in the patients who were intensively treated. They are associated with a reduction in both micro- and macrovascular events.

I would argue that the sulfonylurea agents are not terrible drugs, and although in many cases they are not my first choice, they reduce blood glucose levels with the caveats that they cause hypoglycemia and weight gain and are associated with progressive beta-cell failure. So is metformin. The thiazolidinediones are the only class of drugs thus far that have not been shown to cause progressive beta-cell failure, which is part of the natural history of type 2 diabetes. Nonetheless, I am not opposed to adding a sulfonylurea agent to a patient's regimen.

The agent that I tend to use is glimepiride. I rarely use glyburide -- it is less effective than glimepiride. Sometimes I use short-acting glipizide as a premeal insulin secretagogue. The beauty of the sulfonylurea agents is not only that they lower blood glucose levels, but that they are very inexpensive and have a long-term history. These agents are associated with concern about cardiovascular risk, but they are useful in patients who are very hyperglycemic or when the cost of some of these other agents is prohibitive. Cost is important in choosing drugs for many of our patients who are on limited budgets.

Thiazolidinediones

The next class is the thiazolidinediones, the only available agent of which is pioglitazone. I still like pioglitazone because I believe that it helps preserve beta-cell function over time, but I tend to use a very low dose -- just 15 mg in most cases, and occasionally 30 mg. Conversely, I may prescribe 15 mg on Monday, Wednesday, and Friday, and in many patients, I see a marked improvement in blood glucose levels with very little weight gain or edema, which are 2 side effects of the thiazolidinediones. They don't cause hypoglycemia, but this must be balanced with the risk for weight gain and fluid retention. So, I am not opposed to using pioglitazone, but I will typically use it after prescribing a DPP-4 inhibitor or a GLP-1 receptor agonist. I add pioglitazone at a lower dose to help improve insulin sensitivity and get patients to target.

One of the reasons that the thiazolidinediones are lower down on my paradigm is their cost. In the United States, the thiazolidinediones remain expensive -- although they will soon be available as generic agents -- and in other countries they are cheaper. And they do work. However, I am somewhat concerned about the higher doses (eg, 45 mg) because they may be associated with osteoporosis or at least an increased risk for bone fracture, macular edema, and congestive heart failure. So, I use a lower dose and this seems to produce fewer side effects.

You can add insulin at this point; that is certainly an option. I add basal insulin to metformin, and even NPH insulin works. You can add almost any overnight insulin to get the fasting blood sugar down and continue the metformin as an oral agent. However, I tend not to prescribe insulin at this point if I don't have to, because it causes weight gain and hypoglycemia. I tend to reserve it for a later step.

Insulin and Drug Combinations

The next step (the third step) involves more complicated math because you want to add drugs that make sense with the drugs that the patient is already taking. I tend to use lower doses of pioglitazone and sulfonylurea agents, maximum doses of GLP-1 receptor agonists or DPP-4 inhibitors, and as the third-line, I may add a thiazolidinedione or basal insulin, keeping the patient on the 2 drugs that they were started on initially.

When I am going to a more complicated regimen, I generally keep patients on whatever agents they were on, including basal insulin. I may take away the sulfonylurea agent when I add mealtime insulin. I generally only add mealtime insulin for the biggest meal, or for the breakfast meal and the biggest meal later in the day, and try to get patients balanced.

Meanwhile, through all of this, I work with patients on lifestyle, trying to get them to adhere or improve, and give patients the option of bariatric surgery, which fits in this somewhere as an important way to get patients to target on less medication. For many patients, that is either not an option or it is something they don't want to undergo.

That is how I use these algorithms clinically and how I make choices for my patients, based on their own circumstances. There are many considerations, such as health, comorbidities, financial circumstances, etc. We now have enough tools, however we use them, to get patients to target blood sugar levels. At the same time, I am mindful of treating their lipids, as well as their blood pressure, to create a combination that hopefully will maximally benefit my patient in terms of their lives and their overall outcomes.

This has been Dr. Anne Peters for Medscape. Thank you.

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