COMMENTARY

Critical Issues in Diabetes: Choosing Newer Drugs for T2D

Charles P. Vega, MD; Anne L. Peters, MD

Disclosures

June 05, 2015

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New Drugs to Meet Glycemic Targets

Charles P. Vega, MD: Welcome to Medscape's Critical Issues in Diabetes. I'm Chuck Vega, clinical professor of family medicine here at the University of California at Irvine, and I am joined by Dr Anne Peters, professor of endocrinology at the University of Southern California, Keck School of Medicine, and she runs the clinical diabetes programs there.

We previously discussed glycemic targets and lipid management, and today we want to discuss how to get patients to goal for glycemic targets. Some new options in antidiabetes medications have come on the market in the past several years, and as a group, they can be effective. They generally avoid hypoglycemia, which is very important. Some can promote weight loss, which is a tremendous goal for many of our patients with diabetes, but they also have some down sides and associated risks. Let's go through them one by one. I want to get your take on how they can be applied clinically. What are best practices in applying these drugs to patients with type 2 diabetes?

The DPP-4 Inhibitors

First, I would like to talk about the dipeptidyl peptidase-4 (DPP-4) inhibitors. An advantage of these drugs is that they are largely well-tolerated. They can be used with dose modifications in patients with renal disease, which is a big plus because that is a problem we run into with metformin, for example. But these drugs are only modestly-to-moderately effective, and that's one drawback of these drugs. They play well with others, but for a patient with a glycated hemoglobin (A1c) of 11%, they're only going to have so much efficacy, with a reduction of 0.5% to 1%. What's your take on the DPP-4 inhibitors as a class?

Anne L. Peters, MD: First, I need to give a shout-out to metformin because metformin is the single best drug we have for treating type 2 diabetes, and it is what we use in combination with everything else. Metformin has to be the baseline. Yet there are patients who can't take metformin, either because of gastrointestinal (GI) side effect or for renal dysfunction. DPP-4 inhibitors are a gentle next class. They are very well-tolerated, taken once daily. You can use a drug such as linagliptin alone without any dose adjustment in patients with any degree of renal dysfunction. I tend to use them if I need a patient's A1c to go from 7.4% down to 6.8%. I use them for small goals—no hypoglycemia, no weight change. But cost is always an issue.

I often see patients who need more A1c reduction, so I tend to use other agents. But I often use the DPP-4 inhibitors in the frail elderly, especially with renal dysfunction. I have patients with type 2 diabetes who came to me with a creatinine of 2 mg/dL, who were on prandial basal insulin, and I get them off the prandial insulin by giving them a DPP-4 inhibitor and keep them on the basal insulin. If I can use it to simplify a regimen, reduce hypoglycemia, and get people to their goal more easily, I'll do it. But I don't use them in everybody. A thousand different combinations are available, but I tend to start with metformin and add in whatever the next therapy is. If somebody is higher than 7.5%; if the patient needs a bigger drop in A1c, I'm going to use a different agent.

The GLP-1 Receptor Agonists

Dr Vega: Speaking of large A1c reductions, with the glucagon-like peptide-1 (GLP-1) agonists, you can see improved A1c efficacy; plus these agents offer the benefits of weight loss—between 1 kg and 4 kg in most studies. There is an issue with adverse events. Cost is a universal issue for all of these newer agents. Like many newer drugs, they can be more expensive. They do offer certain advantages that may make it worth it. What is your opinion?

Dr Peters: The GLP-1 receptor agonists are a class of drugs that I've used extensively, and they do have more side effects. The most common side effects are GI, although the benefit is that they cause weight loss. The downside is that they slow gastric emptying owing to central effects on satiety, which can be associated with nausea, vomiting, and diarrhea. In terms of other side effects, these drugs (as well as the DPP-4 inhibitors) are associated with an increase in pancreatitis, although we don't know whether that is causal or if it is a direct effect of the drug. Regardless, don't use either agent in patients with a history of pancreatitis. That being said, I like the GLP-1 receptor agonist class because it gives you such a nice A1c reduction. These drugs are injectable, so you have to get through that barrier. Most of my patients love the improvement in A1c and like losing a little bit of weight. It's not a lot of weight—it's only a couple of kilograms. That tends to be positive for these people who have been trying to lose weight for a long time.

Dr Vega: Right. It can be a kick starter.

Dr Peters: I like that positive energy, and now they are once weekly. Dulaglutide, exenatide, and albiglutide are once weekly. Dulaglutide preparation comes in a pen with a needle that patients don't have to see. It's almost like not giving an injection. Most patients, even the most needle-phobic, can manage a once-weekly injection if they see a nice improvement in their A1c level and a reduction in their weight. It's a good drug to add if you want an A1c reduction of 1% or more, and you can use them in combination with insulin. If you have a patient on basal insulin and you don't want to go to prandial insulin, you can give a once-weekly injection and get them to target. In the current guidelines for the treatment of type 2 diabetes, we suggest using GLP-1 receptor agonists in combination with insulin, as opposed to prandial insulin, which can be hard to use and is associated with hypoglycemia.

Dr Vega: GLP-1 agonists promote weight loss, whereas insulin therapy is associated with weight gain. That's a great point. With respect to side effects, these drugs can mirror metformin, which is also associated with a high rate of GI side effects. If the patient can tolerate it for the first 2 months of therapy, in many cases these side-effect profiles improve, and tolerability is much improved over time. That is when you start experiencing the benefit in terms of glycemic control and weight loss. In one study of liraglutide, more than 50% of patients experienced both an A1c reduction of more than 1% plus a loss of body weight in excess of 3%. That's an outstanding result in my opinion. These drugs definitely have a place moving forward with the limitations you described.

Dr Peters: With both the once-daily liraglutide and the once-weekly preparations, clinically, if you go up more slowly, you can reduce the GI side effects. If a patient starts to experience GI side effects, I back down a bit. I have given it every other week or every other day with liraglutide. Or dial down the dose when you can. There is one study in which they mixed together insulin plus liraglutide and increased in tiny steps, and almost nobody had GI side effects. It's about getting used to it. If somebody takes one big dose, they may well get GI side effects. Everybody does, so titrate slowly when you can. I play a lot with these agents because they work very well. Whether it's once daily or once weekly, you can figure out ways to slow it and uptitrate more slowly.

The SGLT2 Inhibitors

Dr Vega: The weekly is going to help with side effects over the daily, but both have that same side-effect profile. The newest class available is the sodium glucose cotransporter 2 (SGLT2) inhibitors. Here you are talking about the benefit of some weight loss, similar to or perhaps slightly less than with the GLP-1 agonists. They cause a very modest reduction in blood pressure as well (2-4 mm Hg) and a modest, but still significant, reduction in A1c (0.5%-1%). But there are also new side effects to be concerned about in terms of increased risk for mycotic infections and urinary tract infections (UTIs). These genitourinary side effects are completely unique to this class vs other antidiabetes agents. How do you see these agents playing a role in the spectrum of antidiabetes care?

Dr Peters: When I heard about SGLT2 inhibitors, I thought it was a stupid idea because I didn't want to make patients glycosuric. It just didn't make sense to me. But you know what? These drugs work. They are pills. They are taken once daily. They cause weight loss and a nice A1c reduction. I've had a lot of success with these drugs. These drugs are relatively easy for patients to take. But everyone experiences mild side effects because nearly everyone will become polyuric. They urinate more often. The clinical trials found that patients urinated once more daily, but I can tell you that my patients notice more than that. They like the drug enough, however, that they stay on it. I make sure that women are prepared for the mycotic infections. If a patient has had recurrent mycotic vaginal infections, I won't use it.

It's unclear whether UTIs are increased. I make sure that patients know to watch for this side effect and let me know if this occurs because we can treat it. The worst thing is a patient who waits the whole weekend and is miserable and, on Monday morning, the patient is a wreck from having a bad UTI and no sleep. Fortunately, this has not been associated with upper UTIs such as pyelonephritis. Still, I want patients to be aware and informed, and I start with a low dose. If the patient is on a diuretic and his or her blood pressure is well-controlled, I will stop or taper down the diuretic because this is like giving a diuretic for glucose. It can be a problem in the summer, particularly in older patients who have a problem with not having enough volume. I have patients who take the drug and then go out and play tennis, and they feel dizzy. I stress to these patients to make sure that they replace the volume loss. I almost always use these drugs in combination with other drugs, and that helps a lot. Patients like the fact that it's a pill that helps with weight loss. I use the off-label combination of an SGLT2 inhibitor and a GLP-1 receptor agonist because they work incredibly well synergistically. That combination has not been studied but is being studied now. It's also the most expensive combination known to man. But I can also tell you that it works.

Dr Vega: The increased urination is the main practical concern with these medications. It's important to note the risk for UTIs, which are localized to the lower urinary tract. With respect to mycotic infections, we are talking in most cases about localized candidiasis, not systemic fungal infections. I don't think those have been demonstrated at all. We see the routine day-to-day modest-to-moderate increase in urination, so I'm very careful with these medications, just like I am with diuretics. I ask about any kind of symptoms—overactive bladder in particular, which has a prevalence of about 30% among older adults. I make sure that they aren't running to the restroom or experiencing urgency or incontinence because when you ask, you find out that a lot of patients are having symptoms that you didn't know about. They weren't treated for it in the past. That may make this class of drugs a little bit less attractive for those patients, at least until those issues are worked out.

In summary, we have three relatively new classes of medications: the DPP-4 inhibitors, the GLP-1 agonists, and the SGLT2 inhibitors. And that's not just a random collection of letters and numbers. These are strong advances in diabetes care that help us be a little bit more patient-centered and help us achieve new goals that heretofore were difficult for our patients. I'm excited that we have these options. They certainly are going to play a role moving forward in patient care. We are going to learn more about combination therapies that work and really advance the paradigm of improved glycemic control for a broader range of the population. Thanks for your comments. They were right on point and very salient for our clinicians.

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