Innovations on the Horizon for the Treatment of Type 2 Diabetes An Interview With Javier Morales, MD

Evidence-Based Diabetes Management: The scope of challenges we face in patients with type 2 diabetes mellitus (T2DM) today is extremely broad. Let's start with the state of care today. For patients who have been diagnosed and are undergoing treatment, approximately what proportion of these patients reach target glycemic levels?

Javier Morales, MD: It varies based on the patient’s age and comorbidities. One factor that has affected our attempts to reach target glycemic levels is the increased mortality associated with tight glycemic control, which was revealed by the 2008 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.¹ The glycated hemoglobin (A1C) levels used as a target in the ACCORD trial were very aggressive—an A1C level of 6% or lower, compared with the ADA’s recommendation of 7.0% or AACE’s (American Association of Clinical Endocrinologists) standard of less than or equal to 6.5%. Also, ACCORD investigators attempted to reduce A1C levels rapidly, and found that patients with known coronary disease, or who had experienced a previous coronary event, were more likely to suffer a new coronary event or to die as a result of aggressive titration and possibly hypoglycemia. In 2009, a position paper was published in Diabetes Care, which suggested using judgment in liberalizing glycemic control of patients with multiple comorbidities and advancing age.² That was extrapolated even further in the 2012 revised American Diabetes Association guidelines. The ADA has a beautiful diagram looking at various parameters, such as the age of the patient, comorbidities, longevity, and whether clinicians should be treating more or less aggressively.

Liberalizing diabetes control doesn’t mean that an A1C of 8.5% is acceptable. I think that’s where there will be a lot of confusion in the medical community: A relatively high A1C level may be deemed more acceptable to some, which is counter to the conservative, longstanding recommendations. The take-home message is, you need to exercise judgment, but if the patient is younger, more aggressive glycemic control will be better, because it will minimize the risk of microvascular complications in patients with T2DM. In older patients, the benefits of long-term, tight glycemic control, for the sake of minimizing microvascular complications, are fewer, and the risks associated with hypoglycemia may be greater.

EBDM: To what extent were the rigid glycemic control protocols in the ACCORD trial attempted by ordinary practitioners?

Morales: My understanding is that most clinicians are aiming for A1C levels of less than 7.0%. I think they (and their patients) are comfortable with the risk of hypoglycemia in this range. Below this, the hypoglycemic risk may be too great for them.

EBDM: Have changes in insulin formulations also affected the ability to, and comfort with, achieving tight glycemic control?

Morales: Absolutely! We learned from the Diabetes Control and Complications Trial (DCCT) that there is a hyperbolic-shaped hypoglycemic risk as you get closer to target A1C levels. However, at the time the DCCT investigators studied this risk, older insulin formulations were used—NPH and regular insulin; the insulin analogues were not yet available. I believe that with the insulin analogues now available, the hyperbolic response with hypoglycemia is much less pronounced, allowing us to achieve tighter control with fewer hypoglycemic events. The rationale for this is that insulin analogues are much more predictable, or have much less variability. AACE recommends the use of insulin analogues over human insulin, because of the variability factor. Even newer insulin formulations that are currently in development offer even less variability, thus enabling patients to get safely to target a little sooner.

EBDM: Let’s talk specifically about the newer-versus-older basal insulins in patients with T2DM. Insulin degludec may be the newest, ultra long-acting basal, but its approval was delayed by the FDA, pending more detailed evaluation of its cardiovascular risks. If we assume that the FDA approves it over the next 18 months or so, what do you view will be its advantages?

Morales: The first ultra long-acting insulins approved were lente and ultra lente, which are no longer available. The problem with those insulins was significant stacking, which is the continued effect of the previously injected insulin dose superimposed on the increasing effect of the newly injected insulin dose, and high variability in effect. Clinicians started using intermediate-acting insulin instead. Today, the long-acting basal market is dominated by insulin detemir and insulin glargine, and these represent significant strides with respect to basal insulin management. In the T2DM population, differences in variability between insulin detimir and insulin glargine are not clinically significant. Most recently, insulin degludec was approved by the FDA’s Advisory Committee. It is different because it creates a “string-of-pearls effect” in which insulin hexamers break off into monomers and subsequently release into circulation, resulting in a flat glucose infusion rate profile and a relatively steady basal insulin plasma concentration after only two doses, which is very impressive.¹ Keep in mind, there have not been any head-to-head studies looking at the amount of variability among insulin detimir, insulin glargine, and insulin degludec. Investigators did test the glycemic control associated with glargine and degludec head-to-head in basal-bolus treatment (treat to target), as well as the use of these insulins as add-on therapy to orals.¹ The ability to reach target glycemic levels was high in both groups, indicating noninferiority between the insulin studied, allowing a look at other variables and parameters, and significantly less hypoglycemia was seen in the insulin degludec group—on the order of 36% fewer nocturnal hypoglycemic episodes in those patients having received degludec as and on therapy with orals medications.

EBDM: Wouldn’t you expect that insulin degludec, with a longer half-life than insulin glargine, be subject to greater hypoglycemic risk?

Morales: No, because its method of subcutaneous collection and release of insulin degludec is much more predictable and less variable. Remember, in terms of insulin-related hypoglycemia risk, the 1 major factor that affects the rate of hypoglycemia will be the rate of variability in the insulin’s pharmacodynamic activity.

EBDM: Do you think the introduction of insulin degludec (when and if that occurs) will significantly alter the utilization of other basal insulins?

Morales: Yes and no. If you’re trying to reach a fasting glucose of 70 mg/dL, you may be able to get there with less hypoglycemic risk with insulin degludec rather than insulin glargine. The reality is that there will be challenges based on insurance coverage and availability. Furthermore, if liberal control is what the practitioner and patient are aiming for, then there may be little difference between degludec and the currently available basal insulins.

EBDM: New GLP-1 and DPP-4 agents are seemingly being introduced every year or so, and now it appears that the SGLT-2 inhibitors will be joining the party. What is your view on what these new drugs have to offer?

Morales: The incretins are here to stay; they’re a no-brainer. They offer minimal hypoglycemia risk unless utilized in combination with secretagogues. While incretins seem to have an effect on glucose-dependent insulin secretion out of the beta cell, they do have a suppressive effect on glucagon release out of the alpha cell. Other currently available agents don’t offer anything with respect to glucagon release, or even the weight loss that is offered with GLP-1 receptor agonists.The DPP-4 inhibitors’ claim to fame really is more based on glucagonsuppression than it is on insulin secretion, in a glucose-dependent fashion. That’s why the A1C reductions we see with these agents is only about 0.6 percentage points, and slightly higher in treatment-naïve patients. The challenge we face as practitioners is trying to control postmeal glycemic excursions without increasing the risk of hypoglycemia. Often, practitioners will prescribe a DPP-4 rather than a GLP-1, because they believe that a DPP-4 is more or less an oral version of a GLP-1. That’s not really the case; however, the prescriber’s mind-set is influenced by the problem with getting patients to go on injectable therapy. Even though the GLP-1s offer better A1C reduction, systolic blood pressure control, and weight loss than the DPP-4 inhibitors, clinicians will often reach for a DPP-4 rather than a GLP-1. The prescribing community needs to realize that incretin resistance also exists in the T2DM population. In one study, restoring GLP-1 levels to physiologic levels offered very little with respect to insulin secretion in T2DM patients. However, in a different study, a dose of 3 times physiologic levels restored insulin secretion in these patients to near normal levels. Furthermore, it also had a positive effect on first-phase insulin release. Unfortunately, the DPP-4 inhibitors only restore endogenous GLP-1 to physiologic levels.

EBDM: In your own practice, are you shifting more of these patients away from other oral antidiabetic drug classes to the GLP-1s and DPP-4s?

Morales: The best answer to this question is that there will be something for everyone. It depends on what comorbidities you may be treating, who you’re treating, where you are in terms of hemoglobin A1C, the duration of that patient’s diabetes, and his or her likely response to therapy, followed by insurance limitations. The other thing that must be factored into the decision is the sustainability of A1C control. Not only do you want to achieve A1C control but the goal would be to sustain it. The thiazolidiones (TZDs) are the only class of agents found to provide sustained hemoglobin A1C levels. The ADOPT trial showed that a TZD (rosiglitazone) provided A1C control that lasted 5 years.² While data are not yet available, I am optimistic that the incretin agents will demonstrate similar sustainable results over the course of 5 years and beyond. For a new patient with T2DM who is treatment naïve, the standard of care is that you start with metformin, if no contraindication exists, along with exercise and diet modification. But is this enough? We learned from UKPDS and ADOPT trials that sustainability with metformin therapy was not achieved, yet we did see some weight stabilization in those who were obese, and noted cardiovascular protection in the UK PDS trial. Should we be treating with combination therapy sooner, specifically for the sake of beta-cell preservation? I tend to embrace a more synergistic approach to control rather than a stepwise approach. Taking a stepwise approach ends up not working in the long run. In fact, there are data suggesting that the more agents a patient is currently taking to manage their diabetes, the longer we wait to further intensify their therapy. This leads to the progression of underlying microvascular disease, which is what we are trying to avoid by intensive therapy to begin with. As a result, I tend to embrace amore synergistic approach when managing my patients rather than a stepwise approach.

EBDM: Do you think that as clinicians become more comfortable with prescribing the incretins, they will become a de facto third tier of therapy or will they be substituted for another drug class early on?

Morales: Safety always resonates in the medical community. Achieving fasting plasma glucose control safely and minimizing postprandial excursion without hypoglycemia is our goal. The incretins are helpful in this regard. The short-acting GLP-1 agents offer prandial control, while the long-acting GLP-1 agents offer prandial and fasting control. In those using insulin, the combination of these agents shows extremely encouraging results. In fact, there is a new long-acting GLP-1 agent that was studied in combination with basal insulin, versus a short acting insulin analogue looking at prandial control. The GLP-1 agent did better. The DPP-4 agents also result in less insulin need, which may be useful for those taking basal insulin in combination with other oral agents. The newest anti-diabetes drug class, the SGLT-2s, will probably factor into this decision. They are a very interesting class, because they offer a weight-loss benefit. And they do improve glycemic control significantly, but this will have to be weighed against a small but higher risk of urogenital tract infections (relative to placebo).

EBDM: How do you think payers will react to the SGLT-2s? Will they put them on formulary after the usual waiting period, or will they take an extended wait-andsee attitude?

Morales: Of course, there will be a waiting period, just like for any other drug that comes along. The insurance companies need to establish whether there’s a need for these new agents in the marketplace. I think taking into consideration safety and the financial implications of hypoglycemic reactions, namely on emergency department visits, additional phone calls, additional glucose test strips that may be utilized, the insurance companies would err on the side of safety. Like any new kid to the marketplace, there will be a delay before they’re actually embraced and approved by payers.

EBDM: How do you think prescribers will react to the SGLT-2s?

Morales: When it comes to prescribers, there will always be those early adopters who embrace the newest technologies right away, and there will be those who will wait. I tend to be an early adopter and embrace newer technologies. I have an advantage being involved academically and knowing the clinical data.

EBDM: It sounds to me that, in the future, prescribers will be taking a more mix-and-match approach to individual patients, with clinicians using all the different drug classes in their arsenal, and that we may be moving away from a standardized step-therapy approach that is promoted in today’s type 2 diabetes treatment guidelines.

Morales: People have their target glycemic level in mind. It’s just a matter of how they will reach that target. We can’t forget that it’s about safety as well as efficacy. You want to be able to achieve your target glycemic level in a reasonable time frame, but you want the patient to get there safely. The question is, how many practitioners will feel comfortable with utilizing all of these different tools in order to allow their patients to get to their proposed target, and how quickly they will embrace the new agents that will soon be available? While we’ve learned more about the natural history of T2DM progression, other organs involved in glycemic management besides the pancreas, the management of T2DM continues evolving with newer, safer, and more reliable agents. We owe it to our patients to use these tools to their fullest potential.

1. Gough SC, Harris S, Woo V, et al. Insulin degludec: Overview of a novel ultra long-acting basal insulin [published online December 13, 2012]. Diabetes Obes Metab. doi:10.1111/dom.12052.

2. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.

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