Upending of Conventional Combination Therapy in Type 2 Diabetes Mellitus

Rapid innovation in treating type 2 diabetes mellitus (T2DM) has challenged primary care physicians (PCPs) and endocrinologists alike to stay current. Clinicians have a high comfort level with prescribing metformin as a first step after changes in diet and exercise in a patient with newly diagnosed T2DM. However, monotherapy with metformin may work only for a short time for a few patients to sufficiently lower glycated hemoglobin (A1C) levels, owing to the deteriorating nature of beta-cell function.¹

The typical second step, if hyperglycemia persists, has been to add a sulfonylurea (SU), like glipizide; however, clinicians often wait too long before adding the second medication, thus limiting its effectiveness.¹ As a result, consensus is growing to begin combination therapy earlier in treatment. This more aggressive approach to controlling glycemic levels early on, studies suggest, will preserve beta-cell function down the line; the goal is to prevent serious long-term consequences such as kidney disease, neuropathy, and glaucoma.

Although metformin and SU have long been the top choices for initial antidiabetic drug treatment, other noninsulin choices for step 2 therapy abound, from Actos (pioglitazone) to Victoza (liraglutide [rDNA origin] injection). To compound the choice facing clinicians, many manufacturers, when conducting mid-stage and late-stage clinical trials, include a monotherapy trial of their glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 inhibitor (DDP-4), thiazolidinedione, metglitinide, or sodium-glucose cotransporter 2 (SGLT-2) agent. These are often shown to be effective in placebo-controlled clinical trials.

Moving Faster to Effective Therapy

In its 2014 update, the American Diabetes Association (ADA) revised its Clinical Practice Recommendations for treating T2DM. A significant change from past recommendations is a shorter trial of noninsulin monotherapy to control hyperglycemia. According to the new guidelines, physicians should wait no longer than 3 months (instead of up to 6 months) in an average patient before moving to combination therapy.² If adopted, this practice would compel clinicians to decide earlier which second-line therapy is best for their patients. For many, this means prescribing an SU, which they have been doing for years in patients who do not have contraindications.

For others, the more innovative choices can be both attractive and daunting.In its 2014 standards of medical care, the ADA provides open-ended advice: “If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a glucagon-like peptide 1 (GLP-1) receptor agonist, or insulin.”³ In other words, there is little specific information (and evidence) to help providers choose.

In these studies, insulin-based combinations, rather than metformin/SU, are used as the first drug combination. (Some of these studies were previously reported in Evidence-Based Diabetes Managmenent.⁴)

This change is being driven by an overarching clinical and physiological philosophy, according to John Anderson, MD, of the Frist Clinic in Nashville, Tennessee: Stop beta-cell deterioration by getting patients to goal A1C levels as soon as possible. He said that ideally, one would screen patients with prediabetes and treat them at that point with lifestyle interventions or metformin.

“By the time patients are diagnosed with diabetes, we need to get them to glycemic goal as quickly as possible and keep them there as long as you can to reduce beta-cell damage and the long-term risk for micro- and macrovascular disease,” Anderson said.

However, patients are infrequently diagnosed with prediabetes, and may have significantly elevated A1C levels when they are first seen by the clinician. Anderson explained, “If you can get them to goal on metformin monotherapy, that’s fine, but if the patient is first diagnosed with an A1C of 8.5% or 9%, you have precious little chance to get them to goal with 1 treatment. In that case, we need to make changes to their treatment as soon as is feasible. For that patient, you may need to start out not on monotherapy, but on combination therapy.”

Sparing beta cells or limiting beta-cell deterioration has long been an ultimate objective of T2DM care.¹ New studies have demonstrated that using insulin early in the natural history of the disease can actually produce short remissions in hyperglycemia and slow beta-cell dysfunction. Furthermore, investigators found that this occurred after only a few weeks of therapy.⁵ This offers patients the possibility of using insulin early, but not continuously injecting it for the rest of their lives. In this scenario, GLP-1 treatment (which seems to have positive effects on beta-cell number and function)⁶ would be used as maintenance therapy over the long term. This concept is based on an innovative way of thinking about the origins of diabetes, involving the interaction of fatty acids and glucose—a “glucolipotoxicity.”⁴

Insulin and GLP-1 Combination

Novo Nordisk has already developed the idea of a full-fledged combination of insulin and GLP-1, called Xultophy. This combination comprises Novo Nordisk’s new insulin formulation (degludec) and the company’s already approved GLP-1 injectable (liraglutide). The company has filed for approval of the drug combination in Europe, where insulin degludec is already approved. One interesting benefit of this therapeutic combination is that liraglutide’s ability to induce weight loss may help offset insulin’s common side effect of weight gain.

At the recent ADA Scientific Sessions, investigators reported the 1-year results of using Xultophy (IDegLira). Researchers reported that 78% of those taking the combination achieved an A1C level of 7% compared with 63% of those taking insulin degludec alone or 57% of those trying liraglutide monotherapy. The main trial included more than 1600 patients, and the study extension to 1 year, more than 1300. In this investigation, patients taking the combination therapy lost a mean 0.9 pounds compared with a mean 5.1-pound gain for those taking insulin degludec only. Additionally, those taking the combination treatment used an insulin dose that was 37% lower than the dose used by those taking insulin degludec alone. The rate of hypoglycemia was also 37% lower with Xultophy than with the basal insulin alone.⁷

Another study at ADA presented 52-week findings using a different insulin—GLP-1 combination: insulin lispro and dulaglutide, a once-weekly GLP-1 injection. They demonstrated that insulin lispro given at mealtime, along with dulaglutide, offered better glycemic control than basal–bolus therapy with insulin glargine and insulin lispro (ie, 58% of patients attaining A1C levels less than 7% vs 49% using basal/bolus therapy; 1.48 point decrease in A1C vs 1.23 point decrease for the basal/bolus treatment), with a similar side effect profile. Hypoglycemia rates were 31 events/patient/year for the dulaglutide 1.5 mg/lispro combination vs 35 events for the dulaglutide 0.75 mg/lispro combination; the control group, with the lispro/glargine combination, had 39 events.⁸

Said Anderson, “We’re just learning about this combination, but we do know that many things work well in combination with basal insulin. If a person is already taking basal insulin, it might be easier to intensify their regimen with a single shot of a GLP-1 than with 4 bolus shots each day. We don’t have any long-term outcome studies on the comparison between the 2 regimens, however.”

Anderson, who is also the immediate past president of medicine and science at the ADA, added, “You can say that the 26-week data on dulaglutide and basal insulin yielded better results than basal—bolus treatment in getting to A1C goal. We don’t know what the results may look like 10 years down the line, but we don’t have reason to believe the long-term benefit won’t be reflective of the short-term findings announced at ADA.”

SGLT-2 and DPP-4 Inhibitors

Combining 2 medications with different mechanisms of action seems to bear fruit in the control of T2DM. Boehringer Ingelheim and Eli Lilly have filed a new drug application with the FDA for a single pill combination of its recently approved SGLT-2, empagliflozin, with its DPP-4 inhibitor, linagliptin. In this case, the SGLT-2 acts on the kidney to release extra blood glucose into the urine, combined with the DPP-4 inhibitor’s slowing of glucagon release, and increasing insulin production when food is ingested.

Compared with treatment with its individual components (398 patients), the combination (269 patients) caused a significant reduction in the A1C levels in a phase 3 trial (Table 1). In addition, the percentage of patients taking the medication combination who attained an A1C less than or equal to 7% after 24 weeks was far greater than those taking either component alone (odds ratio, 1.9-4.3). Interestingly, in combination, the lower dose of empagliflozin seemed to be more effective than the higher-dose combination.⁹

More in the Arsenal and More Varied Choices

In some ways, diabetes therapy may resemble cancer care in the future. A laundry list of treatments are available, with different mechanisms of action, and it will ultimately be left up to the clinician to choose what he or she believes will work best for the individual patient; specifically, to spare beta cells by reaching glycemic goals rapidly. Of course, payers will continue to exert due caution with regard to both untested therapies and the cost of treatment. For this reason, some clinicians may not retreat from step therapy or prior authorization approaches to diabetes treatment. There may be hand-wringing if inexpensive, generic metformin—SU treatments are replaced en masse with higher-cost combination approaches.

Table 2 shows diabetes prescription data provided by IMS Health, in which the utilization of various diabetes drug categories has changed between 2010 and 2013. While metformin prescribing dominates and has grown slowly over the years, the prescription of other drug categories has changed significantly. For instance, the use of fixed-dose biguanide—SU combination therapy has dropped off, as has the utilization of glitazone-biguanide combination therapy, but the prescription of DPP-4-biguanide combinations had grown substantially until this past year. Although it is not possible to say from these data whether other non–fixed dose combinations are being tried in increasing volumes, it is almost certain that if a combination of 2 agents seems to produce a clinical benefit, the biopharmaceutical industry will work on a new formulation to fill this demand.

Anderson believes that physicians may be willing to move away from SUs but not metformin. He said, “Even today, physicians add sulfonylureas somewhat reluctantly, because they have the potential for hypoglycemia, are associated with weight gain, and may be harmful to beta cells (in theory but not yet proven).” He added, “Yet, they still cost very little, so we know that patients can afford them and can access them. The SUs may be falling out of favor, in favor of combinations of metformin and DPP-4s and other biguanide combinations.”

Anderson added, “When I started in practice, there were hardly any choices. Today, we have many more options with which we can tailor therapy to the individual patient. But it is difficult for diabetes physicians—much less PCPs—to keep up. But we have a diabetes epidemic on our hands, and 90% of the diabetes population are treated by PCPs. We need to learn how to use these various agents and get good at it.” This means not only figuring out which therapies will get specific individuals to goal quickly, but when to move on to the next step in treatment.References

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