Novel Triple Combination Pill Poised to Simplify Diabetes Management

As the challenge of attaining better glucose control grows, introducing the first three-in-one therapy may lead to better outcomes with greater ease and lower cost.

with Mohamed Eid, MD, MPH, MHA, and Daniel Einhorn, MD

The Food and Drug Administration (FDA) approved the New Drug Application (NDA) for Trijardy XR—a novel once-daily, fixed-dose, triple combination therapy—designed to improve glucose control while easing management of symptoms in adults with poorly controlled type 2 diabetes in whom standard therapy has proven inadequate; the NDA was submitted for review by Boehringer Ingelheim and Eli Lilly and Company in June 2019.1

In anticipation of product approval, EndocrineWeb spoke with Mohamed Eid, MD, MPH, MHA, vice president of clinical development and medical affairs for cardiometabolism and respiratory medicine at Boehringer Ingelheim Pharmaceuticals, Inc., to learn more about the development of this triple combination diabetes therapeutic, and Daniel Einhorn, MD, clinical professor of medicine at the University of California at San Diego, and medical director of Scripps Whittier Diabetes Institute.

FDA approves first triple combination therapy for type 2 diabetes.

Addressing Challenges of Polypharmacy for T2D  

“Having a single formulation that enables patients to achieve improved glucose control with a less complex regimen will be beneficial in achieving better diabetes management,” said Eid, "as we expect it will meet their needs for a therapy that is accessible and affordable by eliminating multiple copays and lessening the complexity of polypharmacy therapy.”

The makeup of this triple combination pill is:

  • Empagliflozin (Jardiance)—a sodium glucose co-transporter-2 (SGLT-2) inhibitor that blocks glucose reabsorption in the kidneys, which prompts greater urinary elimination of excess glucose in the urine by blocking glucose re-absorption in the kidney, and has been shown to reduce cardiovascular disease risk as well as to promote weight loss in most individuals.
  • Linaglitin (Tradjenta)—a dipeptidyl peptidase-4 (DPP-4) inhibitor that improve glucose control by increasing release of pancreatic hormones that signal the liver to produce less glucose; and has a demonstrated favorable cardiovascular safety profile.
  • Metformin extended release (XR)—the standard, first-line therapy for individuals diagnosed with type 2 diabetes.

Trijardy XR will be available in four different dosage combinations:

  • 5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release
  • 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release
  • 12.5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release
  • 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release

The NDA submission relied on data garnered from two randomized, open-label trials conducted to assess the bioequivalence of this investigational three-drug, fixed-dose therapy for adults with type 2 diabetes in whom currently available approaches to glucose management have proven insufficient to adequately reduce blood glucose levels, and for which adding a third pill for glucose control alone was viewed as a significant burden for most patients, he said.

While not prepared to share details of the clinical trials until after the FDA has completed their review, Dr. Eid offered that there are safety data on the concomitant admistration of three components in the Trijardy combination tablet for up to 52 weeks of active glucose control in adults with type 2 diabetes.

Current Add-On Approach Falls Short in Glucose Management

“While there are many options to help bring patients into good blood glucose control, including the newer classes of medications (eg, SGLT inhibitors, GLP-1RAs, and DPP4s), these alone may not always work when patients have to handle complicated regimens,” he said. “With this concept in mind, our goal has been to meet the patients where they are. Many of them may find it difficult to add yet another drug to manage their type 2 diabetes.”

“From that understanding, we recognized the challenges presented by polypharmacy in managing the growing number of patients who need more than metformin and a second line agent, including injectables, to address both blood glucose control and the other concomitant diabetes associated conditions (ie, cardiovascular disease, retinopathy, neuropathy, and kidney disease) needed for effective diabetes therapy,” he said. 

Furthermore, when prescribing additional medications to improve glucose control, safety becomes an issue as clinicians need to be mindful of drug interactions so knowing that each of the components has established efficacy and safety data may be helpful in managing patients with progressing T2D,” Dr. Eid told EndocrineWeb.  

Drawing on complementary modes of action, this triple combination therapy aims to be additive, delivering a synergistic effect in which insulin sensitivity is improved and the body is prompted to produce more insulin, in addition to enhanced glucose excretion, said Dr. Eid. “In one tablet, we are able to address multiple metabolic pathways that could be useful in delivering an effective therapy."

How Effective Can a One-Size-Fits-All Tablet Be?

“While a single formulation may not always be enough, for the vast majority of scenarios, clinicians are often faced with the need to consider adding more medications to help improve glucose control in which case this triple combination tablet could make adherence easier and more manageable, or patients than adding on another drug to their already long list of medication,” said Dr. Eid.

Considerations with the Prospect of Cumulative Adverse Effects

This triple combination tablet has not been tested yet for its efficacy regarding heart failure but we know that at these appropriate doses, empagliflozin has achieved CVD endpoints and data on hospitalization for heart failure in the EMPA-REG OUTCOME trial,2 and Linagliptin, too, has amassed significant cardiovascular safety based on results of the Cardiovascular Outcomes Trials (CVOTs): CARMELINA and CAROLINA.3,4

“In our trial of this combination therapy, the most common side effects as reported in 5% or more of patients were urinary tract infections, diarrhea, upper respiratory infections, all of which will be clearly highlighted in the product label,” Dr. Eid said. “For any patients who has had a history of infections, this T2D combination therapy may not be appropriate. So, as always, it remains important to come back to individual patient selection to ensure that the benefits outweigh any possible risks.

“We are all about meeting critical patient needs,”  he said, “and no one medication is right for everyone but it is better to have more viable options as the best way to help healthcare professional deliver better treatment to more patients.”

“We believe this single drug can be logistically attractive and useful in delivering in well-established medications, particularly beneficial in the primary care setting,” Dr. Eid said. If fact, we have found a significant gap in ease of treatment that we are looking to fill, which may be met by this triple combination therapy in providing a good balance between efficacy, safety and convenience."

Sorting Out If and For Which Patients this Triple Daily Pill Might be Suitable

In response to the best role for this newly approved once daily triple treatment, Dr. Einhorn told EndocrineWeb:

“We tend to underappreciate how much we’ve been limited by decades of “step therapy” dogma,” he said., adding this once daily pill appears to address many issues:

  • Simplicity is essential in any chronic disease therapy, and cost is a critical factor.
  • It offers the best chance at optimal control as early on the onset of diabetes as possible since single agent oral therapy is rarely sufficient for the majority of patients as has been demonstrated by DeFronzo and others who have shown that initial triple combination therapy, granted with different agents, produces better and sustained control as compared with sequential therapy.5-7
  • Adding second or third agents separately is typically delayed in usual practice, often by years.  
  • The agents selected [in Trijardy XR] are logical together in that they require no dose adjustment for kidney disease except at the extreme, when function falls below what is recommended for metformin.
  • We do not acknowledge the sense of defeat our patients and their families can feel when additional drugs are added sequentially because glucose control is not good enough, which has been dubbed the ‘treat to failure’ method.”

“By being an FDA approved combination, this pill makes normal what may otherwise be criticized as ‘polypharmacy,’” said Dr. Einhorn. The multiple metabolic defects that may result in chronic type 2 diabetes will require medication with multiple different mechanisms of action and this literally embodies that need.”

That said, Dr. Einhorn pointed out a few concerns requiring consideration before a clinician will want to prescribe this daily triple therapy pill:

  • The fixed doses may not optimize the efficacy of any individual drug.
  • There is an increased risk of side effects and it will be difficult to know which component caused the adverse reactions.

Thus, he said: It behooves clinicians to consider whether each individual medication be tried and optimized first before combining or is the patient better served by go directly to the 3-in-1 pill and only unbundle if there is a problem with tolerance?

“We may ultimately develop a confidence in triple combination therapy so that we could start the single pill early in treatment and unbundle only if there are side effects," said Dr. Einhorn. "However, given the normal caution over individualization and adverse effects, I think most clinicians will choose to titrate each component individually, see how well the triple combination fits the profile of the patient, and then decide based on the other issues such as cost, pill burden, compliance, acceptance of combination therapy, whether this is a good choice for the given patient."

The data from the clinical trials will be presented at one of the medical meetings held in the Spring 2020.

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