Emerging Medical Management of Type 2 Diabetes in Older Adults

Data is accruing to challenge current recommendations to provide less aggressive treatment to lower hemoglobin A1c levels in people over age 65 years in favor of combination therapy.

With Yehuda Handelsman, MD, and Elena A. Christofides, MD

Data is accruing to challenge current recommendation in favor of less aggressive treatment of hemoglobin A1c levels in people over age 65 years.

Many patients with type 2 diabetes (T2D) fail to achieve recommended glycemic goals. In fact, many individuals will require treatment intensification to both improve glycemic control and to address related clinical risks. There is a growing sense of urgency, and a push toward combination therapies using agents with different, yet complementary mechanisms of action.

Triple combination drug therapy initiated early is emerging as the best care.Do older adults with T2D have better outcomes with more aggressive treatment or the current standard of minimal management?

Among the questions to be addressed are:

(1) Which patients should be considered for combination drug management and in whom is this approach contraindicated?

(2) When should they be initiated? and

(3) How do age and comorbid conditions influence decisions for combination therapy?

These questions, particularly the safety and efficacy of dual and triple therapy to improve health outcomes in patients with type 2 diabetes were explored in a series of three papers,1-3 co-authored by Yehuda Handelsman, MD, FACP, FNLA, FASPC, MACE, Medical Director of the Metabolic Institute of America in Tarzana, California.  

Standard Care May Fall Short for Non-Frail Adults with T2D

“Many physicians are hesitant to initiate insulin, owing to concerns about injectable medications and fears of side effects,” said Dr. Handelsman who is also an endocrinologist in private practice.

The standard treatment of care, as put forth in the 2018 American Academy of Clinical Endocrinology/American College of Endocrinology guidelines (AACE/ACE),4 is to first initiate lifestyle interventions: diet and exercise, followed by metformin monotherapy, and then add a second agent if the patient has not achieved the target goal within three months. For patients with higher baseline hemoglobin A1c (HbA1c) (> 7.5%), the AACE/ACE guidelines recommend dual therapy with metformin and another agent after the initial management approach proves insufficient.

More relevant is that the results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study—higher mortality in the group receiving intensive therapy to achieve a HbA1c below 6% after 3-1/2 years of follow-up—led to recommendations opposing aggressive therapy, particularly in the frail elderly.5

However, this is like “’chasing failure’ as not all drugs are efficacious or safe for all patients, particularly for older patients,3 and slowly adding new agents can require a long time before a target HbA1c may be achieved,” Dr. Handelsman told EndocrineWeb.

Dr. Handelsman and colleagues published two different studies exploring the benefits of introducing combination therapies early on in the management of patients with T2D. The first study, published in the Journal of Diabetes Complications, evaluated the safety and efficacy of insulin glargine/lixisenatide (iGlarLixi) titratable fixed-ratio combination in older adults (> 65 years of age) with T2D.1

A second study,2 appearing in Obesity and Metabolism, compared triple therapy of dapagliflozin and saxagliptin with metformin versus dual therapy with sitagliptin plus metformin in patients with uncontrolled type 2 diabetes.

While both studies highlighted significant benefits of introducing combination therapies early in disease management, the exact results require individual consideration,1,2 according to the authors.

Revisit More Aggressive Diabetes Treatment in Aging Adults

The potential to reduce comorbidities and reduce the adverse effects of type 2 diabetes is an ever increasing challenge for practitioners given that 1 in 5 adults 65 years or older have a diagnosis of type 2  diabetes,6 according to the Centers for Disease Control and Prevention. And, this population is faced with diabetes-related complications including heightened risk for acute and chronic microvascular and cardiovascular complications.1

Furthermore, these older patients face a greater risk for cognitive dysfunction and depression,7 which has left many vulnerable patients excluded from clinical trials without the data to access any benefit that might come from more aggressive treatment strategies.

To date, diabetes management of older patients has been extrapolated from studies on younger, healthier patients with T2D, said Dr. Handelsman. In addition, the target glycated HbA1c for these senior patients is less stringent, having been set at 8.0 - 8.5% (64-69 mmol/mol),8 according to American Diabetes Association guidelines.

In addition, older adults are at greater risk for hypoglycemia “unawareness” and hypoglycemia-related consequences, and older adults perceive an unwillingness among providers to manage their multiple comorbid conditions or to develop individualized diabetes treatment plans that encompass all of their medical and psychiatric concerns.9 As such, clinicians are faced with greater challenges in seeking to deliver an optimal therapeutic regimen for older adults.

In the first of the two analyses,1 a post hoc analysis of two large phase 3 studies which examined the safety and efficacy of a fixed ratio combination therapy of basal insulin and glargine (iGlar) 100 units/mL plus lixisenatide, administered as a single daily injection, in adults aged 65 or older.1

This formulation combines a basal insulin, which focuses on improving fasting plasma glucose (FPG) by inhibiting hepatic glucose production and increasing peripheral glucose uptake; and lixisenatide, a short-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), which works to improve postprandial glucose (PPG) by enhancing glucose-stimulated insulin secretion, reducing glucagon secretion, and delaying the rate of gastric emptying.

Combining the two  drugs into one formulation was shown to improve HbA1c, fasting hyperglycemia, and postprandial hyperglycemia, without weight gain, and in a once-daily injection to enhance adherence.1

Recent Results Informs Care of the Older Patient with T2D

Both phase 3 trials included 534 older patients with type 2 diabetes who were insulin-experienced and insulin-naïve.1,2 Patients inadequately controlled on basal insulin for at least six months were randomized to receive either triple combination (iGlarLixi) or iGlar dual therapy in the insulin-experienced arm.1

Insulin-naïve patients who were inadequately controlled on metformin (with or without a second oral anti-diabetes drug) were randomized to iGlarLixi, iGlar, or lixisenatide alone in addition to ongoing metformin therapy. In both arms, patients treated with iGlarLixi achieved significantly greater reductions in HbA1c at Week 30 versus iGlar monotherapy as well as, in the second arm, compared with lixisenatide.1

In both groups, a significantly greater proportion of patients achieved target A1c <7.0% (53 mmol/mol) at week 30 with iGlarLixi than with either monotherapy, with no weight gain and no documented symptomatic hypoglycemia.2 Similarly, treatment with iGlarLixi was also associated with significantly greater reductions in PPG levels at Week 30 compared with iGlar in both trials.There were also considerably lower reports of gastrointestinal side effects in patients treated with iGlarLixi than with lixisenatide, but more than with iGlar monotherapy.

In a similar post hoc analysis,3 the safety and efficacy of a different combination, this one involving insulin degludec and liraglutide, was trialed in older patients aged > 65 years.  As with the iGlarLixi trial,1 the combination treatment led to significantly lower HbA1Cc levels than its comparators (GLP-1RA, insulin degludec, or iGlar U100) after 26 weeks, in patients both under and over age 65 years. Rates of hypoglycemia were lower with the combination treatment than with basal insulin.

“These post hoc study results indicated almost comparable efficacy between older and younger patients, with no increase in adverse effects among the older cohort,” said Dr. Handelsman. “In fact, they enjoyed a lower dose of insulin and less nausea and vomiting versus a GLP1 alone. These results show that initiating combination therapy earlier is very important.”

Reconsider Less Aggressive Treatment in Older Patients

“The strategy behind this study is sound, and AACE has been preaching earlier intervention with combination therapy for some time now,” said Dr. Elena A. Christofides, MD, FACE, chief executive officer of Endocrinology Associates and Endocrinology Research Associates in Columbus, Ohio, and a practicing endocrinologist. She expressed concerns that many practitioners may not be paying sufficient attention to optimizing pharmacologic treatment for (especially older) patients with T2D until after they have exhausted (failed) lifestyle interventions and sequential therapies.

“Patients receiving combination therapy—such as this GLP1/insulin combination—achieved target HbA1c and had less hypoglycemia in contrast to the significant adverse effects of hypoglycemia and weight gain associated with insulin monotherapy,” Dr. Christofides said. These findings just add to the data from a number of other recent studies that indicate, “insulin alone is not the most rational choice in many patients over 65 years old with T2D.”

“There is a societal bias that type 2 diabetes is a function of lifestyle gone awry,” she told EndocrineWeb. Consequently, “practitioners are treating T2D differently than they manage other chronic illnesses, such as hypertension or dyslipidemia, by using sequential add-on therapy instead of early combination therapy, unfortunately, to the detriment of their patients.”

This promulgates the current “attitude of treat to failure.” However, studies such as the Handelsman papers,1,2 which are well-designed studies that highlight the many benefits of combination therapies are necessary and relevant to ensure that practitioners gain comfort with initiating combination therapy earlier in the treatment strategy, said Dr. Christofides, in reviewing the research for EndocrineWeb, having not been involved in the studies.

Triple versus Dual Therapy in Patients with Poorly Controlled Type 2 Diabetes

When and how to intensify treatment for patients with type 2 diabetes whose blood glucose levels are insufficiently controlled with metformin remains unclear. Many patients are likely to require treatment intensification to maintain glycemic control as the disease progresses.

The addition of therapies with different mechanisms of action may accelerate and enhance reductions in HbA1c; however, this benefit must be weighed against any potential increased risk of adverse events. Historically, the approach has been to add a single agent to metformin; however, this has been associated with long periods of hyperglycemia and consequent increased morbidity.10

“What we’ve found is that when we give early combination treatment, we get patients to goal earlier, and they stay there longer,” Dr. Handelsman told EndocrineWeb.

This isn’t the only combination therapy to show good results. A recent multinational randomized, double-blind, active-controlled trial evaluated the efficacy and safety of triple therapy with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (DAPA), the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (SAXA), with metformin, compared with dual therapy of the DPP-4 inhibitor sitagliptin (SITA) with metformin.2

One limitation of the study examining the effects of early triple combination therapy—it did not have a comparison group who received DAPA + MET.This and other studies reported comparable efficacy between SAXA and SITA when added to MET,2,11 about which Dr. Christofides said, “the underlying suggestion is that drugs within the same class (such as SAXA and SITA) are similar enough to make broad comparisons about their safety and efficacy.”

The diabetes triple combination trial was a 26-week, double-blind treatment protocol followed by a 26-week blinded extension phase.2  There were 461 adult patients (aged > 18 years) who had a HbA1c of 8-10.5% (64 – 91 mmol/mol) who were randomized to either DAPA + SAXA + MET (n=232) or SITA + MET (n = 229). 

At both 26- and 52 weeks, patients receiving the triple therapy demonstrated a greater reduction in HbA1c from baseline than those receiving dual therapy (P = 0.0008), as well as a significantly greater proportion of patients who achieved HbA1c <7% (<53 mmol/mol). 2

However, even with triple therapy, the mean final HbA1c values in these participants remained above 7% (53 mmol/mol).2 Patients in the DAPA+SAXA+MET group also had a greater reduction in FPG than did those in the dual therapy group (P < 0.0001). Triple combination therapy was generally well tolerated with no significant difference in the incidence of adverse events between the two treatment arms.Also, there was no increased risk of hypoglycemia or other diabetes-specific events with triple combination therapy.

Apparent Benefits to Early Introduction of Triple Therapy 

“With triple therapy, the patients may get to goal faster with fewer side effects and the same or better benefits,” said Dr. Handelsman. However, “in contrast to the dual therapy study,” Dr. Christofides said, “this study is less straightforward and the results are not quite as clear.”  

While it is fair to compare the two different DPP4 inhibitors, “these studies aren’t comparing them directly–they are adding a boost to SAXA (with the addition of DAPA), which they hadn’t done in the SITA + MET group. As such, it is not clear if the results indicate whether it was the SAXA itself that was superior or the triple combination therapy (SAXA/DAPA/MET) achieving better results over the double combination (SITA/MET) of drug,” she said. 

Dr. Christofides also pointed to the study population, in which one-third of subjects had had “uncontrolled” diabetes for more than a decade, with Hb A1c >8%. “This begs the question –if these people haven’t had an effective therapy for 10 years, giving them anything along with metformin is likely to be immediately more effective: Therefore, is the response related to the efficacy of the drug or is it related to the fact that at this point, doing anything will be more impactful?” she said.

To emphasize this point, Dr. Christofides compared this concept to a dry versus wet sponge–the wet sponge won’t absorb as much water (eg, respond) as the dry one. Making one last point, she expressed concern about the authors’ conclusion with regard to durability, noting one year does not equate with a demonstration of sufficient strength of findings lasting in the life of a person with diabetes.

In effect, both Dr. Handelsman and Dr. Christofides agreed, “we need to be able to continuously prove that combination therapy early on is beneficial and that insulin is not the be-all, end-all treatment.” “While Dr. Handelsman’s study on dual therapy in older patients clearly emphasizes these points,” Dr. Christofides said, “interpreting the results of the triple combination study are less clear owing to the noted methodological limitations.”

Disclosures: The study with triple therapy was funded by Bristol-Myers Squibb and AstraZeneca. None of the authors received any financial or monetary transfer of value for their participation in the preparation of the manuscript. The dual treatment study including writing support was sponsored by Sanofi. Dr. Handelsman received research grants from Bristol-Myers Squibb, among others while Dr. Christifides has no financial conflicts of interest.

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