ENDO 2018: 100th Endocrine Society Annual Meeting :

Cardiometabolic Outcomes Better Endpoint in Newly Diagnosed Diabetes

At a conference ahead of ENDO 2018, two experts debated the benefits of treating type 2 diabetes by stepwise care versus polypharmacy, proposing instead to look at a more innovative approach that focuses on cardiometabolic parameters over hemoglobin A1c as the future driver of care. 

Diabetes is a complex disease. By the time a diagnosis of type 2 diabetes (T2D) is made, 50-80% of beta cell function has been lost, inhibiting adequate insulin secretion. Since there is no way to know how quickly insulin dysfunction will occur, it is difficult to anticipate how aggressive to be with regard to treatment.

In a pre-conference program at ENDO 2018, two of the foremost authorities on diabetes management—Silvio E. Inzucchi, MD, and, Carol H. Wysham, MD—faced off in a debate-style discussion to consider the efficacy of  two treatment approaches for the management of T2D: Stepwise Approach versus Initial Combination Therapy.1

Maintaining Current Standard of Care for T2D

Arguing in favor of the benefits of Stepwise Treatment—Dr. Inzucchi, professor of medicine, clinical director for the section of endocrinology, and medical director of the Yale Diabetes Center at Yale School of Medicine in New Haven, Connecticut.

Dr. Inzucchi made a case in favor of retaining the stepwise approach to diabetes management, given the known benefits of this approach.1 “Stepwise therapy is the current model of care, and what we’ve gotten used to,” he said, in suggesting endocrinologists stay the course.

The overriding goal for good stepwise care is "to keep it simple,” he said. This approach to T2D treatment holds that hemoglobin (Hb) A1c levels are the focus for determining a patient's treatment. As such, for patients with type 2 diabetes, lifestyle modification remains first-line treatment with the addition of metformin in those for which changes in diet and exercise are not sufficient to reduce HbA1c sufficiently.2

Is Monotherapy Effective?

In 80% of patients on metformin, a reduction in HbA1c levels after five years was achieved, performing good durability.3

“The preferred method of treatment for hyperglycemia in patients with diabetes is to add agents sequentially for targeted diabetes control,” Dr. Inzucchi told EndocrineWeb. If the patient presents with cardiovascular (CVD) complications, such as hypertension or hyperlipidemia, then the addition of renin–angiotensin–aldosterone system inhibitors, statins, and acetylsalicylic acid, have been proven effective.4

The benefits to be gained with statins is unequivocal, yet, the quest for the most effective level of potency for statin therapy persists. Not only is a stepwise approach easier, it has a lower cost, and presents less risk for side effects in comparison to combination therapy,5 said Dr. Inzucchi.

Time to Initiate Early Combination Therapy

A more aggressive approach to care was presented by Dr. Wysham, clinical associate professor of medicine, at the University of Washington-School of Medicine (Seattle), and section head at Rockwood Center for Diabetes and Endocrinology, in Spokane, Washington.1

Dr. Wysham offered a compelling argument in favor of adopting initial combination therapy for patients who are newly diagnosed with T2D;1 she cited clinical inertia as a fundamental factor in the failure of clinicians to achieve target goals, specifically Hb A1c.

“Clinical inertia prevents us from getting patients to target goals,” Dr. Wysham said, as has been reinforced by typical patient pleas to "give me just three more months." This inertia manifests as a hesitation to start antidiabetes therapy, yet treatment initiated within the first six months of a diagnosis of T2D has the best chance of preventing the onset of microvascular complications.

Stepwise Care Isn't Working

 “Let's face it; what we are doing now is not working,” she said. 

“Patients are not in good glycemic control and have very high rates of complications.” Dr. Wysham said. For example, a failure to initiate aggressive therapy within the first six months after a diagnosis of diabetes showed a marked increase in the rates of retinopathy.6

The concept of using early combination therapy, while not proven, has the potential to address what we know are real problems of clinical inertia and adherence problems with patients,” Dr. Wysham told EndocrineWeb.

Possibly Greater Efficacy, Better Adherence at Less Cost

Furthermore, results from the EDICT exploratory study demonstrated that patients with newly diagnosed T2D who were treated with a combination of metformin/pioglitazone/exenatide experienced fewer hypoglycemic events than sequential add-on therapy with metformin, sulfonylurea, and basal insulin.7

Specifically, patients who received the triple therapy experienced a 7.5-fold reduction in hypoglycemia, a significant reduction HbA1c levels (in comparison to the group receiving conventional therapy (5.95 vs. 6.50%; p < 0.001), and greater weight loss (1.2 kg versus a mean weight gain of 4.1 kg [p < 0.01]) in comparison to the group receiving conventional therapy.7

“We’ve found that in patients on metformin who exhibited a high HbA1c, only 40-60% managed with a stepwise approach achieved their targets, but the rate rises to 50-100% when combination therapy has been introduced,” said Dr. Wysham.

What Do Patients Expect?

While it may seem counterintuitive, combination therapy has been shown to reduce treatment complexity and improve patient adherence.8 Among patients who failed to adhere to their prescribed stepwise therapy, they also demonstrated a failure to achieve treatment goals and had a greater likelihood of future hospitalization and increased risk for all-cause mortality.

Indications are that anywhere from 38 to 93% of patients have exhibited poor medical adherence as reflected in a failure to fill prescriptions for new antidiabetes medications.9 This inaction has been attributed to multiple factors, including issues of not understanding the benefits gained by starting medications early, fear of side effects, and cost.

“Most importantly, patients have expressed frustration with the length of time anticipated to achieve target treatment goals,” said Dr. Wysham.

Meeting of the Minds Points to Novel Approach  

Metformin has its metabolic limits, given that 28% of patients couldn’t achieve their HbA1c targets, and 57% is primary or secondary treatment therapy failure within 2.3 years due to an issue of adherence, including meeting Hb A1c target, Dr. Wysham offered in rebuttal. Furthermore, “lower doses of multiple drugs may achieve a greater HbA1c target than higher doses of a single treatment,” she said. 

Dr. Inzucchi responded, “[Perhaps,] are we both wrong?”

Findings from the EMPA-REG trial4 suggest that targeting for hemoglobin A1c as a primary endpoint had little to do with T2D morbidity and mortality. Instead, it may be time for endocrinologists to consider a novel approach to improve outcomes for patients with type 2 diabetes,10,11 he said.

Such an approach might begin with an initial combination therapy based on underlying complications, rather treating for HbA1c levels, according to Dr. Inzucchi. When cardiovascular complications are evident, either a sodium/glucose cotransporter 2 (SGLT-2) inhibitors or glucagon-like peptide 1 (GLP-1) agonists should be added to reduce risks of stroke and/or chronic kidney disease.10,11

In the end, both experts agreed that going forward the focus must be to treat to deliver cardioprotective therapy, which will require a novel to approach to diabetes care. This change in practice would necessitate that endocrinologists gravitate toward objective outcomes, rather than a treat-to-target approach centered on lowering HbA1c, per se.1

Currently, there are no clinical trials to provide an evidence basis for one approach over the other, said Dr. Inzucchi, and this will be essential to guide future care in terms of fostering adherence, overcoming inertia, and most importantly, informing cost.


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