Promise of Dual Action Antidiabetic Monotherapy

Preliminary data for investigational ertugliflozin suggests favorable outcomes for people with recalcitrant type 2 diabetes despite improvements in physical activity and diet.

With Juan Frias, MD and J. Michael Gonzalez-Campoy, MD, PhD

Six months of treatment with the experimental drug, ertugliflozin, achieved a reduction in blood glucose and body weight in people with type 2 diabetes (T2D) who failed to see such gains through lifestyle modification,1 as reported in Diabetes, Obesity and Metabolism

Ertugliflozin is one of a relatively new class of antidiabetes medications that function by inhibiting sodium/glucose cotransporter-2 (SGLT2) receptors that are involved in kidneys reabsorption of blood sugar.2 By blocking SGLT2 receptors, the kidneys are able to excrete more glucose and allow the body to use its energy stores more efficiently.

For hard to manage diabetes, ertuglifozin may improve glucose control.

The new findings were gleaned from the 1st stage of a year-long phase 3 trial involving 461 men and women (mean age, 56.4 years) with T2D that remained unresponsive to exercise and improvements in their diet.1 Participants from 67 facilities across 7 countries received either 5 or 15 mg of ertugliflozin for 26 weeks, after which the researchers assessed their HbA1c, body weight, and blood pressure.

How Well Did Ertugliflozin Achieve Primary Outcomes?

Both doses of the medication were associated with statistically significant decreases in HbA1c levels—the primary endpoint of the trial—according to the investigators. The average reduction in blood glucose was 0.99% at 26 weeks of treatment for the 5 mg dose, and 1.16% at the 15 mg dose.1

These findings are significant given a 1% drop in HbA1c can reduce a person’s risk of microvascular complications of diabetes by 37% and can markedly reduce the risk for cardiovascular disease in these patients.3

This monotherapy also appeared to promote modest but statistically significant loss of weight: 1.8 kg and 2.2 kg compared with placebo for the 5- and 15-mg doses, respectively,1 according to the study findings.

Juan Frias, MD, president of the National Research Institute, in Los Angeles, which was 1 of the participating study sites, said the size of the effect is in line with other drugs in the SGLT2 class, and slightly more than what would be expected with gliptin medications, such as sitagliptin, saxagliptin or linagliptin.

“You get that with actual weight loss and a reduction in blood pressure,” Dr. Frias told EndocrineWeb.

Treatment with ertugliflozin, a combination antidiabetes medication being developed by Pfizer and Merck, led to a reduction in HbA1c relative to placebo across all subgroups of patients in the study.1 The gains were greatest in people whose baseline levels of blood glucose were at least 8% at baseline.

Although the study was not powered to determine dose-related differences in the effectiveness of ertugliflozin, the results suggest “incremental” gains from the higher dosage, the authors stated.

Ertugliflozin seemed generally well tolerated. However, there was an increased risk for fungal vaginal infections, particularly in woman—an effect observed similarly across this drug category. In 1 case, a female participant who experienced a genital mycotic infection dropped out of the study.

What to Share With Patients About Possible Side Effects

Dr. Frias advised clinicians to tell patients that these infections can occur, but that they typically respond very well to treatment. “I’ve used these drugs a lot and I’ve studied them a lot and I’m really not that concerned,” he said.

Although low blood sugar was uncommon, 2 patients who were taking the 15-mg dose of ertugliflozin experienced severe hypoglycemia, one of who required medical attention, the researchers reported.

“The fact that these drugs don’t cause low blood sugar is really important,” Dr. Frias said. No patient experienced diabetic ketoacidosis, he pointed out, although the class of medications can cause that complication. “We were looking for that very closely,” Dr. Frias said. 

To date, no head-to-head data on the SGLT2s are available. Researchers are now conducting a trial to see if ertugliflozin can improve adverse cardiovascular side effects associated with hyperglycemia.

Merck and Pfizer submitted their application for FDA approval of ertugliflozin, as well as fixed-dose combinations of the drug plus sitagliptin and metformin, in late 2016.

Expert Clinical Perspective on Industry-Sponsored Research

“The traditional goal of treatment in patients with T2D is to lower the blood glucose as much as possible without incurring hypoglycemia.  This ‘glucocentric’ approach has been replaced with a comprehensive approach to patient care, including aggressive management of other cardiovascular risk factors, such as cessation of tobacco use, lowering blood pressure and lipid management,” J. Michael Gonzalez-Campoy, MD, PhD, FACE, told EndocrineWeb.

Knowing that adipose tissue is an active endocrine organ, and the adipocyte is an endocrine cell, has now made weight management an integral part of individualized care for patients who have T2D, said Dr. Gonzalez-Campoy, is medical director and CEO of the Minnesota Center for Obesity, Metabolism, and Endocrinology in Eagan, Minnesota.

“Bariatric endocrinology takes it one step further. The goal is not just to decrease fat mass, but rather to improve adipose tissue function. In this light, treatments that address both glycemia and improve adipose tissue function are preferred,” he said. 

Moving Toward Dual Action Antidiabetes Medications 

Clinicians now have access to 2 broad options for their patients with diabetes:  hypoglycemic drugs that lower blood glucose, such as sulfonylureas and insulin; and antihyperglycemic drugs that prevent glucose from rising but do not carry the risk of hypoglycemia, such as metformin and the gliptins, and most recently, SGLT2 inhibitors.

“The latter group of medications are most preferred,” Dr. Gonzalez-Campoy said.  “The benefits of these medications include lowering of blood glucose, reducing hypertension (by producing an osmotic diuresis), stimulating adipose loss, which in turn lowers insulin demand, and lastly, leads to improvements in the lipid panel, specifically lower triglycerides, and elevating high density lipoproteins."

“For clinicians, preferential use of antidiabetes medications that decrease fat mass and return adipose tissue function toward normal, including SGLT2 inhibitors, is highly recommended,” said Dr. Gonzalez-Campoy. 

“The stepwise approach to diabetes care that is driven by 3rd party payers forces prescribers and patients into the use of older generic medications (i.e. sulfonylureas), which creates patient harm.  Clinicians should fight this bureaucratic approach to medicine that is based on financial decisions of benefit only insurers,” Dr. Gonzalez-Campoy said.

Continue Reading:
Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
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