With Muhammad Abdul-Ghani, MD, PhD and Elena A. Christofides, MD
Findings from the Qatar Study, an ongoing clinical trial at the Hamad General Hospital in Doha, Qatar, confirm a significantly greater decrease in the hemoglobin A1c (HBA1C) in patients with poorly controlled, long-term type 2 diabetes mellitus (T2D) who were treated with exenatide and pioglitazone versus insulin.1 Additionally, the dual therapy produced significantly less weight gain and a lower rate of hypoglycemia in patients than those receiving insulin therapy.
“The results of this study demonstrate that correcting the metabolic defects (insulin resistance and beta cell dysfunction) responsible for the development of hyperglycemia lowers HBA1c close to the normal level without significant increase in the risk of hypoglycemia,” lead author, Muhammad Abdul-Ghani, MD, PhD, from Hamad General Hospital and the Division of Diabetes at the University of Texas Health Science Center at San Antonio in San Antonio, Texas, told EndocrineWeb. “Remarkably, this approach was effective regardless of the starting HBA1c level.”
Clinical guidelines recommend that clinicians aim to decrease HBA1c levels in patients to < 7.0% (53mmol/mol) to reduce microvascular risks including retinopathy and nephropathy, according to the American Diabetes Association and European Association for the Study of Diabetes.2 Metformin and sulfonylureas also have been usual therapies used to manage HBA1c in patients with T2D, but these drugs lose effectiveness over time as they do not inhibit the progressive decline of b-cell function.3
Insulin therapy is often used to treat hyperglycemia once oral agents have lost their effectiveness, but this treatment has resulted in increased risk for hypoglycemia and undesirable weight gain.4
Like metformin and sulfonylureas, insulin therapy does not address disease processes that produce T2D, such as insulin resistance and loss of insulin-producing b-cells.
“When insulin was discovered, almost all cases of diabetes were type 1, and when cases of T2D became an issue, the medical community assumed that all hypoglycemia was the same,” said Elena A. Christofides, MD, chief operating officer of Endocrinology Associates in Columbus, Ohio, who was not involved in the study but commented as a member of the EndocrineWeb editorial board.
“Today insulin therapy continues to be used, even though people with T2D are not insulin deficient,” said Dr. Christofides. Thiazolidinediones including pioglitazone, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as exenatide, improve b-cell function and produce long-lasting decreases in HBA1c. These agents also have been associated with lower risks for hypoglycemia, and have been previously shown to be superior to insulin therapy for controlling plasma glucose levels in patients with newly diagnosed T2D.5
Dr. Abul-Ghani told EndocrineWeb that clinicians should change the way they approach treating T2D, noting that they “should think about the patient, not just their blood sugar level, and to address all aspects of diabetes. They should remember that hyperglycemia is only a symptom of T2D and clinician should address the disease (diabetes) not only its symptoms.”
“GLP-1 RAs are not new, and that there is evidence of their long-term efficacy, unlike insulin,” noted Dr. Christofides. “The American College of Endocrinology guidelines added GPL-1 RAs into the diabetes treatment algorithm the first year they were available. This class of drugs has been investigated for 30 years. This is not a novel concept, but it takes a long time to reverse course to get clinicians to stop immediately turning to insulin when patients stop responding to other treatments.”
In the Qatar Study, Dr. Abdul-Ghani and colleagues compared the efficacy of exenatide (2 mg/week) and pioglitazone (15 mg/day) to insulin therapy in 231 patients with longstanding T2DM (mean duration of 10.7 years), elevated HBA1c values >7.5% (58 mmol/mol), and who were currently receiving >1500 mg/day of metformin plus a GLA-1 RA.
After a follow-up period of 12 months, combination therapy decreased patients’ mean HBA1c values from 10.0 ± 0.6% (86 ± 5.2 mmol/mol) at baseline to 6.1 ± 0.1% (43 ± 0.7 mmol/mol) versus 7.1 ± 0.1% (54 ± 0.8 mmol/mol) with insulin therapy, a difference that was statistically significant (P <0.0001). Additionally, 83% of patients receiving combination therapy achieved the ADA-recommended HBA1c goal (<7.0%) versus 53% of patients receiving insulin therapy (P = 0.003).
Both study treatments were well tolerated. Hypoglycemia was the most commonly reported adverse event, and hypoglycemic events occurred 3 times more frequently in patients receiving insulin therapy than those in the combination therapy group. Mean weight gain in the combination therapy treatment group was only half that of the insulin group.
“The Qatar Study is ongoing and will examine the question of the durability of the metabolic benefits achieved with combination therapy,” said Dr. Abdul-Ghani. “It remains to be seen whether the difference in HBA1c achieved in combination therapy and insulin therapy in this range of HBA1c (6-7%) will translate to lower risk of microvascular complications.”
1. Abdul-Ghani M, Migahid O, Megahed A, et al. Combination Therapy With Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in Poorly Controlled Patients With Type 2 Diabetes on Sulfonylurea Plus Metformin: The Qatar Study. Diabetes Care. 2017. pii:dc161738. Published online January 17, 2017. Accessed January 15, 2017. Available at: http://care.diabetesjournals.org/content/early/2017/01/11/dc16-17382.
2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364-79.
3. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf. 2013;12(2):153–175.
4. Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes--causes, effects and coping strategies. Diabetes Obes Metab. 2007;9(6):799-812.
5. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268-75.