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Timely augmentation to triple oral antihyperglycemic therapy

An antidote to clinical inertia in type 2 diabetes management

Science China Press

The goal of the management of type 2 diabetes is to achieve and maintain blood glucose levels close to the normal range in order to delay or prevent the development of the long-term complications of the disease, such as myocardial infarction, stroke, vision loss and kidney failure. For most patients, the treatment goal is to keep the glycated hemoglobin (HbA1c) < 7%.

Diabetes is a progressive disease, such that most patients will eventually need to use multiple pharmacological agents in order to reach glycemic targets. In fact, major professional societies, including American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and Chinese Diabetes Society (CDS), strongly advocate a stepwise approach to glycemic control that initiates with metformin and intensifies treatment incrementally to dual and triple therapy at 3-month intervals until the patient is at their individualized goal. Despite the wide acceptance of the benefit associated with tight glucose control, less than 40% of type 2 diabetic patients worldwide are at the glycemic control target (HbA1c < 7%) typically recommended in treatment guidelines. Delay in treatment intensification, also known as 'clinical inertia', is common in real world practice. This is particularly true for patients who are on dual therapy with two oral antihyperglycemic agents (AHA), but whose HbA1c remains above 7%. One of the reasons behind the 'clinical inertia' in patients on dual therapy may be the obstacle of adding or switching to injectable agents, such as insulin or GLP-1 receptor agonists. In this context, it is important to understand the comparative efficacy of the addition of a third oral AHA.

Recently, Professor Jianping Weng from The Third Affiliated Hospital of Sun Yat-Sen University and co-investigators released the results of a large clinical trial aimed at exploring the potential of a variety of oral AHA as a third line agent for type 2 diabetes. The study is entitled 'Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial', and was conducted in 237 centers screening 7880 type 2 diabetic patients across China. This is the first comparative effectiveness trial to evaluate the efficacy and safety of the addition of a third AHA to the metformin/ sitagliptin dual therapy. The trial had a two-phase sequential design, first evaluating the combined effect of metformin with sitagliptin. Those who did not achieve the glycemic control target (HbA1c <7%) in the first phase were then randomized to receive one of the four commonly used oral AHAs for a head-to-head comparison of 4 triple AHA therapies.

Initially, 5535 patients with type 2 diabetes who were unable to control their glucose with life style measures and metformin were enrolled in the first phase of the STRATEGY study. On average, they had diabetes for 5 years and had a baseline of HbA1c of 8.03% at the time entering the study. Their mean age was 53 year old, mean body mass index 25.8 kg/m2, and 60% of the participants were male. At the end of 16 weeks, a mean HbA1c reduction of 0.85% from a baseline was observed when the DPP-4 inhibitor sitagliptin was added to metformin, and 44.3% of study participants achieved the target goal of HbA1c < 7%. This finding is consistent with the reports of combined metformin plus DPP-4 inhibitor regimens in many previous studies.

The second stage of the STRATEGY study randomized 2,202 of those not at HbA1c<7% goal to either a sulfonylurea (glimepiride, gliclazide), a meglitinide (repaglinide), or an alpha glucosidase inhibitor (acarbose) for 24 weeks. The addition of a third oral AHA agent to the metformin + sitaglipin regimen led to a further 0.59% HbA1c reduction from the baseline of 7.7% at the beginning of the triple therapy stage. The magnitude of the reduction in HbA1c in those treated with acarbose (0.45%) was lower than that of glimepiride (0.65%), but the glucose-lowering efficacy of gliclazide and repaglinide (0.70% and 0.61%, respectively) were non-inferior to glimepiride in the setting of the STRATEGY study.

Both dual (metformin + sitagliptin) and triple AHA therapies were found to be safe and well-tolerated in the 'STRATEGY' study. During the triple therapy phase, 8.9%, 3.6%, 6.1%, and 0.5% of those receiving glimepiride, gliclazide, repaglinide, and acarbose, respectively, experienced hypoglycemia. Patients receiving glimepiride, gliclazide and repaglinide gained 0.45, 0.21, and 0.15 kg of body weight, respectively, while those on acarbose lost 0.91 kg.

Intensification to the triple AHA therapies brought 62.3% of the patients to HbA1c target achievement rate over the duration of the entire study. Overall, the study demonstrated that adding a third oral AHA to metformin + sitagliptin is a viable choice to overcome "clinical inertia" and optimize glycemic control in some advanced type 2 diabetes patients. More than 420 million globally have diabetes and over 96 million adults with diabetes in China. With proper control of blood glucose and cardiovascular risk factors, people with diabetes can live with a long, healthy and productive life. The result of the STRATEGY study is likely to provide physicians in China and beyond with some practical guidance to improve the quality of care. As Dr. Zachary Bloomgarden, professor of Medicine at Icahn School of Medicine at Mount Sinai in New York City, put it, 'we should look at this large study as one beginning to explore appropriate therapeutic approaches for type 2 diabetes'.


This research was funded by Merck & Co., Inc. of Kenilworth, New Jersey, the 5010 Project of Sun Yat-sen University (2007030), and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT 0947).

See the article: Xu, W., Mu, Y., Zhao, J., Zhu, D., Ji, Q., Zhou, Z., Yao, B., Mao, A., Engel, S. S., Zhao, B., Bi, Y., Zeng, L., Ran, X., Lu, J., Ji, L., Yang, W., Jia, W., and Weng, J. (2017). Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled non-inferiority clinical trial. Sci China Life Sci 60, 225-238. doi: 10.1007/s11427-016-0409-7

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