The addition of a fourth oral antidiabetic drug to a triple regimen provided superior glycemic control than simply increasing the dose of metformin in patients with type 2 diabetes (T2D) who had elevated A1c level despite triple therapy, a new Korean study showed.

The 24-week EFFORT trial also found that the intensified oral regimen improved insulin resistance and reduced albuminuria, while maintaining a similar safety profile and low incidence of adverse events.

These findings suggest that adding a fourth oral agent may be an effective strategy to intensify treatment before moving to injectable therapies, So Ra Kim, MD, of the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea, and colleagues wrote in the study, recently published online in Diabetes, Obesity and Metabolism.

However, the study authors emphasized that careful patient selection and close monitoring are “essential,” since insulin should be initiated “without delay in patients with hypercatabolic features or clinical suspicion of significant islet failure.”

Synergistic Effects?

In patients experiencing longstanding T2D, glycemic targets are frequently not achieved, despite guideline-based antidiabetic therapy of up to three oral antidiabetic drugs.

Although it is generally recommended that therapy be escalated to more potent injectable agents (eg, GLP-1 receptor agonists and/or insulin) when target A 1c levels aren’t achieved with two or more oral antidiabetic drugs, this progression frequently doesn’t take place due to reluctance on the part of the patient or physician to initiate injection-based treatment, the authors noted.

Diverse oral antidiabetic drugs “allow targeting of multiple pathophysiologic pathways,” and the advent of DPP-4 inhibitors and SGLT2 inhibitors has “broadened therapeutic choices,” they continued.

Oral quadruple therapy has been shown to provide “substantial glucose-lowering” in patients with poor glycemic control on triple oral antidiabetic drugs who decline or cannot use injectables, “with outcomes comparable or superior to those with GLP-1RA or basal insulin regimens,” they explained. 

And if “synergistic benefits” can be obtained through complementary mechanisms of action, oral quadruple therapy may delay or even replace insulin use, Kim and colleagues suggested; however, in the “real world,” a common strategy for enhancing glycemic control in patients receiving triple therapy is to uptitrate metformin.

The researchers decided to compare adding a fourth oral antidiabetic to triple therapy in patients with inadequately controlled T2D (n = 195; median age, 60 years; 65.6% men; median disease duration, 11.1 years; median baseline A1c, 7.5%) who were being treated with oral antidiabetic drugs consisting of metformin plus two of the following: a thiazolidinedione (TZD), an SGLT2 inhibitor, or a DPP-4 inhibitor. 

Patients were randomized to a metformin dose escalation group (n = 48) or an oral quadruple add-on group (n = 147, of whom 145 completed the study). The quadruple group received whichever medication class that they had not previously used (TZD, SGLT2 inhibitor, or DPP-4 inhibitor), whereas the metformin uptitration group increased the metformin dose by up to 500 mg/d. The safety set included all 195 randomized participants. Baseline characteristics were balanced between the groups.

The primary endpoint was the change in A1c level at week 22, with secondary endpoints that included fasting glucose, metabolic parameters, and safety.

Informing Clinical Decisions

At week 24, A1c level decreased from baseline by 0.70% (interquartile range [IQR], 0.40%-1.10%) in the quadruple therapy group compared with only 0.40% (IQR, 0.10%-0.80%) in the metformin uptitration group (P = .002).

The percentage of those achieving glycemic control (A1c ≤ 7.0%) at week 24 was higher in the quadruple therapy than in the metformin uptitration group (69.7% vs 47.9%; P = .006).

Median fasting glucose levels also decreased significantly from baseline at week 24 in the quadruple therapy group (-17.0 mg/dL), and the improvement was sustained over time, with a significant time-by-group interaction (P < .001).

Insulin resistance (as measured by the homeostatic model assessment [HOMA] of insulin resistance) improved only in the quadruple therapy group, and not the metformin uptitration group, and was accompanied by reduced albuminuria.

Adverse events were “mild and comparable between groups,” the authors reported.

They acknowledged, however, that the short duration of follow-up prevented conclusions about the “durability and long-term safety of oral quadruple therapy” and that the small sample size and residual confounding factors limited their ability to draw definitive conclusions. Moreover, the researchers did not evaluate potential lifestyle changes during the study, and the homogeneous study population (all Koreans) limits the generalizability of the findings to other populations.

Nevertheless, they concluded that their findings may “inform decisions between oral quadruple therapy and metformin uptitration.”

Findings Not Surprising

Commenting for Medscape Medical News, Ronald Goldenberg, MD, consultant endocrinologist emeritus, LMC Diabetes and Endocrinology, Vaughan, Ontario, Canada, called the EFFORT study “well conducted.”

Goldenberg, a past president of the Toronto Diabetes Association who was not involved with the study, said that the findings were not surprising. “The result is exactly what we would expect from such a study, as it is well known that adding a new agent is usually more effective for glucose lowering than increasing the dose of a currently used agent.”

He noted that this is especially true when it comes to metformin, “as the dose-response curve for metformin shows that the bulk of glycemic effect from metformin occurs at the 1000 mg/d dose, and uptitrating beyond 1500 mg/d provides a very minor effect regarding further glucose lowering.”

Insufficient Compared to Insulin

Amy Rothberg, MD, clinical professor of medicine, Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health, Ann Arbor, Michigan, was more circumspect about the study’s findings.

“For the reluctant patients who just decline insulin or injectable GLP-1 therapy, this study may support additional oral therapy. But that is qualified by the fact that all physicians should make a more compelling case for patients about optimal therapy, and optimal therapy at this stage is insulin,” she told Medscape Medical News.

“In this study, reduction in A1c with any add-on was less than 1%. That’s not a great improvement in A1c, but since the median was 7.5% and because the study duration was so short, we don’t know if it’s durable or whether the effects would wane over time,” she noted. “Based on HOMA data, beta-cell function and reserve are diminished, so any oral therapy will be insufficient, compared to insulin.”

Rothberg added that SGLT-2 and DPP-4 drugs are expensive, although she acknowledged that might not be the case in Korea.

“If you want better [glycemic] improvement, why not try oral GLP-1 drugs, if patients are reluctant to entertain weekly injections?” she said. The study authors “didn’t try oral semaglutide or sulfonylureas.”

This study was supported by research grants from Chong Kun Dang Pharmaceutical Corp., HK inno.N, and LG Chem Ltd The authors reported no relevant financial relationships. Goldenberg reported receiving research support and/or personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Rothberg reported being engaged in speaking engagements for Eli Lilly on the subject of diabetes remission.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).