VERIFY: Metformin + DPP-4 Inhibitor as Dual Therapy for Diabetes?

Marlene Busko

September 18, 2019

BARCELONA, Spain ― For patients newly diagnosed with type 2 diabetes, the recommended strategy of initiating treatment with metformin and then stepping up treatment with a second agent if monotherapy fails to control blood glucose might not be ideal, a new large, 5-year trial suggests.

Rather, initial dual therapy may be better.

Among patients with newly discovered diabetes whose HbA1C level was 6.5% to 7.5% (48 – 58 mmol/mol), those who initially received combination therapy with metformin plus the dipeptidyl peptidase–4 (DPP-4) inhibitor vildagliptin (Galvus, Novartis) were less likely to experience sustained treatment failure (HbA1C ≥7% [≥53 mmol/mol]) during a 5-year period.

Lead investigator David R. Matthews, DPhil, EASD president and professor emeritus of diabetic medicine, University of Oxford, in the United Kingdom, and two coinvestigators presented these findings from the Vildagliptin Efficacy in Combination With Metformin for Early Treatment of Type 2 Diabetes (VERIFY) trial here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting. The findings were simultaneously published in the Lancet.

This is the largest long-term prospective trial to test the durability of glycemic control in patients with diabetes who were initially treated with dual combination therapy, Ofri Mosenzon, MD, and Gil Leibowitz, MD, from Hebrew University of Jerusalem, Israel, write in an editorial that accompanies the Lancet article.

The study should "reassure" clinicians that initial dual therapy with these two agents "is well tolerated, safe and effective," they note.

Moreover, this finding was not unexpected, because these medications have synergistic mechanisms: metformin increases insulin sensitivity, and vildagliptin enhances beta-cell function.

The study "strengthens the notion that early combination therapy could have long-term clinical benefits regarding glycemic durability," they summarize.

They note, however, that in recent years, a number of large trials have shown that newer glucose-lowering agents, mainly GLP-1-receptor agonists and SGLT2 inhibitors, "have cardiovascular and renal benefits and the place of metformin as the first drug for all patients with type 2 diabetes is [now] questioned."

VERIFY coauthor Michael Stumvoll, MD, University Hospital Leipzig, Germany, told Medscape Medical News that VERIFY was begun long before most current GLP-1 agonists and all SGLT2 inhibitors were available.

Study Validates Off-Label Use of Initial Dual Therapy

When recruitment for VERIFY began in 2012, "we were in a world where gliptins were just becoming fashionable," Stumvoll said.

"Vildagliptin ― a beta-cell-preserving, weight-neutral, safe drug ― was leading the market," he said.

Vildagliptin is still widely used around the world, he stressed.

"It's a 'fire and forget' type of thing, a fixed dose, one in the morning and in the evening," and clinicians don't need to worry about impaired kidney function, weight gain, or hypoglycemia, he said.

Some practitioners have been using initial combination therapy off label, he added. This trial provides evidence to support this practice.

About 40% of patients did not experience treatment failure on metformin monotherapy.

However, Matthews said, "The point is, you don't know who these patients [who do well on monotherapy] are."

"What I think is important," senior author Stefano Del Prato, MD, University of Pisa, Italy, told Medscape Medical News, is that this is the first large, randomized clinical trial that shows that "a combination of the two drugs that are known to be safe...can preserve glycemic control over time." His words echo the comments of the other speakers and editorialists.

He said that further study is needed to see whether improved glycemic control lowers risk for cardiovascular disease.

Start With Metformin or Two Therapies?

VERIFY was designed to determine whether clinicians should start with combined therapies or use a stepwise approach (starting with metformin and then adding vildagliptin if metformin failed to provide adequate glycemic control) for patients with diabetes, Matthews said.

From 2012 to 2014, VERIFY enrolled 2001 patients who had been newly diagnosed with type 2 diabetes in 254 centers in 34 countries.

The patients were 18 to 70 years old and had been diagnosed with type 2 diabetes within the previous 2 years.

In these patients, the range of HbA1C, level was narrow, at 6.5% to 7.5%, Stumvolt noted. Body mass index values ranged from 22 to 40 kg/m².

The patients were randomly assigned either to the early combination treatment group (998 patients) or to the initial metformin monotherapy group (1003 patients).

Those in the combination therapy group received metformin at a dose of 1000 mg, 1500 mg, or 2000 mg per day, plus vildagliptin at a dose of 50 mg twice daily.

The patients in the monotherapy arm received the same daily doses of metformin plus twice-daily placebo.

If at any time from 6 months to 5 years from the start of the trial the HbA1C level was not maintained below 7.0% with initial treatment (confirmed at two consecutive scheduled visits that were 13 weeks apart), patients in the metformin monotherapy group were given vildagliptin 50 mg twice daily (instead of placebo) in addition to metformin.

About 80% patients in each group completed the 5-year study.

During the first phase of the study (before therapy was stepped up for any patients receiving monotherapy) 429 patients (43.6%) in the combination treatment group and 614 patients (62.1%) patients in the monotherapy group experienced treatment failure.

The median time to treatment failure was 36 months in the monotherapy group; treatment failure had not occurred by 5 years in the combination therapy group.

The risk for treatment failure was 49% lower with initial combination therapy than with initial monotherapy (hazard ratio, 0.51; P < .0001).

Both treatment approaches were safe and well tolerated. There were no unexpected or new safety findings, and no deaths occurred that were related to study treatment.

Early combination therapy was not associated with risk for hypoglycemia or increased body weight, Del Prato noted.

"New Era" in Diabetes Treatment?

An ADA-EASD consensus report states that currently, "While there is some support for initial combination therapy due to the greater initial reduction of A1C than can be provided by metformin alone, there is little evidence that this approach is superior to sequential addition of medications for maintaining glycemic control or slowing the progression of diabetes."

According to Del Prado, on the basis of VERIFY, the wording should be changed to "there is now evidence...."

The study can only generate hypotheses regarding cardiovascular risk, because it was not designed to examine this. He believes, however, that the study is "opening up a new era" in diabetes treatment strategies.

VERIFY demonstrated durable glycemic control in a heterogeneous population that reflects typical patients with newly diagnosed type 2 diabetes who are seen in clinical practice, he summarized

"Whether early combination treatment strategy should be applied to all patients with type 2 diabetes" needs to be studied further, according to Mosenzon and Leibowitz.

The findings from VERIFY "suggest that early normalisation of blood glucose has a beneficial legacy effect that attenuates diabetes progression," the editorialists write.

Other studies have shown that normalizing blood glucose during the first year after diagnosis "was associated with decreased risk of microvascular and macrovascular complications," they state.

Often in clinical practice, treatment intensification is delayed, and patients are exposed to prolonged hyperglycemia.

"Early combination therapy with two or more glucose-lowering agents might become an effective strategy to prevent clinical inertia," they suggest.

On the other hand, combination treatment might increase the risk for side effects and is more costly. "Additional studies are needed to confirm that early combination treatment indeed halts the progression of diabetes," they write.

Many type 2 diabetes drugs are currently available that could be combined as initial dual therapy. Thus, "Further studies to assess the effects of different combination therapies on glycaemic durability and more importantly on the risk of late complications are necessary," they write.

The study was funded by Novartis. Matthews has served on advisory boards or as a consultant for Novo Nordisk, GlaxoSmithKline, Novartis, Eli Lilly, Sanofi-Aventis, Janssen, and Servier. He is currently the president of the European Association for the Study of Diabetes and has given lectures for Novo Nordisk, Servier, Sanofi-Aventis, Eli Lilly and Company, Novartis, Janssen, and Aché Laboratories. Stumvolt has received speaker's honoraria and consulting fees from Novartis, Novo Nordisk, AstraZeneca, Aegerion, Eli Lilly and Company, and Boehringer Ingelheim. Del Prato serves or has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia, Janssen Pharmaceutics, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier and Takeda; serves or has served on the speakers' bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen Pharmaceutics, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Takeda; and has received research support from Boehringer Ingelheim, Merck Sharp & Dohme, and Novartis. The three other coauthors are employed by and own stock in Novartis. Mosenzon has received advisory board and speaker's fees and a research grant through her institution from Novo Nordisk; advisory board and speaker's fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim; advisory board and speaker's fees and a research grant through her institution from AstraZeneca; and speaker's fees from Teva that are unrelated to the editorial topic. Leibowitz has received advisory board and speaker's fees from Novo Nordisk; speaker's fees from Eli Lilly & Company; and advisory board and speaker's fees from Sanofi and AstraZeneca that are all unrelated to the editorial topic.

European Association for the Study of Diabetes (EASD) 2019 Annual Meeting: Presented September 19, 2019.

Lancet. Published online September 18, 2019. Abstract, Editorial

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