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VERIFY: Early addition of vildagliptin outperforms metformin alone, later add-on

Among a cohort of adults with recent type 2 diabetes prescribed metformin, those assigned to receive vildagliptin as an add-on therapy maintained better long-term glycemic control than those who continued on monotherapy, according to findings from the VERIFY trial presented at the European Association for the Study of Diabetes annual meeting and simultaneously published in The Lancet.

Stefano Del Prato

In addition, those participants who received vildagliptin earlier in treatment were more successful in maintaining HbA1c below 7% than those whose therapy was intensified with vildagliptin after metformin alone failed to control glucose levels, according to researchers.

“What VERIFY has shown is that the strategy of an early combination treatment approach with vildagliptin plus metformin — which are the two agents that have been tested in this combination — in patients with newly diagnosed type 2 diabetes significantly and consistently improves long-term glycemic durability compared with monotherapy of metformin,” Stefano Del Prato, MD, professor of endocrinology and metabolism at the University of Pisa School of Medicine and chief of the diabetes section at University Hospital of Pisa in Italy, said during a presentation.

Del Prato and colleagues analyzed data from 2,001 adults who had type 2 diabetes for 2 years or less. Participants were recruited between March 2012 and April 2014 and then followed for a median of 59.8 months.

Clifford J. Bailey

The treatment regimens used for comparison were 1,000 mg to 2,000 mg metformin once per day plus 50 mg vildagliptin twice per day, or 1,000 mg to 2,000 mg metformin alone once per day. According to Clifford J. Bailey, PhD, FRCP, FRCPath, professor of clinical science at Aston University in the U.K., DPP-IV inhibitors such as vildagliptin are “suited to combination with metformin” because metformin addresses the insulin-resistant aspect of type 2 diabetes while vildagliptin tackles deterioration of beta-cell function.

“Those benefits are complementary, and that’s in essence the value of putting these two classes together,” Bailey said during his commentary following the presentation.

The researchers randomly assigned 998 participants to the combination therapy (mean age, 54.1 years; 54.6% women) and 1,003 to metformin alone (mean age, 54.6 years; 51.3% women) for the first phase of the study.

Treatment differences

During the first phase, the researchers measured HbA1c quarterly. An HbA1c of 7% or higher in back-to-back visits was considered treatment failure for either regimen, according to the researchers. Among those receiving metformin alone, 62.1% reached treatment failure, and 43.6% of those receiving combination therapy reached treatment failure. Among those receiving metformin alone, it took a median of 36.1 months to reach treatment failure while those receiving combination therapy took a median of 61.9 months to reach treatment failure based on projections from the researchers.

 
Among a cohort of adults with recent type 2 diabetes prescribed metformin, those assigned to receive vildagliptin as an add-on therapy maintained better long-term glycemic control than those who continued on monotherapy.
Source: Adobe Stock

In phase 2 of the study, participants in the monotherapy group who reached treatment failure during phase 1 also began taking 50 mg vildagliptin two times per day. The researchers continued to measure HbA1c quarterly and used the same definition of treatment failure during phase 2. Participants who received combination therapy in both phases had lower relative risks for treatment failure during the entire study (HR = 0.51; 95% CI, 0.45-0.58) and during phase 2 (HR = 0.74; 95% CI, 0.63-0.86) than those who received metformin alone during phase 1.

“The point we have to remember here is that during this assessment, both groups were on combination therapy, so what happened here is probably affected considerably by what was going on during the period of time before,” Bailey said. “So, as these diverge, and the rate of divergence is different, we are seeing evidence here for the legacy effect.”

Potential for additional benefits

The researchers also found that those who received combination therapy during the entire study had lower relative risk for a macrovascular event vs. those who received metformin alone in phase 1 (HR = 0.71; 95% CI, 0.42-1.19), but this finding “must be interpreted with caution” since it did not reach statistical significance, they wrote. Rates of adverse events, such as hypoglycemia, pancreatitis and neoplasms, were similar between the two groups.

“If you can achieve better glycemic control without increasing the risk of side effects, you can also expect patients to be more adherent to the treatment. If you can provide more sustained glycemic control all the time, you can also expect this could reduce clinical inertia,” Del Prato said. “Finally, this may be one opportunity to address individual patient needs.”

Ofri Mosenzon

In a commentary accompanying the article in The Lancet, Ofri Mosenzon, MD, MSc, and Gil Leibowitz, MD, of the diabetes unit in the department of endocrinology and metabolism at Hadassah Medical Center and the faculty of medicine at the Hebrew University of Jerusalem, wrote that “early combination therapy with metformin and vildagliptin seems superior to sequential intensification of metformin” and that these effects can be sustained in the long term, including potential benefits for beta-cell function. Despite these apparent benefits, Mosenzon and Leibowitz urged caution, noting that costs can be greater and overtreatment is possible with these combination therapies.

Vildagliptin is not currently approved for use in the United States. – by Phil Neuffer

References:

Mathieu C, et al. Abstract S23. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 16-20, 2019; Barcelona, Spain.

Matthews DR, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)32131-2.

Mosenzon O, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)32165-8.

Disclosures: Bailey reports no relevant financial disclosures. Del Prato reports he has received research support from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme and served on the advisory board for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co., GlaxoSmithKline, Laboratoires Servier, Merck Sharp & Dohme, Mundipharma, Novartis Pharmaceuticals, Novo Nordisk, Sanofi and Takeda Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures. Leibowitz reports he has received advisory board and speakers fees from AstraZeneca, Novo Nordisk and Sanofi, and speakers fees from Eli Lilly. Mosenzon reports she has received advisory board and speakers fees and research grants from AstraZeneca and Novo Nordisk as well as advisory board and speakers fees from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Sanofi, and speakers fees from Teva.

Among a cohort of adults with recent type 2 diabetes prescribed metformin, those assigned to receive vildagliptin as an add-on therapy maintained better long-term glycemic control than those who continued on monotherapy, according to findings from the VERIFY trial presented at the European Association for the Study of Diabetes annual meeting and simultaneously published in The Lancet.

Stefano Del Prato

In addition, those participants who received vildagliptin earlier in treatment were more successful in maintaining HbA1c below 7% than those whose therapy was intensified with vildagliptin after metformin alone failed to control glucose levels, according to researchers.

“What VERIFY has shown is that the strategy of an early combination treatment approach with vildagliptin plus metformin — which are the two agents that have been tested in this combination — in patients with newly diagnosed type 2 diabetes significantly and consistently improves long-term glycemic durability compared with monotherapy of metformin,” Stefano Del Prato, MD, professor of endocrinology and metabolism at the University of Pisa School of Medicine and chief of the diabetes section at University Hospital of Pisa in Italy, said during a presentation.

Del Prato and colleagues analyzed data from 2,001 adults who had type 2 diabetes for 2 years or less. Participants were recruited between March 2012 and April 2014 and then followed for a median of 59.8 months.

Clifford J. Bailey

The treatment regimens used for comparison were 1,000 mg to 2,000 mg metformin once per day plus 50 mg vildagliptin twice per day, or 1,000 mg to 2,000 mg metformin alone once per day. According to Clifford J. Bailey, PhD, FRCP, FRCPath, professor of clinical science at Aston University in the U.K., DPP-IV inhibitors such as vildagliptin are “suited to combination with metformin” because metformin addresses the insulin-resistant aspect of type 2 diabetes while vildagliptin tackles deterioration of beta-cell function.

“Those benefits are complementary, and that’s in essence the value of putting these two classes together,” Bailey said during his commentary following the presentation.

The researchers randomly assigned 998 participants to the combination therapy (mean age, 54.1 years; 54.6% women) and 1,003 to metformin alone (mean age, 54.6 years; 51.3% women) for the first phase of the study.

Treatment differences

During the first phase, the researchers measured HbA1c quarterly. An HbA1c of 7% or higher in back-to-back visits was considered treatment failure for either regimen, according to the researchers. Among those receiving metformin alone, 62.1% reached treatment failure, and 43.6% of those receiving combination therapy reached treatment failure. Among those receiving metformin alone, it took a median of 36.1 months to reach treatment failure while those receiving combination therapy took a median of 61.9 months to reach treatment failure based on projections from the researchers.

 
Among a cohort of adults with recent type 2 diabetes prescribed metformin, those assigned to receive vildagliptin as an add-on therapy maintained better long-term glycemic control than those who continued on monotherapy.
Source: Adobe Stock

In phase 2 of the study, participants in the monotherapy group who reached treatment failure during phase 1 also began taking 50 mg vildagliptin two times per day. The researchers continued to measure HbA1c quarterly and used the same definition of treatment failure during phase 2. Participants who received combination therapy in both phases had lower relative risks for treatment failure during the entire study (HR = 0.51; 95% CI, 0.45-0.58) and during phase 2 (HR = 0.74; 95% CI, 0.63-0.86) than those who received metformin alone during phase 1.

“The point we have to remember here is that during this assessment, both groups were on combination therapy, so what happened here is probably affected considerably by what was going on during the period of time before,” Bailey said. “So, as these diverge, and the rate of divergence is different, we are seeing evidence here for the legacy effect.”

Potential for additional benefits

The researchers also found that those who received combination therapy during the entire study had lower relative risk for a macrovascular event vs. those who received metformin alone in phase 1 (HR = 0.71; 95% CI, 0.42-1.19), but this finding “must be interpreted with caution” since it did not reach statistical significance, they wrote. Rates of adverse events, such as hypoglycemia, pancreatitis and neoplasms, were similar between the two groups.

“If you can achieve better glycemic control without increasing the risk of side effects, you can also expect patients to be more adherent to the treatment. If you can provide more sustained glycemic control all the time, you can also expect this could reduce clinical inertia,” Del Prato said. “Finally, this may be one opportunity to address individual patient needs.”

Ofri Mosenzon

In a commentary accompanying the article in The Lancet, Ofri Mosenzon, MD, MSc, and Gil Leibowitz, MD, of the diabetes unit in the department of endocrinology and metabolism at Hadassah Medical Center and the faculty of medicine at the Hebrew University of Jerusalem, wrote that “early combination therapy with metformin and vildagliptin seems superior to sequential intensification of metformin” and that these effects can be sustained in the long term, including potential benefits for beta-cell function. Despite these apparent benefits, Mosenzon and Leibowitz urged caution, noting that costs can be greater and overtreatment is possible with these combination therapies.

Vildagliptin is not currently approved for use in the United States. – by Phil Neuffer

References:

Mathieu C, et al. Abstract S23. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 16-20, 2019; Barcelona, Spain.

Matthews DR, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)32131-2.

Mosenzon O, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)32165-8.

Disclosures: Bailey reports no relevant financial disclosures. Del Prato reports he has received research support from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme and served on the advisory board for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co., GlaxoSmithKline, Laboratoires Servier, Merck Sharp & Dohme, Mundipharma, Novartis Pharmaceuticals, Novo Nordisk, Sanofi and Takeda Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures. Leibowitz reports he has received advisory board and speakers fees from AstraZeneca, Novo Nordisk and Sanofi, and speakers fees from Eli Lilly. Mosenzon reports she has received advisory board and speakers fees and research grants from AstraZeneca and Novo Nordisk as well as advisory board and speakers fees from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Sanofi, and speakers fees from Teva.

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