In the JournalsPerspective

Diabetes more effectively treated with immediate sitagliptin, metformin combination therapy

Insulin is needed less frequently and HbA1c is lowered more robustly when adults with type 2 diabetes do not delay combination therapy but begin treatment by taking sitagliptin and metformin together, according to findings published in Diabetic Medicine.

“Clinical practice guidelines recommend adding second-line agents, such as DPP-IV inhibitors, if glycemic targets are not met with metformin alone and after considering the individual’s overall clinical state; however, there may be therapeutic benefits to starting a DPP-IV inhibitor early, if not at the same time metformin is initiated,” Peter Light, PhD, BSc, professor and director of the Alberta Diabetes Institute and Dr. Charles A. Allard chair in diabetes research, and colleagues wrote. “Although HbA1c targets and glycemic control may be achieved with metformin alone, costarting therapy with a DPP-IV inhibitor, such as sitagliptin, and metformin may improve long-term glycemic control and slow diabetes progression.”

Light and colleagues assessed insulin use and HbA1c after 1 year of therapy among 8,764 adults with type 2 diabetes (mean age, 52.1 years; 35.4% women). Data from 2008 to 2015 were included and extracted from Alberta Health databases.

Sitagliptin (Januvia, Merck) and metformin were begun in combination by 13.2% of the study population, and 15% of these participants eventually started on insulin; 19.1% of those who started on metformin alone needed insulin (P < .001). In addition, participants who began with the combination therapy were 24% less likely to need insulin compared with those who delayed starting sitagliptin (adjusted OR = 0.76; 95% CI, 0.64-0.9). In addition, “sensitivity analyses revealed the opposite association with insulin initiation when we substituted sulfonylureas for sitagliptin,” the researchers wrote.

 
Insulin is needed less frequently and HbA1c is lowered more robustly when adults with type 2 diabetes do not delay combination therapy but begin treatment by taking sitagliptin and metformin together.
Source: Shutterstock

The researchers also found that the HbA1c decrease achieved with immediate combination therapy was 0.5% higher than that achieved by those who delayed sitagliptin (95% CI, 0.3-0.7).

“These observations suggest that costarting sitagliptin with metformin delays the progression of type 2 diabetes,” the researchers wrote. “Much like early initiation of insulin therapy, costarting sitagliptin with metformin may change the natural history of the disease, which could ultimately lead to fewer medications and a lower risk of complications.”

Despite these findings, the researchers noted that socioeconomic determinants should be considered.

“Costarters may have a different ability to pay for a DPP-IV inhibitor and consequently may choose to initiate sitagliptin therapy with metformin,” the researchers wrote. “Although we adjusted for demographic, clinical and drug therapy characteristics, information on socioeconomic status and other lifestyle choices was not available.” – by Phil Neuffer

Disclosures: The authors report no relevant financial disclosures.

Insulin is needed less frequently and HbA1c is lowered more robustly when adults with type 2 diabetes do not delay combination therapy but begin treatment by taking sitagliptin and metformin together, according to findings published in Diabetic Medicine.

“Clinical practice guidelines recommend adding second-line agents, such as DPP-IV inhibitors, if glycemic targets are not met with metformin alone and after considering the individual’s overall clinical state; however, there may be therapeutic benefits to starting a DPP-IV inhibitor early, if not at the same time metformin is initiated,” Peter Light, PhD, BSc, professor and director of the Alberta Diabetes Institute and Dr. Charles A. Allard chair in diabetes research, and colleagues wrote. “Although HbA1c targets and glycemic control may be achieved with metformin alone, costarting therapy with a DPP-IV inhibitor, such as sitagliptin, and metformin may improve long-term glycemic control and slow diabetes progression.”

Light and colleagues assessed insulin use and HbA1c after 1 year of therapy among 8,764 adults with type 2 diabetes (mean age, 52.1 years; 35.4% women). Data from 2008 to 2015 were included and extracted from Alberta Health databases.

Sitagliptin (Januvia, Merck) and metformin were begun in combination by 13.2% of the study population, and 15% of these participants eventually started on insulin; 19.1% of those who started on metformin alone needed insulin (P < .001). In addition, participants who began with the combination therapy were 24% less likely to need insulin compared with those who delayed starting sitagliptin (adjusted OR = 0.76; 95% CI, 0.64-0.9). In addition, “sensitivity analyses revealed the opposite association with insulin initiation when we substituted sulfonylureas for sitagliptin,” the researchers wrote.

 
Insulin is needed less frequently and HbA1c is lowered more robustly when adults with type 2 diabetes do not delay combination therapy but begin treatment by taking sitagliptin and metformin together.
Source: Shutterstock

The researchers also found that the HbA1c decrease achieved with immediate combination therapy was 0.5% higher than that achieved by those who delayed sitagliptin (95% CI, 0.3-0.7).

“These observations suggest that costarting sitagliptin with metformin delays the progression of type 2 diabetes,” the researchers wrote. “Much like early initiation of insulin therapy, costarting sitagliptin with metformin may change the natural history of the disease, which could ultimately lead to fewer medications and a lower risk of complications.”

Despite these findings, the researchers noted that socioeconomic determinants should be considered.

“Costarters may have a different ability to pay for a DPP-IV inhibitor and consequently may choose to initiate sitagliptin therapy with metformin,” the researchers wrote. “Although we adjusted for demographic, clinical and drug therapy characteristics, information on socioeconomic status and other lifestyle choices was not available.” – by Phil Neuffer

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Kevin M. Pantalone

    Kevin M. Pantalone

    This study provides additional support to the ever expanding pool of evidence that endorses the early use of combination therapy, rather than metformin therapy alone, in the management of type 2 diabetes.  The historical approach to type 2 diabetes management has been referred to as a “treat-to-failure” approach. However, this and many other research articles published over the past decade appear to lend support to an alternative treatment approach that is commonly referred to as “treat-to-target.”  The treat-to-target approach emphasizes the early and aggressive intensification of therapy, including the use of early combination therapy, rather than the initiation of metformin alone. 

    The type 2 diabetes management guidelines set forth by ADA/EASD and AACE have recently encouraged the use of early combination therapy — particularly when patients present with a more prominent elevation of their HbA1c — but this has yet to translate into routine clinical practice.  The thresholds for when combination therapies should be used among the guidelines has made the process unclear. In addition, many patients and providers are reluctant to initiate combination therapy for a multitude of reasons.  It is clear that multiple anti-diabetes medications used in combination will be required to obtain glycemic control in the majority of patients with type 2 diabetes. It is a complex disorder with multiple underlying pathophysiologies that must be addressed to obtain glycemic control.  Eventually, clinicians and patients need to accept the fact that the current conservative approach fails to maintain glycemia long term in the vast majority of patients.  

    • Kevin M. Pantalone, DO, ECNU, FACE
    • Staff Endocrinologist
      Director of Diabetes Initiatives
      Department of Endocrinology
      Cleveland Clinic

    Disclosures: Pantalone reports that he has received speaker honoraria from AstraZeneca, Novo Nordisk and Merck, research support from Novo Nordisk and Merck and consulting honoraria from Novo Nordisk, Merck, Sanofi and Bayer.