In the JournalsPerspective

Addition of linagliptin to metformin reduces prediabetes progression

Prediabetes was less likely to progress to type 2 diabetes among adults who took a combination of linagliptin and metformin vs. metformin alone; the combination group was also more likely to achieve normal glucose levels, according to findings published in Metabolism.

“It has been demonstrated that treatment of prediabetes reduces the risk of micro- and macrovascular complications, as well as global mortality, highlighting the relevance of early treatments for glucose abnormalities,” Rodolfo Guardado-Mendoza, MD, PhD, of the research department at Hospital Regional de Alta Especialidad del Bajío and the department of medicine and nutrition at the University of Guanajuato in Mexico, and colleagues wrote. “Evaluation of new alternatives for patients with prediabetes is needed to generate scientific evidence about the safety and efficacy profile of these therapies to treat hyperglycemia at early stages.”

Guardado-Mendoza and colleagues examined how often type 2 diabetes developed or normal glycemic levels were achieved using data from across 24 months for 144 adults with prediabetes in the Prevention with Linagliptin, Lifestyle and Metformin (PRELLIM) study. The researchers randomly assigned participants to a twice per day regimen of 2.5 mg linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) and 850 mg metformin (n = 74; mean age, 48 years; 66.2% women) or a twice per day regimen of 850 mg metformin (n = 70; mean age, 50 years; 55.7% women). The researchers performed oral glucose tolerance tests and hyperglycemic clamps at 6-month intervals to examine beta-cell function, serum glucose, insulin C-peptide and plasma glucagon levels. The researchers also collected HbA1c data.

Participants assigned the combination experienced a 0.04% decrease in HbA1c at 24 months vs. a rise of 0.42% among those assigned metformin alone (P < .01). The researchers wrote that “glucose levels improved during the whole OGTT and during the entire follow-up, and these improvements were significantly better” when comparing those taking the combination with those taking metformin alone.

 
Prediabetes was less likely to progress to type 2 diabetes among adults who took a combination of linagliptin and metformin vs. metformin alone; the combination group was also more likely to achieve normal glucose levels.
Source: Adobe Stock

At 24 months, four participants assigned the combination had type 2 diabetes and 10 assigned metformin alone had the condition (HR = 4; 95% CI, 1.24-13.04). In addition, at 24 months, 52.7% of those assigned the combination achieved normal glycemic levels vs. 33.3% of those assigned metformin alone. In fact, participants assigned the combination were 3.31 times more likely to achieve normal glycemic levels than those assigned metformin alone (OR = 3.31; 95% CI, 1.54-7.09).

The researchers used an OGTT disposition index, which was a calculation combining acute insulin response and fasting insulin, as the metric for beta-cell function, with higher scores indicating superior function. Participants assigned the combination had scores of 2.41, 2.13 and 2.07 on the index vs. 1.56, 1.6 and 1.72 for those assigned metformin alone at 6, 12 and 24 months, respectively (P < .05 at each timepoint). 

“Together, these improvements in pancreatic beta- and alpha-cell function with combined treatments, like the one that we used in the linagliptin plus metformin group, highlights the role of pancreatic islet cell function as an integrative functional unit to control glucose metabolism and prevent type 2 diabetes, and perhaps due to this effect, the most effective therapies to prevent type 2 diabetes would be those with an important effect on pancreatic islet function combined with lifestyle,” the researchers wrote. – by Phil Neuffer

Disclosures: The authors report no relevant financial disclosures.

Prediabetes was less likely to progress to type 2 diabetes among adults who took a combination of linagliptin and metformin vs. metformin alone; the combination group was also more likely to achieve normal glucose levels, according to findings published in Metabolism.

“It has been demonstrated that treatment of prediabetes reduces the risk of micro- and macrovascular complications, as well as global mortality, highlighting the relevance of early treatments for glucose abnormalities,” Rodolfo Guardado-Mendoza, MD, PhD, of the research department at Hospital Regional de Alta Especialidad del Bajío and the department of medicine and nutrition at the University of Guanajuato in Mexico, and colleagues wrote. “Evaluation of new alternatives for patients with prediabetes is needed to generate scientific evidence about the safety and efficacy profile of these therapies to treat hyperglycemia at early stages.”

Guardado-Mendoza and colleagues examined how often type 2 diabetes developed or normal glycemic levels were achieved using data from across 24 months for 144 adults with prediabetes in the Prevention with Linagliptin, Lifestyle and Metformin (PRELLIM) study. The researchers randomly assigned participants to a twice per day regimen of 2.5 mg linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) and 850 mg metformin (n = 74; mean age, 48 years; 66.2% women) or a twice per day regimen of 850 mg metformin (n = 70; mean age, 50 years; 55.7% women). The researchers performed oral glucose tolerance tests and hyperglycemic clamps at 6-month intervals to examine beta-cell function, serum glucose, insulin C-peptide and plasma glucagon levels. The researchers also collected HbA1c data.

Participants assigned the combination experienced a 0.04% decrease in HbA1c at 24 months vs. a rise of 0.42% among those assigned metformin alone (P < .01). The researchers wrote that “glucose levels improved during the whole OGTT and during the entire follow-up, and these improvements were significantly better” when comparing those taking the combination with those taking metformin alone.

 
Prediabetes was less likely to progress to type 2 diabetes among adults who took a combination of linagliptin and metformin vs. metformin alone; the combination group was also more likely to achieve normal glucose levels.
Source: Adobe Stock

At 24 months, four participants assigned the combination had type 2 diabetes and 10 assigned metformin alone had the condition (HR = 4; 95% CI, 1.24-13.04). In addition, at 24 months, 52.7% of those assigned the combination achieved normal glycemic levels vs. 33.3% of those assigned metformin alone. In fact, participants assigned the combination were 3.31 times more likely to achieve normal glycemic levels than those assigned metformin alone (OR = 3.31; 95% CI, 1.54-7.09).

The researchers used an OGTT disposition index, which was a calculation combining acute insulin response and fasting insulin, as the metric for beta-cell function, with higher scores indicating superior function. Participants assigned the combination had scores of 2.41, 2.13 and 2.07 on the index vs. 1.56, 1.6 and 1.72 for those assigned metformin alone at 6, 12 and 24 months, respectively (P < .05 at each timepoint). 

“Together, these improvements in pancreatic beta- and alpha-cell function with combined treatments, like the one that we used in the linagliptin plus metformin group, highlights the role of pancreatic islet cell function as an integrative functional unit to control glucose metabolism and prevent type 2 diabetes, and perhaps due to this effect, the most effective therapies to prevent type 2 diabetes would be those with an important effect on pancreatic islet function combined with lifestyle,” the researchers wrote. – by Phil Neuffer

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Kevin M. Pantalone

    Kevin M. Pantalone

    Patients with prediabetes are not routinely treated with pharmacotherapy, and it can be challenging for many patients to continue aggressive lifestyle modifications over the long-term even if such interventions are instituted. A multifaceted approach to reduce the risk of developing type 2 diabetes, one that combines pharmacotherapy and lifestyle modification, would appear to be a very sound approach. The recent report by Guardado-Mendoza and colleagues demonstrated that an approach which combines two medications — linagliptin plus metformin — in addition to lifestyle intervention improved glucose metabolism and pancreatic beta-cell function and reduced the incidence of type 2 diabetes in subjects with prediabetes as compared with metformin and lifestyle intervention alone.

    While there are many potential interventions to reduce the risk of developing type 2 diabetes in patients with prediabetes — and help many of them lose weight — first and foremost, we must do a better job of identifying patients with prediabetes and initiating an intervention early in the disease process, when patients still have significant beta-cell function remaining, to really make a significant impact on reducing the incidence of type 2 diabetes. In the coming years, it will be paramount that we do so in order to reduce the worldwide prevalence of type 2 diabetes, which has been predicted to double by 2030.

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

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