DIABETES TECHNOLOGY & THERAPEUTICS Volume 17, Number 7, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.0412
ORIGINAL ARTICLE
Add-On Treatment with Liraglutide Improves Glycemic Control in Patients with Type 2 Diabetes on Metformin Therapy Eusebio Chiefari, MD, PhD,1,* Carmelo Capula, MD,2,*,{ Ada Vero, PhD,2 Rosa Oliverio, MD,1 Luigi Puccio, MD,2 Rossella Liguori, MD,1 Vittorio Pullano, MD,2 Manfredi Greco, MD,3 Daniela Foti, MD, PhD,1 Domenico Tirinato, MD,4 Raffaella Vero, MD,2 and Antonio Brunetti, MD, PhD1
Abstract
Background: Liraglutide is a glucagon-like peptide-1 receptor analog recently approved for the treatment of type 2 diabetes mellitus (T2DM). We aimed to assess the efficacy and safety of liraglutide versus glimepiride, as adjunct treatments to metformin, in achieving glycemic control in Italian patients with T2DM uncontrolled by metformin alone. Subjects and Methods: One hundred seventy-nine diabetes patients treated with metformin plus liraglutide (1.8 mg) or glimepiride (4 mg) were retrospectively assessed at baseline, during, and after 18 months of continuous therapy. Results: Treatment with liraglutide resulted in mean decreases in hemoglobin A1c (HbA1c) of - 1.4%, when compared with glimepiride (- 0.4%) (P < 0.001), and was followed by a significant reduction (P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently from weight loss, which was significantly reduced (P < 0.001) in liraglutide-treated patients. The percentage of subjects reaching HbA1c levels below 7% or £6.5% was significantly different between the two treated groups (P < 0.001). Treatment with liraglutide reduced waist circumference (WC) (P < 0.001) and decreased both systolic and diastolic blood pressure (BP) (P < 0.001). It is interesting that the study also showed the impact of female gender in predicting a better glycemic response to liraglutide (P = 0.028). Conclusions: Liraglutide was more effective than glimepiride in reducing HbA1c levels in treated patients with T2DM. This was evident in both genders, but particularly in women. Furthermore, liraglutide reduced body weight, WC, and BP, which are critical risk factors for cardiovascular disease. function in diabetes has shown continuing long-term efficacy. In this regard, evidence is emerging indicating liraglutide, a recent glucagon-like peptide-1 mimetic, provides superior glycemic control compared with other antidiabetes agents, including the glucagon-like peptide-1 receptor agonists albiglutide and exenatide, and appears to preserve b-cell function in patients with new-onset T2DM.2–5 Moreover, liraglutide-treated patients were more likely to have clinically relevant weight loss and less incidence of hypoglycemia, associated with beneficial effects on both systolic and
Introduction
T
ype 2 diabetes mellitus (T2DM) is the most common metabolic disease1 and is linked to the progressive decline of pancreatic b-cell function and increased peripheral insulin resistance. Current therapies in the management of T2DM include lifestyle modifications, including diet and exercise, as well as the use of a variety of oral and/or injected hypoglycemic agents. Nevertheless, no currently available therapy for the progressive decline of pancreatic b-cell
Departments of 1Health Sciences and 3Experimental and Clinical Medicine, University ‘‘Magna Græcia’’ of Catanzaro, Catanzaro, Italy. 2 Complex Operative Structure of Endocrinology-Diabetology, Pugliese-Ciaccio Hospital, Catanzaro, Italy. 4 Diabetologic Unit, Soverato Hospital, Soverato, Italy. *The first two authors contributed equally to this work. { We dedicate this article to the memory of Dr. Carmelo Capula, who prematurely died on March 30, 2015. Parts of this study were presented in abstract form at the 74th Scientific Session of the American Diabetes Association, held in San Francisco, California, June 13–17, 2014.
1
2
diastolic blood pressure (BP) and lipid profile.6 Although some patients may experience minor nausea at treatment initiation, adverse effects of liraglutide are otherwise minimal, and a dose titration regimen, which increases the dose gradually (from 0.6 to 1.8 mg/day), is used to improve its tolerability.7 Nevertheless, the U.S. Food and Drug Administration warns people with or a family history of thyroid cancer or pancreatitis against taking liraglutide (www.fda.gov/Safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/ucm258826.htm). The risk of developing diabetes increases as body mass index (BMI) increases. Consistent with this trend, the higher prevalence of obesity in Calabria, Southern Italy, parallels the greater proportion of individuals with T2DM in this area, compared with the entire Italian population (www.istat.it). Use of liraglutide in the management of T2DM in Italy is only permitted in combination with other oral hypoglycemic agents. Therefore, here we aimed to assess the efficacy and safety of liraglutide in combination with metformin, in Calabrian patients with T2DM uncontrolled by metformin alone. In addition, a comparison group of patients who were receiving metformin plus glimepiride, a third-generation sulfonylurea hypoglycemic agent,7 was also analyzed. Patients and Methods Participants
Data were retrospectively collected from 76 diabetes patients who started treatment with liraglutide (in addition to metformin [2.31 – 0.47 g/day]) on the basis of current recommendations for management and treatment of hyperglycemia in T2DM.8 Participants were recruited after the launch of liraglutide in Italy (September 2010) and until April 2012 from the diabetes outpatient clinic of the Hospital PuglieseCiaccio in Catanzaro (n = 57), from the University of Catanzaro outpatient clinics (n = 13), and from the diabetes outpatient clinic of Soverato (n = 6). The following inclusion criteria were applied: 18–80 years of age, BMI £45 kg/m2, poor glycemic control (hemoglobin A1c [HbA1c] levels of > 7% and
ORIGINAL ARTICLE
Add-On Treatment with Liraglutide Improves Glycemic Control in Patients with Type 2 Diabetes on Metformin Therapy Eusebio Chiefari, MD, PhD,1,* Carmelo Capula, MD,2,*,{ Ada Vero, PhD,2 Rosa Oliverio, MD,1 Luigi Puccio, MD,2 Rossella Liguori, MD,1 Vittorio Pullano, MD,2 Manfredi Greco, MD,3 Daniela Foti, MD, PhD,1 Domenico Tirinato, MD,4 Raffaella Vero, MD,2 and Antonio Brunetti, MD, PhD1
Abstract
Background: Liraglutide is a glucagon-like peptide-1 receptor analog recently approved for the treatment of type 2 diabetes mellitus (T2DM). We aimed to assess the efficacy and safety of liraglutide versus glimepiride, as adjunct treatments to metformin, in achieving glycemic control in Italian patients with T2DM uncontrolled by metformin alone. Subjects and Methods: One hundred seventy-nine diabetes patients treated with metformin plus liraglutide (1.8 mg) or glimepiride (4 mg) were retrospectively assessed at baseline, during, and after 18 months of continuous therapy. Results: Treatment with liraglutide resulted in mean decreases in hemoglobin A1c (HbA1c) of - 1.4%, when compared with glimepiride (- 0.4%) (P < 0.001), and was followed by a significant reduction (P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently from weight loss, which was significantly reduced (P < 0.001) in liraglutide-treated patients. The percentage of subjects reaching HbA1c levels below 7% or £6.5% was significantly different between the two treated groups (P < 0.001). Treatment with liraglutide reduced waist circumference (WC) (P < 0.001) and decreased both systolic and diastolic blood pressure (BP) (P < 0.001). It is interesting that the study also showed the impact of female gender in predicting a better glycemic response to liraglutide (P = 0.028). Conclusions: Liraglutide was more effective than glimepiride in reducing HbA1c levels in treated patients with T2DM. This was evident in both genders, but particularly in women. Furthermore, liraglutide reduced body weight, WC, and BP, which are critical risk factors for cardiovascular disease. function in diabetes has shown continuing long-term efficacy. In this regard, evidence is emerging indicating liraglutide, a recent glucagon-like peptide-1 mimetic, provides superior glycemic control compared with other antidiabetes agents, including the glucagon-like peptide-1 receptor agonists albiglutide and exenatide, and appears to preserve b-cell function in patients with new-onset T2DM.2–5 Moreover, liraglutide-treated patients were more likely to have clinically relevant weight loss and less incidence of hypoglycemia, associated with beneficial effects on both systolic and
Introduction
T
ype 2 diabetes mellitus (T2DM) is the most common metabolic disease1 and is linked to the progressive decline of pancreatic b-cell function and increased peripheral insulin resistance. Current therapies in the management of T2DM include lifestyle modifications, including diet and exercise, as well as the use of a variety of oral and/or injected hypoglycemic agents. Nevertheless, no currently available therapy for the progressive decline of pancreatic b-cell
Departments of 1Health Sciences and 3Experimental and Clinical Medicine, University ‘‘Magna Græcia’’ of Catanzaro, Catanzaro, Italy. 2 Complex Operative Structure of Endocrinology-Diabetology, Pugliese-Ciaccio Hospital, Catanzaro, Italy. 4 Diabetologic Unit, Soverato Hospital, Soverato, Italy. *The first two authors contributed equally to this work. { We dedicate this article to the memory of Dr. Carmelo Capula, who prematurely died on March 30, 2015. Parts of this study were presented in abstract form at the 74th Scientific Session of the American Diabetes Association, held in San Francisco, California, June 13–17, 2014.
1
2
diastolic blood pressure (BP) and lipid profile.6 Although some patients may experience minor nausea at treatment initiation, adverse effects of liraglutide are otherwise minimal, and a dose titration regimen, which increases the dose gradually (from 0.6 to 1.8 mg/day), is used to improve its tolerability.7 Nevertheless, the U.S. Food and Drug Administration warns people with or a family history of thyroid cancer or pancreatitis against taking liraglutide (www.fda.gov/Safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/ucm258826.htm). The risk of developing diabetes increases as body mass index (BMI) increases. Consistent with this trend, the higher prevalence of obesity in Calabria, Southern Italy, parallels the greater proportion of individuals with T2DM in this area, compared with the entire Italian population (www.istat.it). Use of liraglutide in the management of T2DM in Italy is only permitted in combination with other oral hypoglycemic agents. Therefore, here we aimed to assess the efficacy and safety of liraglutide in combination with metformin, in Calabrian patients with T2DM uncontrolled by metformin alone. In addition, a comparison group of patients who were receiving metformin plus glimepiride, a third-generation sulfonylurea hypoglycemic agent,7 was also analyzed. Patients and Methods Participants
Data were retrospectively collected from 76 diabetes patients who started treatment with liraglutide (in addition to metformin [2.31 – 0.47 g/day]) on the basis of current recommendations for management and treatment of hyperglycemia in T2DM.8 Participants were recruited after the launch of liraglutide in Italy (September 2010) and until April 2012 from the diabetes outpatient clinic of the Hospital PuglieseCiaccio in Catanzaro (n = 57), from the University of Catanzaro outpatient clinics (n = 13), and from the diabetes outpatient clinic of Soverato (n = 6). The following inclusion criteria were applied: 18–80 years of age, BMI £45 kg/m2, poor glycemic control (hemoglobin A1c [HbA1c] levels of > 7% and
