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Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations
Journal of Diabetes and Its Complications 24 (2010) 79 – 83 WWW.JDCJOURNAL.COM
Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations Raffaele Marfella a,⁎, Michelangela Barbieri a , Rodolfo Grella a , Maria Rosaria Rizzo a , Giovanni Francesco Nicoletti b , Giuseppe Paolisso a a
Department of Geriatrics and Metabolic Diseases Second University of Naples, Naples, Italy b Plastic and Reconstructive Surgery, Second University of Naples, Naples, Italy
Received 14 September 2008; received in revised form 4 December 2008; accepted 21 January 2009
Abstract There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications. We evaluated the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin. Forty-eight-hour continuous subcutaneous glucose monitoring (CSGM) was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. During a standardized meal, glucagon-like peptide-1 (GLP-1), glucagon, and insulin were measured. CSGM shows large MAGE decrements in the vildagliptin group compared with the sitagliptin group (Pb.01). A marked increase in GLP-1 occurred during interprandial period in vildagliptin bid-treated toward sitagliptin 100 mg once daily (Pb.01). Glucagon was more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (Pb.01). Since MAGE is associated with an activation of oxidative stress, our data suggest that dipeptidyl peptidase IV inhibition therapy should target not only reducing HbA1c but also flattening acute glucose fluctuations over a daily period. © 2010 Elsevier Inc. All rights reserved. Keywords: Dipeptidyl peptidase IV-inhibitors; Glicemic control
1. Introduction There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications (Monnier et al., 2006). Exposure to glycemic disorders can be described as a function of two components: the duration and magnitude of chronic sustained hyperglycemia and the acute fluctuations of glucose over a daily period (Klein, 1995; Stratton et al., 2000). The first component was integrated by HbA1c, which depends on both interprandial and postprandial hyperglycemia (Monnier, Lapinski, & Colette, 2003). The second ⁎ Corresponding author. 80138 Napoli, Italy. Tel.: +39 081 5665110; fax: +39 081 5096142. E-mail address: [email protected] (R. Marfella). 1056-8727/09/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2009.01.004
component, that is, the acute fluctuations of glucose around a mean value, has been proved independent of mean glycemia and may be due to defects in insulin secretion and suppression of glucagon secretion (Drucker & Nauck, 2006). Glucagon-like peptide-1 (GLP-1), enhancing insulin secretion and inhibiting glucagon release, reduces postprandial hyperglycemia and may also improve acute fluctuations of glucose (Drucker & Nauck, 2006). While studies have shown that the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase IV (DPP-4), such as vildagliptin and sitagliptin, enhances glucose-induced insulin secretion, decreases glucagon secretion, and reduces postprandial glycemic excursions (Drucker & Nauck, 2006), prior studies have not examined the effects of DPP-4 inhibition on the glucose fluctuations over a daily period. Because the regulation strategy of daily glucose fluctuations attempts to
80
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
stabilize DPP-4 inhibition over a daily period, a crosssectional study was conducted to compare the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations, evaluated by 48hour continuous subcutaneous glucose monitoring (CSGM), in patients with type 2 diabetes that was inadequately controlled by metformin.
2. Research design and methods This cross-sectional study included 38 randomly selected type 2 diabetic patients without adequate glycemic control (HbA1c N7.0%) while on of metformin treatment at maximal dose (3000 mg/day) (Table 1). After institutional review board approval, we retrieved the clinical and laboratory data for the previous 9 months. Among 109 subjects with diabetes, we had follow-up of clinical data and CSGM for 20 patients with type 2 diabetes before the start of therapy
with sitagliptin 100 mg once daily and for 18 patients with type 2 diabetes before the start of therapy with vildagliptin 50 mg bid. All patients who followed a stable therapy with metformin plus vildagliptin or sitagliptin over a period of 3 months were enrolled in the study. After enrollment, CSGM measurements were monitored over a period of three consecutive days by using a continuous glucose monitoring system (Glucoday, Menarini. Italy) in all patients. The sensor was inserted on Day 1 and removed on Day 3 at mid morning. Glucose levels were calibrated on Days 1 and 2, determining fasting and postprandial glycemia by venous sample. The characteristic glucose pattern of each patient was calculated by averaging the profiles obtained on Study Days 1 and 2. The mean amplitude of glycemic excursions (MAGE), which has been described by Service et al. (1970), was used for assessing glucose fluctuations during the day. The measurement of this parameter is of particular interest because when MAGE is greater, glycemic instability is higher (Service, O'Brien, & Rizza, 1987). Standardized meal
Table 1 Clinical characteristics and metabolic profile before and 3 months after vildagliptin 50 mg twice daily or sitagliptin 100 mg once daily Sitagliptin 100 mg once daily
Vildagliptin 50 mg twice daily
Variables
Baseline
After 3 months
P
Baseline
After 3 months
P
Age (years) Male/female gender (n) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Diabetes duration (years) Risk factors Hypertension [n (%)] Hypercholesterolemia [n (%)] Obesity [n (%)] Smokers [n (%)] Coronary artery disease [n (%)] Laboratory Fasting glycemia (mg/dl) 2-h postprandial glycemia (mg/dl) MAGE (mg/dl of glucose) HbA1c (%) 24-h mean glycemia (mg/dl) Insulin (pmol/l) 2-h postmeal insulin (pmol/l) Triglycerides (mg/dl) Total cholesterol (mg/dl) Active therapy ACE inhibitors [n (%)] AT2 antagonists [n (%)] Diuretics [n (%)] β-Blockers [n (%)] Aspirin [n (%)] Statins [n (%)] Duration of metformin treatment (months) Duration of sitagliptin treatment (months) Duration of vildagliptin treatment (months)
61±7 11/9 29.7±5 124±16 82±4 7.7±4
– 11/9 29.4±3 123±12 83±3 –
– – NS NS NS –
60±6 9/9 29.6±4 125±13 81±4 7.8±6
– 9/9 29.2±2 126±10 80±5 –
– – NS NS NS –
/ – – – –
– – – – –
– – – – –
– – – – –
169±24 196±22 69±18 8.3±0.6 159±31 – – 189±47 209±38
145±13 166±17 59±16 ⁎ 7.5±0.4 131±27 207±84 413±124 188±41 206±44
.01 .01 NS .01 .01 – – NS NS
171±31 197±19 70±22 8.4±0.5 157±39 – – 191±39 210±45
146±14 165±15 34±7 7.4±0.5 128±36 221±98 428±148 187±42 205±40
.01 .01 .01 .01 .01 – – NS NS
5 (25) 4 (20) 2 (10) 3 (15) 10 (50) 8 (40) 28.5±6 4.4±1.4 4.5±1.4
– – – – – – – –
– – – – – – – –
4 (22) 4 (22) 2 (12) 3 (16) 10 (55) 7 (39) 29.1±7 –
– – – – – – – –
– – – – – – – –
5 3 3 2 2
(25) (15) (15) (10) (10)
4 (22) 2 (12) 3 (16) 2 (12) 2 (12)
Fasting plasma glucose, serum total cholesterol, and triglycerides were determined by enzymatic colorimetric method; serum high-density lipoprotein cholesterol was measured by enzymatic colorimetric method after precipitation with polyethylene glycol. Plasma insulin levels were determined by RIA. Data are as expressed as means±S.D. ⁎ Pb.05 compared to vildagliptin group.
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
tests with 24-h sampling comprising three mixed meals were performed on Days 1, 2, and 3. After an overnight fast, patients received medications at 0700 h and consumed breakfast 30 min after treatment. Lunch and dinner were provided 5 and 10 h after the beginning of breakfast, respectively, and the medication was administered 30 min before breakfast (sitagliptin 100 mg; vildagliptin 50 mg) and
81
dinner (vildagliptin 50 mg). Standardized breakfast contained 419 kcal (57% carbohydrate, 17% protein, and 26% fat), lunch contained 692 kcal (66% carbohydrate, 16% protein, and 18% fat), while dinner contained 507 kcal (41% carbohydrate, 26% protein, and 32% fat). During the standardized meal, blood samples for measurement of plasma glucose, GLP-1, glucagon, and insulin were obtained
Fig. 1. Box plot (a plot type that displays the central line representing the median, the boxes span from the 25th to 75th percentiles, and the error bars extend from the 10th to 90th percentiles) showing the reductions of fasting glycemia (FPG), PPG levels, 24-hour mean plasma glucose (MPG) levels and MAGE in sitagliptin and vildagliptin groups (Panel A). Plasma levels of intact GLP-1(Panel B) and glucagon (Panel C) during 24-h sampling comprising three standardized meals after 3 months of treatment with vildagliptin (○, 50 mg, twice daily) or sitagliptin (■, 100 mg once daily) in type 2 diabetic patients. Values are the mean±S.D. ⁎Pb.05 compared to the vildagliptin group. The parameter MAGE was designed to quantify major fluctuations of glycemia and to exclude minor ones. Calculation of the MAGE was obtained by measuring the arithmetic mean of the differences between consecutive peaks and nadirs.
82
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
at the following times: −20, 0, 15, 30, 60, 90, 120, 180, 240, and 300 min, with the meal beginning immediately after the Time 0 sample and consumed within 15 min. HbA1c values were evaluated by high-pressure liquid chromatography. Plasma insulin levels were determined by RIA. Plasma glucagon was measured by ELISA (D.B.A., Italy). Plasma levels of intact GLP-1 were measured by ELISA using an antibody specific for the N terminus (D.B.A., Italy). The data evaluations and statistical analysis obtained from this study were conducted using in-house blinding procedures. For the purpose of the final analysis, the clinical database was blinded until medical/scientific review has been completed. Differences in the means were evaluated using Student's t test. A P value b.05 was defined as statistical significance.
3. Results The two groups were well matched at baseline, without significant differences in antropometric and metabolic parameters (Table 1). Decrease in HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) were almost similar in the two groups after 3 months of both sitagliptin and vildagliptin treatments, while MAGE decreased significantly along with vildagliptin group (Table 1). Indeed, CSGM measurements provided evidence for large MAGE decrements in vildagliptin group compared with sitagliptin group (Pb.01) (Fig. 1). As shown in Fig. 1, decrements in mean 24-h glucose levels, and fasting and postmeal plasma glucose levels were superimposable in the two study groups. Focusing on hormone profiles during standard meal and interprandial periods, one can highlight that increase in GLP1 after food intake was substantially identical in the two groups, whereas a significant (Pb.05) and sustained increase during interprandial period of active GLP-1 in vildagliptin bid-treated toward sitagliptin 100 mg once daily occurred (Fig. 1). In addition, plasma glucagon levels were more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (Fig. 1), but such differences did not reach statistical significance during the postprandial period. Finally, both postmeal and interprandial plasma insulin levels reductions were similar in the two groups (Table 1).
4. Conclusions As previously shown, both vildagliptin and sitagliptin when added to metformin treatment are effective at improving glycemic control for 12 weeks in patients with type 2 diabetes (Ahrén, 2007). In this study, the efficacy of vildagliptin was comparable to sitagliptin on the main glucose control parameters HbA1c, FPG, and PPG reductions over a 3-month study period; nevertheless, the effects on glucose fluctuations over a day, as estimated from MAGE
indexes that reflect both upward and downward glucose changes, were more pronounced in the vildagliptin than in the sitagliptin group, which could be due to different mode of administration: vildagliptin 50 mg twice daily while sitagliptin 100 mg once daily. Moreover, vildagliptin showed a significantly better daily GLP-1 inhibition profile, which could be responsible for a MAGE within a shorter range. Thus, although similar in DPP-4 inhibition, the differences in pharmacokinetic profiles may induce a different activity over a daily period: plasma DPP-4 activity is inhibited by almost 100% already at 15–30 min, and N80% inhibition lasts for almost 14 h after a single dose of sitagliptin at 100 mg (Herman et al., 2006); vildagliptin at 50 mg bid inhibits DPP4 activity by almost 97% over a daily period (Mari et al., 2005). This may be a potential mechanism for the different effects on glucose fluctuations over a daily period observed in bid vildagliptin-treated diabetic patients, but the effects need to be assessed in further studies on more patients. However, we cannot exclude that the effect of vildagliptin is superior to that of sitagliptin in respect of the amelioration of pancreatic dysfunction. From a more practical point of view, since glucose variations over time, linked to daily fluctuations of glucose, are associated with an activation of oxidative stress, the main mechanisms that lead to chronic diabetic complications (Monnier et al., 2006), the present data suggest that the DPP-4 inhibition therapy should target not only reducing HbA1c, PPG, and mean hyperglycemia but also flattening acute glucose fluctuations over a daily period.
References Ahrén, B. (2007). Dipeptidyl peptidase-4 inhibitors: Clinical data and clinical implications. Diabetes Care, 30, 1344−1350. Drucker, D. J., & Nauck, M. A. (2006). The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 368, 1696−1705. Herman, G. A., Bergman, A., Stevens, C., Kotey, P., Yi, B., Zhao, P., Dietrich, B., Golor, G., Schrodter, A., Keymeulen, B., Lasseter, K. C., Kipnes, M. S., Snyder, K., Hilliard, D., Tanen, M., Cilissen, C., De Smet, M., de Lepeleire, I., Van Dyck, K., Wang, A. Q., Zeng, W., Davies, M. J., Tanaka, W., Holst, J. J., Deacon, C. F., Gottesdiener, K. M., & Wagner, J. A. (2006). Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism, 91, 4612−4619. Klein, R. (1995). Hyperglycemia and microvascular disease in diabetes. Diabetes Care, 18, 258−268. Mari, A., Sallas, W. M., He, Y. L., Watson, C., Ligueros-Seylan, M., Dunning, B. E., Deacon, C. F., Holst, J. J., & Foley, J. E. (2005). Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves modelassessed beta-cell function in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism, 90, 4888−4894. Monnier, L., Lapinski, H., & Colette, C. (2003). Contribution of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: Variations with increasing levels of HbA1c. Diabetes Care, 26, 881−885. Monnier, L., Mas, E., Ginet, C., Michel, F., Villon, L., Cristol, J. P., & Colette, C. (2006). Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA, 295, 1681−1687.
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83 Service, F. J., Molnar, G. D., Rosevear, J. W., Ackerman, E., Taylor, W. F., Cremer, G. M., & Moxness, K. E. (1970). Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes, 19, 644−655. Service, F. J., O'Brien, P. C., & Rizza, R. A. (1987). Measurements of glucose control. Diabetes Care, 10, 225−237.
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Stratton, I. M., Alder, A. I., Neil, H. A., Matthews, D. R., Manley, S. E., Cull, C. A., Hadden, D., Turner, R. C., & Holman, R. R. (2000). UK Prospective Diabetes Study Group. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35). BMJ, 321, 405−412.
Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations Raffaele Marfella a,⁎, Michelangela Barbieri a , Rodolfo Grella a , Maria Rosaria Rizzo a , Giovanni Francesco Nicoletti b , Giuseppe Paolisso a a
Department of Geriatrics and Metabolic Diseases Second University of Naples, Naples, Italy b Plastic and Reconstructive Surgery, Second University of Naples, Naples, Italy
Received 14 September 2008; received in revised form 4 December 2008; accepted 21 January 2009
Abstract There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications. We evaluated the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin. Forty-eight-hour continuous subcutaneous glucose monitoring (CSGM) was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. During a standardized meal, glucagon-like peptide-1 (GLP-1), glucagon, and insulin were measured. CSGM shows large MAGE decrements in the vildagliptin group compared with the sitagliptin group (Pb.01). A marked increase in GLP-1 occurred during interprandial period in vildagliptin bid-treated toward sitagliptin 100 mg once daily (Pb.01). Glucagon was more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (Pb.01). Since MAGE is associated with an activation of oxidative stress, our data suggest that dipeptidyl peptidase IV inhibition therapy should target not only reducing HbA1c but also flattening acute glucose fluctuations over a daily period. © 2010 Elsevier Inc. All rights reserved. Keywords: Dipeptidyl peptidase IV-inhibitors; Glicemic control
1. Introduction There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications (Monnier et al., 2006). Exposure to glycemic disorders can be described as a function of two components: the duration and magnitude of chronic sustained hyperglycemia and the acute fluctuations of glucose over a daily period (Klein, 1995; Stratton et al., 2000). The first component was integrated by HbA1c, which depends on both interprandial and postprandial hyperglycemia (Monnier, Lapinski, & Colette, 2003). The second ⁎ Corresponding author. 80138 Napoli, Italy. Tel.: +39 081 5665110; fax: +39 081 5096142. E-mail address: [email protected] (R. Marfella). 1056-8727/09/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2009.01.004
component, that is, the acute fluctuations of glucose around a mean value, has been proved independent of mean glycemia and may be due to defects in insulin secretion and suppression of glucagon secretion (Drucker & Nauck, 2006). Glucagon-like peptide-1 (GLP-1), enhancing insulin secretion and inhibiting glucagon release, reduces postprandial hyperglycemia and may also improve acute fluctuations of glucose (Drucker & Nauck, 2006). While studies have shown that the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase IV (DPP-4), such as vildagliptin and sitagliptin, enhances glucose-induced insulin secretion, decreases glucagon secretion, and reduces postprandial glycemic excursions (Drucker & Nauck, 2006), prior studies have not examined the effects of DPP-4 inhibition on the glucose fluctuations over a daily period. Because the regulation strategy of daily glucose fluctuations attempts to
80
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
stabilize DPP-4 inhibition over a daily period, a crosssectional study was conducted to compare the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations, evaluated by 48hour continuous subcutaneous glucose monitoring (CSGM), in patients with type 2 diabetes that was inadequately controlled by metformin.
2. Research design and methods This cross-sectional study included 38 randomly selected type 2 diabetic patients without adequate glycemic control (HbA1c N7.0%) while on of metformin treatment at maximal dose (3000 mg/day) (Table 1). After institutional review board approval, we retrieved the clinical and laboratory data for the previous 9 months. Among 109 subjects with diabetes, we had follow-up of clinical data and CSGM for 20 patients with type 2 diabetes before the start of therapy
with sitagliptin 100 mg once daily and for 18 patients with type 2 diabetes before the start of therapy with vildagliptin 50 mg bid. All patients who followed a stable therapy with metformin plus vildagliptin or sitagliptin over a period of 3 months were enrolled in the study. After enrollment, CSGM measurements were monitored over a period of three consecutive days by using a continuous glucose monitoring system (Glucoday, Menarini. Italy) in all patients. The sensor was inserted on Day 1 and removed on Day 3 at mid morning. Glucose levels were calibrated on Days 1 and 2, determining fasting and postprandial glycemia by venous sample. The characteristic glucose pattern of each patient was calculated by averaging the profiles obtained on Study Days 1 and 2. The mean amplitude of glycemic excursions (MAGE), which has been described by Service et al. (1970), was used for assessing glucose fluctuations during the day. The measurement of this parameter is of particular interest because when MAGE is greater, glycemic instability is higher (Service, O'Brien, & Rizza, 1987). Standardized meal
Table 1 Clinical characteristics and metabolic profile before and 3 months after vildagliptin 50 mg twice daily or sitagliptin 100 mg once daily Sitagliptin 100 mg once daily
Vildagliptin 50 mg twice daily
Variables
Baseline
After 3 months
P
Baseline
After 3 months
P
Age (years) Male/female gender (n) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Diabetes duration (years) Risk factors Hypertension [n (%)] Hypercholesterolemia [n (%)] Obesity [n (%)] Smokers [n (%)] Coronary artery disease [n (%)] Laboratory Fasting glycemia (mg/dl) 2-h postprandial glycemia (mg/dl) MAGE (mg/dl of glucose) HbA1c (%) 24-h mean glycemia (mg/dl) Insulin (pmol/l) 2-h postmeal insulin (pmol/l) Triglycerides (mg/dl) Total cholesterol (mg/dl) Active therapy ACE inhibitors [n (%)] AT2 antagonists [n (%)] Diuretics [n (%)] β-Blockers [n (%)] Aspirin [n (%)] Statins [n (%)] Duration of metformin treatment (months) Duration of sitagliptin treatment (months) Duration of vildagliptin treatment (months)
61±7 11/9 29.7±5 124±16 82±4 7.7±4
– 11/9 29.4±3 123±12 83±3 –
– – NS NS NS –
60±6 9/9 29.6±4 125±13 81±4 7.8±6
– 9/9 29.2±2 126±10 80±5 –
– – NS NS NS –
/ – – – –
– – – – –
– – – – –
– – – – –
169±24 196±22 69±18 8.3±0.6 159±31 – – 189±47 209±38
145±13 166±17 59±16 ⁎ 7.5±0.4 131±27 207±84 413±124 188±41 206±44
.01 .01 NS .01 .01 – – NS NS
171±31 197±19 70±22 8.4±0.5 157±39 – – 191±39 210±45
146±14 165±15 34±7 7.4±0.5 128±36 221±98 428±148 187±42 205±40
.01 .01 .01 .01 .01 – – NS NS
5 (25) 4 (20) 2 (10) 3 (15) 10 (50) 8 (40) 28.5±6 4.4±1.4 4.5±1.4
– – – – – – – –
– – – – – – – –
4 (22) 4 (22) 2 (12) 3 (16) 10 (55) 7 (39) 29.1±7 –
– – – – – – – –
– – – – – – – –
5 3 3 2 2
(25) (15) (15) (10) (10)
4 (22) 2 (12) 3 (16) 2 (12) 2 (12)
Fasting plasma glucose, serum total cholesterol, and triglycerides were determined by enzymatic colorimetric method; serum high-density lipoprotein cholesterol was measured by enzymatic colorimetric method after precipitation with polyethylene glycol. Plasma insulin levels were determined by RIA. Data are as expressed as means±S.D. ⁎ Pb.05 compared to vildagliptin group.
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
tests with 24-h sampling comprising three mixed meals were performed on Days 1, 2, and 3. After an overnight fast, patients received medications at 0700 h and consumed breakfast 30 min after treatment. Lunch and dinner were provided 5 and 10 h after the beginning of breakfast, respectively, and the medication was administered 30 min before breakfast (sitagliptin 100 mg; vildagliptin 50 mg) and
81
dinner (vildagliptin 50 mg). Standardized breakfast contained 419 kcal (57% carbohydrate, 17% protein, and 26% fat), lunch contained 692 kcal (66% carbohydrate, 16% protein, and 18% fat), while dinner contained 507 kcal (41% carbohydrate, 26% protein, and 32% fat). During the standardized meal, blood samples for measurement of plasma glucose, GLP-1, glucagon, and insulin were obtained
Fig. 1. Box plot (a plot type that displays the central line representing the median, the boxes span from the 25th to 75th percentiles, and the error bars extend from the 10th to 90th percentiles) showing the reductions of fasting glycemia (FPG), PPG levels, 24-hour mean plasma glucose (MPG) levels and MAGE in sitagliptin and vildagliptin groups (Panel A). Plasma levels of intact GLP-1(Panel B) and glucagon (Panel C) during 24-h sampling comprising three standardized meals after 3 months of treatment with vildagliptin (○, 50 mg, twice daily) or sitagliptin (■, 100 mg once daily) in type 2 diabetic patients. Values are the mean±S.D. ⁎Pb.05 compared to the vildagliptin group. The parameter MAGE was designed to quantify major fluctuations of glycemia and to exclude minor ones. Calculation of the MAGE was obtained by measuring the arithmetic mean of the differences between consecutive peaks and nadirs.
82
R. Marfella et al. / Journal of Diabetes and Its Complications 24 (2010) 79–83
at the following times: −20, 0, 15, 30, 60, 90, 120, 180, 240, and 300 min, with the meal beginning immediately after the Time 0 sample and consumed within 15 min. HbA1c values were evaluated by high-pressure liquid chromatography. Plasma insulin levels were determined by RIA. Plasma glucagon was measured by ELISA (D.B.A., Italy). Plasma levels of intact GLP-1 were measured by ELISA using an antibody specific for the N terminus (D.B.A., Italy). The data evaluations and statistical analysis obtained from this study were conducted using in-house blinding procedures. For the purpose of the final analysis, the clinical database was blinded until medical/scientific review has been completed. Differences in the means were evaluated using Student's t test. A P value b.05 was defined as statistical significance.
3. Results The two groups were well matched at baseline, without significant differences in antropometric and metabolic parameters (Table 1). Decrease in HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) were almost similar in the two groups after 3 months of both sitagliptin and vildagliptin treatments, while MAGE decreased significantly along with vildagliptin group (Table 1). Indeed, CSGM measurements provided evidence for large MAGE decrements in vildagliptin group compared with sitagliptin group (Pb.01) (Fig. 1). As shown in Fig. 1, decrements in mean 24-h glucose levels, and fasting and postmeal plasma glucose levels were superimposable in the two study groups. Focusing on hormone profiles during standard meal and interprandial periods, one can highlight that increase in GLP1 after food intake was substantially identical in the two groups, whereas a significant (Pb.05) and sustained increase during interprandial period of active GLP-1 in vildagliptin bid-treated toward sitagliptin 100 mg once daily occurred (Fig. 1). In addition, plasma glucagon levels were more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (Fig. 1), but such differences did not reach statistical significance during the postprandial period. Finally, both postmeal and interprandial plasma insulin levels reductions were similar in the two groups (Table 1).
4. Conclusions As previously shown, both vildagliptin and sitagliptin when added to metformin treatment are effective at improving glycemic control for 12 weeks in patients with type 2 diabetes (Ahrén, 2007). In this study, the efficacy of vildagliptin was comparable to sitagliptin on the main glucose control parameters HbA1c, FPG, and PPG reductions over a 3-month study period; nevertheless, the effects on glucose fluctuations over a day, as estimated from MAGE
indexes that reflect both upward and downward glucose changes, were more pronounced in the vildagliptin than in the sitagliptin group, which could be due to different mode of administration: vildagliptin 50 mg twice daily while sitagliptin 100 mg once daily. Moreover, vildagliptin showed a significantly better daily GLP-1 inhibition profile, which could be responsible for a MAGE within a shorter range. Thus, although similar in DPP-4 inhibition, the differences in pharmacokinetic profiles may induce a different activity over a daily period: plasma DPP-4 activity is inhibited by almost 100% already at 15–30 min, and N80% inhibition lasts for almost 14 h after a single dose of sitagliptin at 100 mg (Herman et al., 2006); vildagliptin at 50 mg bid inhibits DPP4 activity by almost 97% over a daily period (Mari et al., 2005). This may be a potential mechanism for the different effects on glucose fluctuations over a daily period observed in bid vildagliptin-treated diabetic patients, but the effects need to be assessed in further studies on more patients. However, we cannot exclude that the effect of vildagliptin is superior to that of sitagliptin in respect of the amelioration of pancreatic dysfunction. From a more practical point of view, since glucose variations over time, linked to daily fluctuations of glucose, are associated with an activation of oxidative stress, the main mechanisms that lead to chronic diabetic complications (Monnier et al., 2006), the present data suggest that the DPP-4 inhibition therapy should target not only reducing HbA1c, PPG, and mean hyperglycemia but also flattening acute glucose fluctuations over a daily period.
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