Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes
Article Figures & Tables
Figures
- Figure 1
Schematic illustration of the study with the overall crossover design (top panel) and the clamp procedure (bottom panel).
- Figure 2
Glucose, glucagon, cortisol, PP, norepinephrine, and epinephrine levels during the hyperinsulinemic hypoglycemic clamp after 6 weeks of treatment with lixisenatide (filled symbols) or placebo (open symbols) in 18 patients with insulin-treated type 2 diabetes. Dotted lines show the time intervals for the two steps of the hypoglycemia clamp (3.5 and 2.8 mmol/L, respectively). Means ± SEM are shown.
Tables
- Table 1
Baseline and 6-week change in HbA1c level, FBG level, body weight, and daily insulin dose during the study
Lixisenatide Placebo P valuea Baseline HbA1c (mmol/mol; IFCC) 61.4 ± 3.0 59.9 ± 2.8 0.548 Baseline HbA1c (%; DCCT) 7.7 ± 0.3 7.6 ± 0.3 0.548 6-week HbA1c (mmol/mol; IFCC) 55.6 ± 2.4 58.8 ± 2.9 0.020 6-week HbA1c (%; DCCT) 7.3 ± 0.2 7.5 ± 0.3 0.020 Change in HbA1c (mmol/mol; IFCC) −5.8 ± 1.2 (P < 0.001)b −1.0 ± 1.3 (P = 0.432)b 0.042 Change in HbA1c (%; DCCT) −0.5 ± 0.1 (P < 0.001)b −0.1 ± 0.1 (P = 0.432)b 0.042 Baseline FBG (mmol/L) 9.7 ± 0.6 9.3 ± 0.7 0.547 6-week FBG (mmol/L) 8.3 ± 0.6 9.3 ± 0.7 0.023 Change in FBG (mmol/L) −1.6 ± 0.4 (P = 0.002)b 0.0 ± 0.6 (P = 0.986)b 0.046 Baseline body weight (kg) 99.5 ± 4.6 99.8 ± 4.5 0.962 6-week body weight (kg) 97.7 ± 4.4 99.1 ± 4.4 0.823 Change in body weight (kg) −1.7 ± 0.4 (P < 0.001)b −0.6 ± 0.4 (P = 0.095)b 0.043 Baseline daily insulin dose (units) 39 ± 24 39 ± 25 0.934 6-week daily insulin dose (units) 37 ± 24 40 ± 24 0.684 Change in daily insulin dose (units) −1.8 ± 4.1 (P = 0.076)b 0.8 ± 2.1 (P = 0.135)b 0.023 Data are reported as the mean ± SD, unless otherwise indicated.
↵aP value for the probability level of random difference between the two treatments.
↵bP value for the probability level of random difference before and after treatment within each treatment arm. DCCT, Diabetes Control and Complications Trial unit; IFCC, International Federation of Clinical Chemistry and Laboratory Medicine unit.
- Table 2
Glucagon levels and counterregulation during the hyperinsulinemic hypoglycemic clamp test in subjects with insulin-treated type 2 diabetes
Lixisenatide Placebo P value Glucagon level at 0 min (pmol/L) 10.7 ± 1.3 9.8 ± 1.2 0.18 Glucagon level at 60 min (pmol/L) 4.5 ± 0.7 6.0 ± 0.8 0.005 Glucagon level at 120 min (pmol/L) 11.2 ± 1.7 16.1 ± 2.6 0.045 ∆Glucagon at 3.5 mmol/L (60–120 min) (pmol/L) 6.7 ± 1.6 10.1 ± 2.3 0.20 Mean glucagon at 3.5 mmol/L (60–120 min) (pmol/L) 8.1 ± 1.1 11.4 ± 1.6 0.008 AUC glucagon at 3.5 mmol/L (60–120 min) (pmol/L · min) 471 ± 63 668 ± 91 0.013 Glucagon level at 180 min (pmol/L) 21.7 ± 3.4 21.1 ± 3.0 0.827 ∆Glucagon at 2.8 mmol/L (120–180 min) (pmol/L) 10.5 ± 2.3 4.9 ± 2.3 0.042 Mean glucagon at 2.8 mmol/L (min 120–180 min) (pmol/L) 19.2 ± 2.9 20.7 ± 2.9 0.63 AUC glucagon at 2.8 mmol/L (120–180 min) (pmol/L · min) 988 ± 147 1,116 ± 152 0.36 ∆Glucagon during whole clamp (60–180 min) (pmol/L) 17.2 ± 3.0 15.0 ± 2.5 0.45 AUC glucagon during whole clamp (60–180 min) (pmol/L · min) 1,460 ± 208 1,782 ± 29 0.12 Glucagon level at 240 min 13.8 ± 1.9 23.8 ± 2.3 <0.001 Data are reported as the mean ± SEM, unless otherwise indicated. ∆, change in level.
- Table 3
Cortisol, PP, norepinephrine, and epinephrine levels and counterregulation during the hyperinsulinemic hypoglycemic clamp test in subjects with insulin-treated type 2 diabetes
Cortisol (pmol/L or nmol/L · min) PP (pg/mL or pg/mL · min) Norepinephrine (pmol/L or pmol/L · min) Epinephrine (pmol/L or pmol/L · min) Lixisenatide Placebo Lixisenatide Placebo Lixisenatide Placebo Lixisenatide Placebo Level 0 min 411 ± 29 463 ± 32 171 ± 55 157 ± 55 2.0 ± 0.2 2.1 ± 0.2 0.09 ± 0.02 0.11 ± 0.03 Level 60 min 420 ± 28 404 ± 35 157 ± 63 145 ± 53 2.5 ± 0.2 2.7 ± 0.2 0.19 ± 0.06 0.23 ± 0.07 Level 120 min 629 ± 78 691 ± 89 321 ± 77 381 ± 96 2.4 ± 0.2 3.0 ± 0.3 1.19 ± 0.34 2.06 ± 0.54a ∆At 3.5 mmol/L (60–120 min) 219 ± 78 308 ± 85 163 ± 59 235 ± 79 0.0 ± 0.1 0.3 ± 0.2 0.99 ± 0.31 1.82 ± 0.53a Mean level 60–120 min 558 ± 52 574 ± 60 247 ± 66 312 ± 77 2.4 ± 0.58 2.8 ± 0.23 0.78 ± 0.18 1.47 ± 0.39a AUC at 3.5 mmol/L (60–120 min) 31.2 ± 2.7 32.2 ± 3.1 14.1 ± 4.0 15.8 ± 4.0 144 ± 12 173 ± 15 41.5 ± 11.5 68.7 ± 16.8a Level at 180 min 931 ± 46 989 ± 64 660 ± 99 624 ± 96 3.3 ± 0.3 4.1 ± 0.4 2.77 ± 0.51 3.35 ± 0.83 ∆At 2.8 mmol/L (120–180 min) 328 ± 34 287 ± 58 339 ± 88 243 ± 79 1.1 ± 0.23 1.0 ± 0.27 1.54 ± 0.34 1.29 ± 0.49 Mean level at 120–180 min 716 ± 104 804 ± 106 562 ± 88 482 ± 91 2.4 ± 0.30 3.9 ± 0.53 2.61 ± 0.45 3.15 ± 0.69 AUC at 2.8 mmol/L (120–180 min) 47.6 ± 4.1 50.1 ± 4.3 29.5 ± 4.8 27.2 ± 5.4 166 ± 14 215 ± 19 120 ± 24 162 ± 40 ∆At whole clamp (60–180 min) 511 ± 51 684 ± 66 503 ± 88 479 ± 79 0.77 ± 0.21 1.4 ± 0.31 2.58 ± 0.49 3.11 ± 0.82 Data are reported as the mean ± SEM. ∆, change in level. Concentrations (pmol/L or pg/mL) refer to values taken at specific time points, whereas concentrations times minutes (nmol/L · min or pg/mL · min) refer to values for AUC.
↵aProbability level of random difference between the two treatments at P < 0.05 or less (for details, see results).
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