Incretin-based Therapies for Type 2 Diabetes A 24-week RCT of saxagliptin monotherapy in 401 antihyperglycemic
drug-naive patients revealed significant reductions in HbA1c (placebo-adjusted change: -0.62 % and -0.65 % with saxagliptin 2.5 mg and 5.0 mg, respectively [both p<0.0001 versus placebo]), FPG (placebo-adjusted change: -14.94 and -9.00 mg/dl with saxagliptin 2.5 mg and 5.0 mg, respectively [p<0.05 versus placebo]), and two-hour PPG (-38.88 and -36.90 mg/dl, respectively, with saxagliptin 2.5 mg [significance not tested] and 5.0 mg [p<0.05 versus placebo]).40
In a study of 743 patients whose type 2 diabetes was inadequately controlled by ongoing metformin treatment (mean diabetes duration
6.5 years), adding saxagliptin to metformin significantly improved HbA1c values, the percentage of patients with HbA1c values ≤7.0 %, and both fasting and post-prandial glucose levels (all p<0.0001 from baseline versus placebo).34
Treatment differences in HbA1c, FPG, and PPG were similar with linagliptin as an add-on to metformin in a 24-week study of 701 patients
with type 2 diabetes. Placebo-corrected changes were -0.64 %,
-21.6 mg/dl, and -66.6 mg/dl for HbA1c, FPG, and PPG, respectively (all p<0.0001).44
Another study, including 333 patients with inadequate glycemic control with metformin alone, showed similar results after 12 weeks of linagliptin 5 mg or glimepiride treatment (0.75 % and 0.9 %
placebo-corrected HbA1c reductions, respectively [p<0.001]). Mean type 2 diabetes disease duration was 6.2–8.2 years.45
Neither study reported
significant body weight changes in the linagliptin treatment groups.44,45 In another study, patients randomized to an initial combination regimen of linagliptin plus pioglitazone had treatment differences of -0.51 % and -14.22 mg/dl in HbA1c and FPG, respectively (both p<0.0001).46
A second RCT revealed the efficacy and safety profile of saxagliptin with metformin as a first-line antihyperglycemic regimen for patients with relatively recent diagnoses of type 2 diabetes and inadequate glycemic control (n=1,306, mean disease duration 1.4–2 years). Both fasting and post-prandial glucose parameters fell even more significantly after 24 weeks of combination therapy versus either drug as a single agent (all p≤0.0002).37
A 24-week RCT in 1,058 patients whose type 2 diabetes was inadequately controlled with metformin plus sulfonylurea treatment also linked add-on linagliptin with significant improvements in glycemic control.47
Placebo-adjusted changes in HbA1c and FPG were -0.62 % and -12.6 mg/dl, respectively (both p<0.0001).47
According to a 52-week study in 858 patients, saxagliptin is non-inferior to glipizide as an adjunct to inadequate metformin treatment, with a between-group difference in HbA1c reduction of 0.06 %.35
A 76-week study in 1,306 treatment-naive patients with type 2 diabetes has also shown the sustained long-term additive efficacy of saxagliptin with metformin as initial combination therapy for up to 76 weeks.
HbA1c fell by 2.31 % and 2.33 % with metformin plus saxagliptin 5 mg or 10 mg, respectively, compared with 1.79 % with metformin alone and 1.55 % with saxagliptin 10 mg monotherapy (p<0.0001 for combinations versus monotherapies).39
In 768 randomized patients, adding saxagliptin to a submaximal dose of
glyburide was linked with significantly improved HbA1c and both fasting and post-challenge plasma glucose after 24 weeks, compared with increasing the glyburide dose (p≤0.0218). Mean disease duration was 6.8–7.1 years; patients entered the study with inadequate glycemic control on submaximal doses of sulfonylurea.41
According to a 24-week RCT in 565 patients with type 2 diabetes,
saxagliptin can also significantly reduce HbA1c and fasting or post-prandial glucose levels when added to a thiazolidinedione. Patients
had insufficient glycemic control (HbA1c ≥7.0 % to ≤10.0 %) with ongoing pioglitazone or rosiglitazone treatment (mean disease duration 5.1–5.3 years).42
A 52-week extension to this study reported significant
HbA1c reductions from baseline versus placebo with both 2.5 mg and 5.0 mg saxagliptin. Placebo-subtracted changes in HbA1c were -0.39 % and -0.89 % with 2.5 mg and 5.0 mg saxagliptin, respectively (p<0.0019 and p<0.0001) in the 360 patients who completed the full 76-week follow-up.36
Linagliptin
A phase III RCT including 503 patients with type 2 diabetes, who were either treatment-naive or had received one oral antihyperglycemic drug, showed the significant benefits of linagliptin monotherapy over 24 weeks. Linagliptin-treated patients experienced placebo-corrected reductions in HbA1c (0.69 %), FPG (23.4 mg/dl), and PPG (57.6 mg/dl) [all p<0.0001].43
US ENDOCRINOLOGY
Glucagon-like Peptide-1 Receptor Agonists Data from non-comparative trials regarding the efficacy of GLP-1 receptor agonists is summarized in Table 2.
Exenatide Twice Daily A 24-week RCT revealed significant (and dose-dependent)
improvements in HbA1c and daily mean post-prandial glucose peaks in treatment-naive patients with two years’ type 2 diabetes disease duration receiving first-line antihyperglycemic exenatide treatment
twice daily after failed glycemic control using diet and exercise (HbA1c -0.7 % and -0.9 % versus -0.2 % [all p≤0.003]; FPG: -17.46 mg/dl and -18.72 mg/dl versus -5.22 mg/dl [p≤0.029 for 5 µg and 10 µg exenatide twice daily versus placebo, respectively]).48
Investigators demonstrated the efficacy of exenatide twice daily as an add-on to existing oral agents in three simultaneous 30-week Phase III studies in the US (total randomized population: 1,447).49–51
Patients with poor glycemic control with metformin experienced significant
improvements in HbA1c and both fasting and post-prandial glucose levels after 30 weeks of treatment with 5 µg or 10 µg exenatide twice daily.
HbA1c values fell by 0.4 % and 0.78 % with 5 µg and 10 µg exenatide twice daily, respectively, compared with a 0.08 % increase in the placebo group (p<0.001 overall).50
Similar HbA1c reductions were seen in
sulfonylurea-treated patients receiving 5 µg and 10 µg exenatide twice daily: 0.46 % and 0.86 %, respectively, versus a 0.12 % increase with a sulfonylurea alone (p<0.0002 pairwise comparisons).49
The third study
also demonstrated consistent HbA1c lowering when exenatide twice daily was added to metformin plus sulfonylurea combination therapy: 0.55 %
and 0.77 % decreases were seen with 5 µg and 10 µg exenatide twice daily, respectively, compared with a 0.23 % increase with placebo (p<0.001). Post-prandial glucose AUC fell significantly more with exenatide twice daily than with placebo (p<0.01).51
duration ranged from 4.9 to 9.4 years for all three 30-week studies.
In another study, exenatide twice daily was shown to improve both HbA1c and fasting plasma glucose as well as post-prandial glucose values over
85
Mean diabetes
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