|Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP4) inhibitors, ATC code: A10BH03 |
Mechanism of action and pharmacodynamic effects Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP4 inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP4 inhibition resulted in a 2 -to 3-fold increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.
Clinical efficacy and safety In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes have been treated with saxagliptin.
Glycaemic controlA total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with, saxagliptin were randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. Treatment with saxagliptin 5 mg once daily produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and in combination with a thiazolidinedione (see Table 2). There was also no apparent change in body weight associated with saxagliptin. Reductions in HbA1c were seen across subgroups including gender, age, race, and baseline body mass index (BMI) and higher baseline HbA1c was associated with a greater adjusted mean change from baseline with saxagliptin.
Saxagliptin as monotherapyTwo double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the efficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies, once-daily treatment with saxagliptin provided significant improvements in HbA1c (see Table 2). The findings of these studies were confirmed with two subsequent 24-week regional (Asian) monotherapy studies comparing saxagliptin 5 mg with placebo.
Saxagliptin add-on to metformin therapyAn add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant improvements in HbA1c, FPG, and PPG compared to placebo (n=175).
Improvements in HbA1c, PPG, and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin (n=15) was -0.8% at Week 102.
Saxagliptin add-on to metformin compared with SU add-on to metforminA 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with a sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control (HbA1c 6.5%-10%) on metformin alone. The mean metformin dose was approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. 0.8%, respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first 24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide. Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).
Saxagliptin add-on to metformin compared with sitagliptin add-on to metforminAn 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After 18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets. The reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and -0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and -0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for both groups.
Saxagliptin in combination with metformin as initial therapy A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin as initial combination therapy in treatment-naïve patients with inadequate glycaemic control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin (n=306) provided significant improvements in HbA1c, FPG, and PPG compared to with either saxagliptin (n=317) or metformin alone (n=313) as initial therapy. Reductions in HbA1c from baseline to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater reductions observed in patients with a baseline HbA1c ≥10% (see Table 2). Improvements in HbA1c, PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin plus placebo (n=147) was -0.5% at Week 76.
Saxagliptin add-on to glibenclamide therapyAn add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control at enrolment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in combination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was compared to titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plus glibenclamide group were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250) provided significant improvements in HbA1c, FPG, and PPG compared to titration to a higher dose of glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitrated glibenclamide plus placebo (n=27) was -0.7% at Week 76.
Saxagliptin add-on combination therapy with insulin (with or without metformin)A total of 455 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c ≥ 7.5% and ≤ 11%) on insulin alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulin with or without metformin. Similar HbA1c reductions versus placebo were achieved for patients receiving saxagliptin 5 mg add-on to insulin regardless of metformin use (−0.4% for both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add-on to insulin group compared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1c change for the saxagliptin group (n=244) compared to placebo (n=124) was -0.4% at Week 52.
Saxagliptin add-on to thiazolidinedione therapyA placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in HbA1c, FPG, and PPG compared to placebo (n=180). Improvements in HbA1c, PPG and FPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76.
Saxagliptin add-on combination therapy with metformin and sulphonylureaA total of 257 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) in combination with metformin plus sulphonylurea (SU) in patients with inadequate glycemic control (HbA1c ≥ 7% and ≤ 10%). Saxagliptin (n=127) provided significant improvements in HbA1c and PPG compared with the placebo (n=128). The HbA1c change for saxagliptin compared to placebo was -0.7% at Week 24.
Patients with renal impairmentA 12 week, multi-centre, randomised, double-blind, placebo controlled study was conducted to evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal impairment (moderate [n=90]; severe [n=41]; or ESRD [n=39]). In this study, 98.2% of the patients received other antihyperglycaemic treatments (75.3% on insulin and 31.2% on oral antihyperglycaemics; some received both). Saxagliptin significantly decreased HbA1c compared with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to Week 52, however the number of patients who completed 52 weeks without modification of other antihyperglycaemic treatments was low (26 subjects in the saxagliptin group versus 34 subjects in the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.
Table 2 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy trials and in add-on combination therapy trials
n=Randomized patients (primary efficacy-intention-to-treat analysis) with data available.
1Placebo group had uptitration of glibenclamide from 7.5 to 15 mg total daily dose.
2 Adjusted mean change from baseline adjusted for baseline value (ANCOVA).
3 p<0.0001 compared to placebo.
4 p=0.0059 compared to placebo.
5 p=0.0157 compared to placebo.
6 Metformin was uptitrated from 500 to 2000 mg per day as tolerated.
7 Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups (p<0.0001).
8 Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups.
| || Mean baseline HbA1c (%)||Mean change2 from baseline HbA1c (%) at Week 24|| Placebo-corrected mean change in HbA1c (%) at Week 24 (95% CI)|
|MONOTHERAPY STUDIES|| || || |
| • Study CV181011 (n=103)
||-0.6 (-0.9, -0.4)3|
| • Study CV181038 (n=69)
|| -0.7 (morning)
||-0.4 (-0.7, -0.1) 4|
|| -0.6 (evening)
||-0.4 (-0.6, -0.1) 5|
|ADD-ON/COMBINATION STUDIES|| || || |
| • Study CV181014: add-on to metformin (n=186)
||-0.8 (-1.0, -0.6)3|
|• Study CV181040: add-on to SU1 (n=250)
||-0.7 (-0.9, -0.6)3|
| • Study D1680L00006: add-on to metformin plus SU (n=257)
||-0.7 (-0.9, -0.5) 3|
| • Study CV181013: add-on to TZD (n=183)
||-0.6 (-0.8, -0.4)3|
|• Study CV181039: initial combination with metformin6 Overall population (n=306)
Baseline HbA1c ≥10% stratum (n=107)
-0.5 (-0.7, -0.4) 7-0.6 (-0.9, -0.3) 8
|• Study CV181057: add-on to insulin (+/-metformin)|
Overall population (n=300)
| 8.7 || -0.7 || -0.4 (-0.6, -0.2)3|
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus- Thrombolysis in Myocardial Infarction (SAVOR) Study SAVOR was a CV outcome trial in 16,492 patients with HbA1c ≥ 6.5% and < 12% (12959 with established CV disease; 3533 with multiple risk factors only) who were randomised to saxagliptin (n=8280) or placebo (n=8212) added to regional standards of care for HbA1c and CV risk factors. The study population included those ≥ 65 years (n=8561) and ≥ 75 years (n=2330), with normal or mild renal impairment (n=13,916) as well as moderate (n=2240) or severe (n=336) renal impairment. The primary safety (noninferiority) and efficacy (superiority) endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following major adverse CV events (MACE): CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke.
After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptin does not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo when added to current background therapy.
No benefit was observed for MACE or all cause mortality.
Table 3: Primary and Secondary Clinical Endpoints by Treatment Group in the SAVOR Study*
* Intent-to-treat population
Hazard ratio adjusted for baseline renal function category and baseline CVD risk category.
p-value <0.001 for noninferiority (based on HR <1.3) compared to placebo.
§ p-value = 0.99 for superiority (based on HR <1.0) compared to placebo.
# Events accumulated consistently over time, and the event rates for Onglyza and placebo did not diverge notably over time.
¶ Significance not tested.
One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; (95% CI 1.07, 1.51); P = 0.007]. Clinically relevant factors predictive of increased relative risk with saxagliptin treatment could not be definitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatment assignment, could be identified by known risk factors for heart failure such as baseline history of heart failure or impaired renal function. However, subjects on saxagliptin with a history of heart failure or impaired renal function at baseline were not at an increased risk relative to placebo for the primary or secondary composite endpoints or all-cause mortality.Another secondary endpoint, all cause mortality, occurred at a rate of 5.1% in the saxagliptin group and 4.6% in the placebo group (see Table 3). CV deaths were balanced across the treatment groups. There was a numerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than placebo (1.4%) [HR = 1.27; (95% CI 1.00, 1.62); P = 0.051].
A1C was lower with saxagliptin compared to placebo in an exploratory analysis.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with Onglyza in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
|Saxagliptin (N=8280)||Placebo (N=8212)|| Hazard Ratio (95% CI)|
|Subjects with events n (%)||Event rate per 100 patient-yrs||Subjects with eventsn (%)||Event rate per 100 patient-yrs|
|Primary composite endpoint: MACE
||1.00 (0.89, 1.12),§, #|
|Secondary composite endpoint: MACE plus
||1.02 (0.94, 1.11)¶|
||1.11 (0.96, 1.27)¶|
Elderly populationIn the SAVOR study subgroups over 65 and over 75 years of age, efficacy and safety was consistent with the overall study population.
GENERATION was a 52-week glycaemic control study in 720 elderly patients, the mean age was 72.6 years; 433 subjects (60.1%) were < 75 years of age, and 287 subjects (39.9%) were ≥ 75 years of age. Primary endpoint was the proportion of patients reaching HbA1c < 7% without confirmed or severe hypoglycaemia. There appeared to be no difference in percentage responders: saxagliptin 37.9% (saxagliptin) and 38.2% (glimepiride) achieved the primary endpoint. A lower proportion of patients in the saxagliptin group (44.7%) compared to the glimepiride group (54.7%) achieved an HbA1c target of 7.0%. A lower proportion of patients in the saxagliptin group (1.1%) compared to the glimepiride group (15.3%), experienced a confirmed or severe hypoglycaemic event.