Saxagliptin for the treatment of type 2 diabetes mellitus: Focus on recent studies

Figures & data

Table I. Overview of the benefits and risks associated with traditional oral antidiabetic drugs and insulin (2).

	Metformin	Sulfonylurea	Thiazolidinedione	Meglitinide	α-Glucosidase inhibitor	Insulin
Benefits
Lowering PPG	Mild	Moderate	Mild	Moderate	Moderate	Moderate to marked
Lowering FPG	Moderate	Moderate	Moderate	Mild	Neutral	Moderate to marked
Risks
Hypoglycemia	Neutral	Moderate	Neutral	Mild	Neutral	Moderate to severe
GI symptoms	Moderate	Neutral	Neutral	Neutral	Moderate	Neutral
Weight gain	Benefit	Mild	Moderate	Mild	Neutral	Mild to moderate
Fractures	Neutral	Neutral	Moderate	Neutral	Neutral	Neutral
Heart failure/edema	Contraindicated in CHF	Neutral	Mild to moderate; contraindicated in class 3 or 4 CHF	Neutral	Neutral	Neutral unless used with thiazolidinedione
Risk of use in renal insufficiency	Severe	Moderate	Mild	Neutral	Neutral	Moderate
Contraindicated in liver failure or predisposition to lactic acidosis	Severe	Moderate	Moderate	Moderate	Neutral	Neutral

Adapted from Rodbard HW et al., Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control. Endocrine Practice. 2009;15:540–59; reprinted with permission from the American Association of Clinical Endocrinologists.

CHF = congestive heart failure; FPG = fasting plasma glucose; GI = gastrointestinal; PPG = postprandial glucose.

Table II. Overview of effects on glycemic control with DPP-4 inhibitors in 24-week placebo-controlled trials (7–10).

	Linagliptin	Sitagliptin	Vildagliptin	Saxagliptin
	5 mg	100 mg	100 mg ^f	2.5 mg	5 mg
Monotherapy
Base-line HbA1c, %	8.0	8.0	8.6, 8.4	7.9	8.0
Δ HbA1c, %	–0.4	–0.6	–0.8, –0.7	–0.4	–0.5
Difference versus Δ with placebo, %	–0.7^a	–0.8^b	–0.5^c, –0.7^c	–0.6^d	–0.6^d
Achieved HbA1c < 7%	25%	41%	–	35%	38%^c
Base-line FPG, mg/dL	164	170	–	178	171
Δ FPG, mg/dL	–9	–12	–	–15	–9
Difference versus Δ with placebo, mg/dL	–23^a	–17^b	–	–21^c	–15^c
Base-line PPG, mg/dL	258	257	–	279	278
Δ PPG, mg/dL	–34	–49	–	–45	–43
Difference versus Δ with placebo, mg/dL	–58^a	–47^b	–	–39^e	–37^c
Add-on to metformin
Base-line HbA1c, %	8.1	8.0	8.4	8.1	8.1
Δ HbA1c, %	–0.5	–0.7	–0.9	–0.6	–0.7
Difference versus Δ with placebo, %	–0.6^a	–0.7^b	–1.1^c	–0.7^d	–0.8^d
Achieved HbA1c < 7%	28%	47%	–	37%^c	44%^c
Base-line FPG, mg/dL	169	170	–	174	179
Δ FPG, mg/dL	–11	–17	–	–14	–22
Difference versus Δ with placebo, mg/dL	–0.21^a	–25^b	–	–16^c	–23^c
Base-line PPG, mg/dL	270	275	–	294	296
Δ PPG, mg/dL	–49	–62	–	–62	–58
Difference versus Δ with placebo, mg/dL	–67^a	–51^b	–	–44^c	–40^c

Statistical significance versus placebo: ^a95% confidence interval does not cross 0; ^bP < 0.001; ^cP < 0.05; ^dP < 0.0001; ^enot compared.

^fAdministered as 50 mg twice daily.

Δ = change from base-line; DPP-4 = dipeptidyl peptidase-4; FPG = fasting plasma glucose; HbA_1c = glycated hemoglobin; PPG = postprandial glucose.

Table III. Glycemic parameters in pivotal, 24-week, phase III clinical trials of saxagliptin 5 mg once daily in T2DM patients (18–22).

	Monotherapy		Add-on to MET		Add-on to GLY		Add-on to TZD		Initial combination with MET
	SAXA n = 106	PBO n = 95	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Mean base-line HbA1c, %	8.0	7.9	8.1		8.5	8.4	8.4	8.2	9.4	9.4
Δ HbA1c, %	−0.5^a	0.2	−0.7^a	0.1	−0.6^a	0.1	−0.9^a	−0.3	−2.5^a	−2.0
Δ FPG, mg/dL	−9.0^b	6.0	−22.0^a	1.2	−10.0^e	1.0	−18.0	−3.6	−60.0^a	−47.0
Δ 2-hour PPG, mg/dL	−43.0^c	−6.0	−58.2^a	−18.0	−34.0^a	8.0	−72.0^g	−18.0	−138.0^a	−97.0
HbA1c < 7%, % of patients	38.0^d	24.0	43.5^a	16.6	22.8^a	9.1	41.8^h	25.6	60.3^a	41.1
HbA1c ≤ 6.5%, % of patients	—	—	—	—	10.4^f	4.5	20.7	9.4	45.3^a	29.0

Statistical significance versus placebo: ^aP = 0.0001; ^bP = 0.0074; ^cP = 0.0009; ^dP = 0.0443; ^eP = 0.0020; ^fP = 0.0117; ^gP < 0.005; ^hP = 0.0013.

Δ = adjusted mean change from base-line; FPG = fasting plasma glucose; GLY = glyburide; HbA_1c = glycated hemoglobin; MET = metformin; PBO = placebo; PPG = postprandial glucose; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide.

Table IV. Incidence of hypoglycemia and adverse events (incidence ≥ 5%) occurring more frequently in patients treated with saxagliptin 5 mg than in those receiving control treatment in the pivotal 24-week trials (18–22).

Events, reported as n (%)	Monotherapy		Add-on to MET		Add-on to GLY		Add-on to TZD		Initial combination with MET
	SAXA n = 106	PBO n = 95	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Headache	10 (9.4)	7 (7.4)	11 (5.8)	13 (7.3)	19 (7.5)	15 (5.6)	10 (5.4)	7 (3.8)	24 (7.5)	17 (5.2)
Peripheral edema	–	–	–	–	–	–	15 (8.1)	8 (4.3)	–	–
URTI	9 (8.5)	11 (11.6)	9 (4.7)	9 (5.0)	16 (6.3)	18 (6.7)	17 (9.1)	13 (7.1)	–	–
Urinary tract infection	9 (8.5)	4 (4.2)	10 (5.2)	8 (4.5)	27 (10.7)	22 (8.2)	12 (6.5)	12 (6.5)	–	–
Reported hypoglycemia^a	5 (4.7)	6 (6.3)	10 (5.2)	9 (5.0)	37 (14.6)	27 (10.1)	5 (2.7)	7 (3.8)	11 (3.4)	13 (4.0)
Confirmed hypoglycemia^b	0 (0)	0 (0)	1 (0.5)	1 (0.6)	2 (0.8)	2 (0.7)	0 (0)	0 (0)	0 (0)	1 (0.3)

^aEvents consistent with symptoms of hypoglycemia with or without documented blood glucose levels.

^bFingerstick glucose < 50 mg/dL with associated symptoms.

GLY = glyburide; MET = metformin; PBO = placebo; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide; URTI = upper respiratory tract infection.

Table V. Glycemic parameters in long-term extension studies with saxagliptin 5 mg (38–41).

	102-week LTE: Add-on to MET		76-week LTE: Add-on to GLY		76-week LTE: Add-on to TZD		76-week LTE: Initial combination with MET
	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Mean base-line HbA1c, %	8.1	8.1	8.5	8.4	8.4	8.2	9.41	9.42
Δ HbA1c, %	−0.40	0.32	0.03	0.69	−1.09	−.20	−2.3	−1.8
Δ FPG, mg/dL	−11.3	6.8	7.9	4.2	−21.4	−4.5	−53.9	−40.3
Δ 2-hour PPG, mg/dL	−31.5	6.1	−19.5	19.1	−75.2	−20.7	−137.0	−85.8
HbA1c <7%, % of patients	30.4	11.6	9.6	5.3	41.3	24.4	51.1	34.7
HbA1c ≤6.5%, % of patients	18.5	8.1	5.2	1.5	22.8	13.9	38.4	20.1

Δ = adjusted mean change from base-line; FPG = fasting plasma glucose; GLY = glyburide; HbA_1c = glycated hemoglobin; LTE = long-term extension; MET = metformin; PBO = placebo; PPG = postprandial glucose; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide.

Table VI. Incidence of hypoglycemia and adverse events (incidence ≥ 5%) occurring more frequently in patients treated with saxagliptin 5 mg than in those receiving control treatment in the long-term extension studies (38–41).

Events, reported as n (%)	102-week LTE: Add-on to MET		76-week LTE: Add-on to GLY		76-week LTE: Add-on to TZD		76-week LTE: Initial combination with MET
	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Nasopharyngitis	21 (11.0)	19 (10.6)	26 (10.3)	29 (10.9)	15 (8.1)	15 (8.2)	29 (9.1)	19 (5.8)
Influenza	22 (11.5)	23 (12.8)	19 (7.5)	27 (10.1)	6 (3.2)	4 (2.2)	20 (6.3)	19 (5.8)
Headache	17 (8.9)	20 (11.2)	25 (9.9)	23 (8.6)	15 (8.1)	12 (6.5)	31 (9.7)	18 (5.5)
Pharyngitis	2 (1.0)	4 (2.2)	19 (7.5)	15 (5.6)	7 (3.8)	5 (2.7)	7 (2.2)	9 (2.7)
Peripheral edema	11 (5.8)	9 (5.0)	6 (2.4)	11 (4.1)	26 (14.0)	19 (10.3)	8 (2.5)	6 (1.8)
URTI	17 (8.9)	14 (7.8)	24 (9.5)	25 (9.4)	24 (12.9)	19 (10.3)	15 (4.7)	10 (3.0)
Urinary tract infection	15 (7.9)	12 (6.7)	42 (16.6)	32 (12.0)	20 (10.8)	17 (9.2)	13 (4.1)	25 (7.7)
Bronchitis	18 (9.4)	11 (6.1)	11 (4.3)	8 (3.0)	7 (3.8)	9 (4.9)	14 (4.4)	4 (1.2)
Sinusitis	10 (5.2)	9 (5.0)	5 (2.0)	5 (1.9)	5 (2.7)	3 (1.6)	–	–
Diarrhea	14 (7.3)	23 (12.8)	16 (6.3)	27 (10.1)	10 (5.4)	14 (7.6)	26 (8.1)	30 (9.1)
Arthralgia	16 (8.4)	9 (5.0)	20 (7.9)	20 (7.5)	10 (5.4)	13 (7.1)	7 (2.2)	6 (1.8)
Musculoskeletal pain	4 (2.1)	9 (5.0)	5 (2.0)	9 (3.4)	12 (6.5)	6 (3.3)	7 (2.2)	4 (1.2)
Dizziness	8 (4.2)	9 (5.0)	3 (1.2)	11 (4.1)	7 (3.8)	14 (7.6)	3 (0.9)	8 (2.4)
Cough	7 (3.7)	9 (5.0)	15 (5.9)	17 (6.4)	5 (2.7)	13 (7.1)	9 (2.8)	5 (1.5)
Toothache	8 (4.2)	11 (6.1)	9 (3.6)	8 (3.0)	5 (2.7)	3 (1.6)	5 (1.6)	6 (1.8)
Back pain	15 (7.9)	16 (8.9)	16 (6.3)	18 (6.7)	12 (6.5)	7 (3.8)	13 (4.1)	11 (3.4)
Pain in extremity	6 (3.1)	13 (7.3)	15 (5.9)	19 (7.1)	6 (3.2)	2 (1.1)	5 (1.6)	10 (3.0)
Hypertension	9 (4.7)	12 (6.7)	23 (9.1)	15 (5.6)	11 (5.9)	12 (6.5)	27 (8.4)	17 (5.2)
Reported hypoglycemia^a	17 (8.9)	18 (10.1)	58 (22.9)	55 (20.6)	9 (4.8)	11 (6.0)	15 (4.7)	19 (5.8)
Confirmed hypoglycemia^b	2 (1.0)	1 (0.6)	8 (3.2)	9 (3.4)	0 (0.0)	1 (0.5)	0 (0.0)	2 (0.6)

^aEvents consistent with symptoms of hypoglycemia with or without documented blood glucose levels.

^bFingerstick glucose < 50 mg/dL with associated symptoms.

GLY = glyburide; LTE = long-term extension; MET = metformin; PBO = placebo; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide; URTI = upper respiratory tract infection.

Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, . Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. EndocrPract. 2009;15:540–59.

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ONGLYZA® (saxagliptin). Full prescribing information. Bristol-Myers Squibb, Princeton, NJ, USA; 2011.

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