Emerging use of combination therapies for the management of type 2 diabetes – focus on saxagliptin and dapagliflozin

Figures & data

Table 1 Baseline demographic and characteristics of the five phase III trials of dapagliflozin/saxagliptin compared with saxagliptin or dapagliflozin added to metformin baseline therapy

Trial, year	n	Follow-up (weeks)	Background therapy	Intervention	Comparator	Baseline characteristicsa
						Age (years)	Womenb	BMI (kg/m^2)	HbA1c (%)	Duration of diabetes (years)
Rosenstock et al^Citation99 (NCT01606007), 2015	534	24	Metforminc	Saxagliptind+dapagliflozine	Saxagliptin or dapagliflozine	54±10	266 (50)	31.7±5.1	8.94±1.13	7.6±5.3
Matthaei et al^Citation100 (NCT01619059), 2015	315	24	Metforminc+open-label dapagliflozin, 16 weeks run-in	Saxagliptind	Placebo	54.6±9.6	166 (52.7)	31.4±5.3	7.91±0.88	7.7±6.4
Matthaei et al^Citation101 (NCT01619059), 2016	297	52	Metforminc+open-label dapagliflozin, 16 weeks run-in	Saxagliptind	Placebo
Mathieu et al^Citation102 (NCT01646320), 2015	320	24	Metforminc+open-label saxagliptind, 8–16 weeks run-in	Dapagliflozine	Placebo	55.1±9.1	174 (54.4)	31.7±5.1	8.20±0.97	7.6±6.1
Mathieu et al^Citation103 (NCT01646320), 2016	294	52	Metforminc+open-label saxagliptind, 8–16 weeks run-in	Dapagliflozine	Placebo

Notes: Paired trials are shaded to match with the same baseline characteristics.

a Mean ± SD unless otherwise specified.

b Number (percentage of total study population).

c Metformin TDDs of ≥1,500 mg/day.

d Saxagliptin 5 mg daily.

e Dapagliflozin 10 mg daily.

Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; TDD, total daily dose; SD, standard deviation.

Table 2 Key primary and secondary outcomes from five phase III trials of dapagliflozin/saxagliptin compared with saxagliptin or dapagliflozin added to metformin baseline therapy

Trial, year	Comparison	Adj HbA1ca Δ	HbA1ca <7%	Adj FBG Δa(mmol/L)	Adj PPG Δa(mmol/L)	WT Δ (kg)a	SBP Δb (mmHg)	DBP Δb (mmHg)	LDLb (%)	HDLb (%)
Rosenstock et al,^Citation99 2015	Metf + Saxa + Dapa	−1.47% (−1.62, −1.31)	41% (34.5, 48.2)	−2.11 (−2.40, −1.79)	−4.44 (−4.79, −4.04)	−2.1 (−2.5, −1.6)	−1.9±12.0	−1.0±8.0	3.7 (−0.9, 8.6)	5.4 (3.0, 7.8)
	Metformin+saxagliptin	−0.88% (−1.03, −0.72), p<0.0001	18% (13.0, 23.5)	−0.78 (−1.09, −0.47), NT	−2.00 (−2.36, −1.59), p<0.0001	0 (−0.5, 0.5)	0.3±10.2	−0.4±7.0	−0.6 (−5.1, 4.1), p=0.20	0.9 (−1.4, 3.3), p=0.009
	Metformin+dapagliflozin	−1.20% (−1.35, −1.04), p=0.0166	22% (16.1, 28.3)	−1.78 (−2.07, −1.46), NT	−3.89 (−4.30, −3.53), p=0.06	−2.4 (−2.9, −1.9)	−3.5±12.9	−1.4±8.4	1.5 (−3.1, 6.4), p=0.52	7.7 (5.2, 10.2), p=0.19
Matthaei et al,^Citation100 2015	Metformin+dapagliflozin+saxagliptin	−0.51% (−0.63, −0.39)	35.3% (28.2, 42.4)	−0.50 (−0.79, −0.22)	−2.06 (−2.42, −1.71)	−0.53 (–)	–	–	−1.0 (−5.1, 3.4)	1.3 (−1.1, 3.8)
	Metformin+dapagliflozin	−0.16% (−0.28, −0.04), p<0.0001	23.1% (16.9, 23.9)	−0.28 (−0.58, 0.01), NT	−1.72 (−2.08, −1.39), p=0.2014	−0.51 (–)	–	–	1.5 (−2.7, 5.9)	0.1 (−2.3, 2.5)
Matthaei et al,^Citation101 2016	Metformin+dapagliflozin+saxagliptin Metformin+dapagliflozin	Between-group difference −0.42% (−0.64, −0.20)	29.3% (−) 13.1% (–)	Between-group difference −0.5 (−0.91, −0.006)	– –	−1.13 (–) −1.50 (–)	0.8 (–) 0.8 (–)	0.3 (–) 0.3 (–)	– –	– –
Mathieu et al,^Citation102 2015	Metformin+saxagliptin+dapagliflozin	−0.82% (−0.89, −0.75)	38% (30.9, 45.1)	−1.83 (−2.13, −1.51)	−4.11 (−4.53, −3.64)	−1.9 (−2.34, −1.48)	−1.9 (–)	−1.7 (–)	4.7 (0.9, 8.7)	6.2 (3.4, 9.0)
	Metformin+saxagliptin	−0.10% (−0.17, −0.03), p<0.0001	12.4% (7.0, 17.9), p<0.0001	−0.28 (−0.62, 0.03), p<0.0001	−2.11 (−2.56, −1.66), p<0.0001	−0.4 (−0.86, 0.04), p<0.0001	2.0 (–)	0.3 (–)	2.8 (−0.9, 6.6)	2.8 (0.2, 5.5)
Mathieu et al,^Citation103 2016	Metformin+saxagliptin+dapagliflozin	−0.74% (−0.90, −0.57)	29.4% (22.7, 36.2)	−1.50 (−1.90, −1.08)	–	−2.1 (−2.70, −1.56)	–	–	–	–
	Metformin+saxagliptin	0.07% (−0.13, 0.27)	12.6% (7.4, 17.9)	0.56 (0.09, 1.04)	–	−0.4 (−1.01, 0.26)	–	–	–	–

Notes: Paired trials are shaded to match.

a Mean (95% CI:).

b Mean ± SD unless otherwise specified. p-Values reported are for difference relative to triple-therapy intervention. – denotes where data were not reported or could not be obtained from authors. To convert glucose from mmol/L to mg/dL, divide by 0.05556.

Abbreviations: Adj, adjusted from baseline; HbA1c, hemoglobin A1c; FBG, fasting blood glucose; PPG, post-prandial glucose; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CI, confidence interval; SD, standard deviation; Metf, metformin; Saxa, saxagliptin; Dapa, dapagliflozin; WT, weight; SBP, systolic blood pressure; DBP, diastolic blood pressure; NT, not tested under pre-specified sequential testing procedure of the respective studies.

Table 3 Total adverse events experienced by patients across (A) all five phase III trials comparing dapagliflozin/saxagliptin add-on therapy against either dapagliflozin- or saxagliptin- only add-on to metformin baseline therapy; and (B) only the three phase III trials at 24-week follow-up

A
Trial, year	Comparison [n]	≥1 AE	≥1 Serious AEs	AEs leading to discontinuation	UTI	Genital infection	All-reported hypoglycemia	Volume depletion	Heart failure	eGFR decrease
Rosenstock et al,^Citation99 2015	Metformin+saxagliptin+dapagliflozin [179] Metformin+saxagliptin [176] Metformin+dapagliflozin [179]	87 (49) 93 (53) 87 (49)	2 (1) 6 (3) 2 (1)	1 (0.6) 0 (0) 1 (0.6)	1 (0.6) 9 (5) 7 (5)	0 (0) 1 (0.6) 10 (6)	2 (1) 2 (1) 2 (1)	– – –	– – –	3 (2) 1 (0.6) 0 (0)
Matthaei et al,^Citation100 2015	Metformin+dapagliflozin+saxagliptin [153] Metformin+dapagliflozin [162]	73 (47.7) 70 (43.2)	5 (3.3) 5 (3.1)	1 (0.7) 3 (1.9)	8 (5.2) 6 (3.7)	0 (0) 4 (2.5)	2 (1.3) 4 (2.5)	0 (0) 2 (1.2)	1 (0.7) 2 (1.2)	0 (0) 2 (1.2)
Matthaei et al,^Citation101 2016	Metformin+dapagliflozin+saxagliptin [153] Metformin+dapagliflozin [162]	89 (58.2) 94 (58.0)	7 (4.6) 11 (6.8)	3 (2.0) 5 (3.1)	12 (7.8) 12 (7.4)	5 (3.3) 10 (6.2)	2 (1.3) 4 (2.5)	1 (0.7) 3 (1.9)	1 (0.7) 4 (2.5)	2 (1.3) 2 (1.2)
Mathieu et al,^Citation102 2015	Metformin+saxagliptin+dapagliflozin [160] Metformin+saxagliptin [160]	90 (56.3) 94 (58.8)	5 (3.1) 3 (1.9)	8 (5.0) 2 (1.3)	8 (5.0) 10 (6.3)	8 (5.0) 1 (0.6)	2 (1.3) 0 (0)	– –	2 (1.3) 0 (0)	2 (1.3) 0 (0)
Mathieu et al,^Citation103 2016	Metformin+saxagliptin+dapagliflozin [160] Metformin+saxagliptin [160]	106 (66.3) 114 (71.3)	7 (4.4) 4 (2.5)	9 (5.6) 3 (1.9)	15 (9.4) 16 (10)	10 (6.3) 2 (1.3)	3 (1.9) 0 (0)	– –	3 (1.9) 2 (1.3)	5 (3.1) 3 (1.9)
B
Study	Comparison [n]	≥1 AE	≥1 Serious AEs	AEs leading to discontinuation	UTI	Genital infection	All-reported hypoglycemia	Volumea Depletion	Hearta failure	eGFR decrease
24-week follow-up^Citation99,Citation101,Citation102	Metformin+saxagliptin+dapagliflozin [492] Metformin+saxagliptin [336] Metformin+dapagliflozin [341]	250 (50.8) 187 (55.7) 157 (46.0)	12 (2.4) 9 (2.7) 7 (2.1)	10 (2.0) 2 (0.6) 4 (1.2)	17 (3.5) 19 (5.7) 13 (3.8)	8 (1.6) 2 (0.6) 14 (4.1)	6 (1.2) 2 (0.6) 6 (1.8)	– – –	– – –	5 (1.0) 1 (0.3) 2 (0.6)

Notes: (A) Paired trials are shaded to match. [n] is the number of patients exposed to at least one dose of the assigned therapy, excluding patients who have been exposed to rescue medication during study. All event data are n (%) of the treatment arm. – denotes data that are not reported. (B) Data from identical treatment arms were summed across the studies only if data are available for all three trials to avoid reporting bias. [n] is the total number of patients across all three studies with reported data. All events are reported as n (%) of the treatment arm.

a Insufficient data for summation.

Abbreviations: AE, adverse event; UTI, genitourinary tract infection; eGFR, estimated glomerular filtration rate.

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