Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism

Figures & data

Figure 1 Disposition of subjects. NOMAC/E2, nomegestrol acetate/17β-oestradiol; LNG/EE, levonorgestrel/ethinylestradiol.

Table 1 Subject characteristics at screening.

	NOMAC/E2 (n = 60)	LNG/EE (n = 58)	Total (n = 118)
Age (years), mean (SD)	28.2 (8.2)	29.1 (7.8)	28.7 (8.0)
Race, n (%)
Black	1 (1.7)	0	1 (0.8)
White	59 (98.3)	58 (100.0)	117 (99.2)
Weight (kg), mean (SD)	62.8 (9.7)	61.7 (9.0)	62.3 (9.3)
BMI (kg/m^2), mean (SD)	23.0 (2.9)	22.3 (2.5)	22.7 (2.7)
Nulligravida, n (%)	35 (58.3)	34 (58.6)	69 (58.5)
Parity*, n (%)
NA (0 without pregnancy)	35	34	69
0 (with pregnancy)	4 (16.0)	3 (12.5)	7 (14.3)
1	7 (28.0)	6 (25.0)	13 (26.5)
≥ 2	14 (56.0)	15 (62.5)	29 (59.2)
Last contraceptive method used within three months prior to screening**, n (%)
None	1 (1.7)	4 (6.9)	5 (4.2)
Combined oral contraceptive	19 (31.7)	22 (37.9)	41 (34.7)
Progestogen-only-pill	3 (5.0)	1 (1.7)	4 (3.4)
IUD (hormonal)	5 (8.3)	1 (1.7)	6 (5.1)
IUD (non-hormonal)	1 (1.7)	2 (3.4)	3 (2.5)
Vaginal ring or transdermal patch	5 (8.3)	7 (12.1)	12 (10.2)
Foam, condom, suppositories, diaphragm	26 (43.3)	21 (36.2)	47 (39.8)
Smoking status
Smokers, n (%)	14 (23.3)	7 (12.1)	21 (17.8)
Non-smokers, n (%)	46 (76.7)	51 (87.9)	97 (82.2)

NOMAC/E2, nomegestrol acetate/17β-oestradiol; LNG/EE, levonorgestrel/ethinylestradiol; SD, standard deviation; BMI, body mass index; NA, not applicable; IUD, intrauterine device.

*Gestational age ≥ 28 weeks;

**Single most important contraceptive method.

Table 2 Comparison of the effects of nomegestrol acetate/17β-oestradiol (NOMAC/E2) and levonorgestrel/ethinylestradiol (LNG/EE) on thrombin turnover/fibrinolysis indices, anticoagulatory factors, and procoagulatory factors (medians [interquartile ranges]).

Thrombin turnover/fibrinolysis indices
Treatment	Baseline	Cycle 3	Cycle 6	Change from baseline to cycle 6	% change from baseline to cycle 6	p-value*
Prothrombin fragments 1 + 2 (nmol/l)
NOMAC/E2	0.15 (0.07)	0.15 (0.08)	0.14 (0.10)	− 0.00 (0.06)	− 1.7 (46.0)	0.085
LNG/EE	0.17 (0.10)	0.21 (0.12)	0.21 (0.12)	0.02 (0.10)	13.5 (59.6)
D-dimer (mg/l FEU)
NOMAC/E2	0.11 (0.19)	0.11 (0.16)	0.11 (0.12)	0.00 (0.00)	0.0 (0.0)	^†
LNG/EE	0.11 (0.15)	0.22 (0.26)	0.11 (0.22)	0.00 (0.17)	0.0 (68.0)
Anticoagulatory factors
ETP-based APC sensitivity ratio
NOMAC/E2	0.70 (0.40)	1.10 (0.60)	1.10 (0.40)	0.40 (0.60)	60.0 (80.0)	< 0.001
LNG/EE	0.70 (0.60)	2.20 (1.00)	1.90 (1.25)	1.20 (1.00)	146.4 (160.0)
aPTT-based APC sensitivity ratio
NOMAC/E2	1.00 (0.20)	0.98 (0.17)	1.05 (0.16)	0.03 (0.17)	3.3 (16.4)	0.97
LNG/EE	0.99 (0.14)	0.99 (0.13)	1.02 (0.13)	0.02 (0.15)	2.0 (14.9)
Antithrombin III (%)
NOMAC/E2	99.5 (13.5)	100.0 (15.0)	103.0 (12.0)	4.0 (14.0)	3.9 (13.4)	0.004
LNG/EE	99.0 (15.0)	95.5 (10.0)	95.5 (16.5)	− 3.5 (14.0)	− 3.6 (14.1)
Protein C (U/l)
NOMAC/E2	105.5 (17.5)	101.0 (19.0)	104.0 (29.0)	− 3.0 (19.0)	− 3.1 (18.3)	0.002
LNG/EE	102.5 (25.0)	111.0 (24.0)	113.0 (25.5)	8.5 (20.0)	8.2 (20.2)
Free protein S (%)
NOMAC/E2	84.0 (20.5)	96.0 (22.0)	99.0 (33.0)	11.0 (18.0)	13.3 (21.0)	0.97
LNG/EE	85.0 (18.0)	93.5 (22.0)	102.0 (24.5)	11.5 (21.5)	11.9 (25.9)
Total protein S (%)
NOMAC/E2	79.0 (13.5)	85.0 (17.0)	83.0 (17.0)	4.0 (16.0)	4.7 (20.5)	< 0.001
LNG/EE	78.0 (14.0)	74.5 (12.0)	75.0 (11.5)	− 3.0 (14.0)	− 3.6 (17.5)
Procoagulatory factors
Factor II (%)
NOMAC/E2	93.0 (15.0)	97.0 (14.0)	95.0 (19.0)	− 1.0 (18.0)	− 0.9 (18.5)	0.50
LNG/EE	94.5 (15.0)	101.5 (14.0)	95.0 (20.0)	3.0 (19.5)	3.0 (22.7)
Factor VIIa (U/l)
NOMAC/E2	80.0 (41.5)	84.0 (44.0)	82.0 (47.0)	7.0 (46.9)	8.8 (63.3)	0.42
LNG/EE	71.0 (35.0)	91.5 (45.0)	86.0 (37.5)	9.0 (30.0)	14.4 (42.0)
Factor VIIc (%)
NOMAC/E2	102.0 (30.5)	105.0 (36.0)	103.0 (28.0)	1.0 (33.0)	1.0 (33.3)	0.001
LNG/EE	101.0 (30.0)	98.5 (25.0)	94.5 (31.5)	− 13.0 (27.5)	− 12.7 (24.1)
Factor VIII (%)
NOMAC/E2	87.0 (45.0)	86.0 (45.0)	85.0 (45.0)	3.0 (47.0)	4.8 (51.8)	0.38
LNG/EE	88.5 (42.0)	87.0 (41.0)	95.5 (43.0)	6.0 (34.5)	6.8 (40.6)

FEU, Fibrinogen equivalent units; ETP, endogenous thrombin potential; aPTT, activated partial thromboplastin time; APC, activated protein C; Factor VIIa, activated Factor VII; factor VIIc, coagulated activated Factor VII.

*The Cochran-Mantel-Haenszel test adjusted for age class using standardised midranks, applied on the absolute changes from baseline to cycle 6. A p-value ≤ 0.05 indicates that the difference from baseline to cycle 6 (NOMAC/E2 vs LNG/EE) was statistically significant.

^†The p-value is not presented because > 50% of subjects had D-dimer values below the lower limit of quantification (LLOQ) of 0.22 mg/l FEU.

Table 3 Comparison of the effects of nomegestrol acetate/17β-oestradiol (NOMAC/E2) and levonorgestrel/ethinylestradiol (LNG/EE) on lipid indices, CRP, and SHBG (medians [interquartile ranges]).

Lipid indices
Treatment	Baseline	Cycle 3	Cycle 6	Change from baseline to cycle 6	% change from baseline to cycle 6	p-value*
Total cholesterol (mmol/l)
NOMAC/E2	4.33 (1.23)	4.22 (1.04)	4.35 (1.09)	0.08 (0.65)	1.3 (16.9)	0.69
LNG/EE	4.43 (1.01)	4.37 (0.91)	4.40 (1.14)	− 0.03 (0.75)	− 0.7 (15.8)
HDL-C (mmol/l)
NOMAC/E2	1.58 (0.41)	1.58 (0.44)	1.63 (0.44)	0.02 (0.32)	1.6 (21.0)	< 0.001
LNG/EE	1.66 (0.42)	1.47 (0.37)	1.35 (0.34)	− 0.23 (0.32)	− 13.1 (18.0)
LDL-C (mmol/l)
NOMAC/E2	2.28 (0.92)	2.07 (0.91)	2.15 (0.78)	− 0.02 (0.48)	− 0.5 (26.2)	0.046
LNG/EE	2.41 (0.81)	2.43 (0.98)	2.43 (1.09)	0.11 (0.52)	6.8 (20.1)
Total triglycerides (mmol/l)
NOMAC/E2	0.90 (0.32)	0.88 (0.47)	0.92 (0.41)	0.06 (0.29)	7.5 (34.8)	0.008
LNG/EE	0.75 (0.32)	0.93 (0.49)	0.99 (0.48)	0.15 (0.44)	17.0 (56.4)
Lipoprotein (a) (g/l)
NOMAC/E2	0.10 (0.15)	0.10 (0.16)	0.10 (0.19)	0.00 (0.03)	0.0 (20.3)	< 0.001
LNG/EE	0.11 (0.19)	0.10 (0.13)	0.10 (0.18)	− 0.02 (0.05)	− 14.0 (30.7)
Apolipoprotein A1 (g/l)
NOMAC/E2	1.59 (0.30)	1.66 (0.42)	1.73 (0.44)	0.20 (0.30)	12.1 (20.2)	0.006
LNG/EE	1.56 (0.32)	1.65 (0.35)	1.66 (0.30)	0.09 (0.26)	4.6 (17.5)
Apolipoprotein B (g/l)
NOMAC/E2	0.61 (0.21)	0.60 (0.24)	0.62 (0.26)	0.03 (0.12)	4.6 (20.0)	< 0.001
LNG/EE	0.63 (0.16)	0.77 (0.27)	0.79 (0.28)	0.16 (0.21)	28.0 (32.0)
CRP (mg/l)
NOMAC/E2	0.40 (0.60)	0.60 (1.40)	0.70 (1.00)	0.20 (0.80)	66.7 (200.0)	< 0.001
LNG/EE	0.40 (1.30)	1.75 (3.00)	1.70 (2.85)	0.95 (2.20)	258.3 (495.5)
SHBG (nmol/l)
NOMAC/E2	65.5 (33.6)	96.3 (55.5)	107.9 (57.8)	33.8 (52.0)	44.1 (78.8)	0.019
LNG/EE	76.5 (40.6)	93.9 (47.6)	98.3 (30.8)	15.3 (42.6)	22.4 (64.1)

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CRP, C-reactive protein; SHBG, sex hormone-binding globulin.

*The Cochran-Mantel-Haenszel test adjusted for age class using standardised midranks, applied on the absolute changes from baseline to cycle 6. A p-value ≤ 0.05 indicates that the difference from baseline to cycle 6 (NOMAC/E2 vs LNG/EE) was statistically significant.

Table 4 Comparison of the effects of nomegestrol acetate/17β-oestradiol (NOMAC/E2) and levonorgestrel/ethinylestradiol (LNG/EE) on carbohydrate indices (medians [interquartile ranges]).

Carbohydrate indices
Treatment	Baseline	Cycle 3	Cycle 6	Change from baseline to cycle 6	% change from baseline to cycle 6	p-value*
AUC3 for glucose (hours × mmol/l)
NOMAC/E2	15.73 (3.49)	15.95 (3.46)	15.31 (3.75)	0.79 (3.37)	6.1 (25.7)	0.002
LNG/EE	14.12 (3.26)	16.19 (4.58)	16.34 (4.71)	2.08 (3.16)	13.9 (24.5)
Incremental AUC3 for glucose (hours × mmol/l)
NOMAC/E2	1.15 (3.35)	1.27 (3.29)	1.25 (2.93)	0.61 (3.02)	25.4 (207.6)	< 0.001
LNG/EE	0.64 (3.06)	2.95 (4.05)	2.87 (4.03)	2.07 (3.50)	56.5 (273.0)
AUC3 for insulin (hours × mmol/l)
NOMAC/E2	585.6 (304.0)	654.5 (488.3)	620.3 (357.1)	− 4.1 (240.6)	− 0.9 (33.1)	< 0.001
LNG/EE	540.6 (218.7)	702.6 (375.0)	704.7 (356.0)	177.9 (275.2)	26.4 (53.7)
Incremental AUC3 for insulin (hours × mmol/l)
NOMAC/E2	447.6 (302.3)	496.1 (387.3)	481.1 (270.5)	− 29.5 (241.3)	− 6.1 (57.1)	0.002
LNG/EE	432.1 (179.2)	592.8 (348.5)	588.3 (284.7)	147.9 (299.8)	35.9 (69.5)
HbA1c (%)
NOMAC/E2	5.35 (0.35)	5.40 (0.30)	5.30 (0.30)	0.00 (0.20)	0.0 (3.7)	0.37
LNG/EE	5.30 (0.20)	5.40 (0.20)	5.30 (0.30)	0.00 (0.20)	0.0 (3.7)

AUC₃, area under the curve over three hours; HbA_1c, haemoglobin type A_1c.

*The Cochran-Mantel-Haenszel test adjusted for age class using standardised midranks, applied on the absolute changes from baseline to cycle 6. A p-value ≤ 0.05 indicates that the difference from baseline to cycle 6 (NOMAC/E2 vs LNG/EE) was statistically significant.

Figure 2 Box whisker plots for NOMAC/E2 and LNG/EE of relative changes from baseline to end of cycle 6 in selected haemostatic and lipid parameters and SHBG. The edges of the boxes present the 25th and 75th sample percentiles (quartiles). The distance between these sample percentiles is the interquartile range. The vertical line in the box shows the median and the whiskers are drawn up to the smallest and largest value within 1.5-times the interquartile range. NOMAC, nomegestrol acetate/17β-oestradiol; LNG, levonorgestrel/ethinylestradiol; APCsr, activated protein C sensitivity ratio; ETP, endogenous thrombin potential; aPTT, activated partial thromboplastin time; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SHBG, sex hormone-binding globulin.