Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

Figures & data

Table 1 Effect of empagliflozin and sibutramine on urinary glucose excretion and body composition of diet-induced obese rats at study conclusion

	UGE (mg/200 g)	Water (g)	Fat (g)	Protein (g)
Vehicle	1.4±0.1	219.4±3.6	180.1±6.3	70.5±1.5
Empagliflozin (10 mg/kg PO)	150.1±32.9***	216.5±4.3	162.0±6.1*	70.2±1.7
Empagliflozin (30 mg/kg PO)	269.6±31.7***	213.1±3.5	158.6±6.6*	67.6±1.4
Empagliflozin (60 mg/kg PO)	367.9±90.3***	213.7±3.8	143.8±3.3***	67.7±1.8
Sibutramine (5 mg/kg PO)	1.0±0.2	206.7±4.9*	130.6±8.7***	68.1±1.6

Notes:

* P<0.05

*** P<0.001 (significant differences from the vehicle-treated group). Data are means and standard error (n=8–10).

Abbreviations: UGE, urinary glucose excretion; PO, per os (by mouth).

Figure 1 The effect of empagliflozin on rat body weight (A) average daily food intake (B) and average daily water intake (C).

Notes: *P<0.05; **P<0.01; ***P<0.001. Data are means and standard error (n=8–10). Percentage values indicate weight loss relative to vehicle-treated controls on Day 29.
Abbreviation: PO, per os (by mouth).

Table 2 Effect of empagliflozin and sibutramine on the plasma levels of various metabolic parameters on day 28 in diet-induced obese rats

	Glucose (mM)	Insulin (ng/mL)	Leptin (ng/mL)	HbA1c (%)
Baseline	7.27±0.11	3.87±0.25	34.2±1.7	6.9±0.03
Vehicle	7.37±0.30	3.42±0.49	26.6±1.8	6.85±0.04
Empagliflozin (10 mg/kg PO)	6.70±0.11	2.47±0.22	22.5±2.3	6.87±0.07
Empagliflozin (30 mg/kg PO)	6.60±0.17	2.16±0.35	17.8±2.2**	6.83±0.06
Empagliflozin (60 mg/kg PO)	6.73±0.21*	2.49±0.26	14.6±1.5***	6.88±0.05
Sibutramine (5 mg/kg PO)	5.77±0.33***	1.83±0.25**	17.9±1.4**	6.81±0.06
	Adiponectin (μg/mL)	TAG (mM)	NEFA (μM)	HOMA-IR
Baseline	25.3±0.8	0.310±0.02	1,034±27	27.30±1.91
Vehicle	23.2±1.1	0.292±0.03	982±72	24.74±4.01
Empagliflozin (10 mg/kg PO)	20.5±0.8	0.271±0.02	1,124±80	16.16±1.50*
Empagliflozin (30 mg/kg PO)	21.2±0.9	0.321±0.02	1,144±73	13.72±2.24*
Empagliflozin (60 mg/kg PO)	19.4±0.8*	0.368±0.04	1,086±41	16.37±1.96*
Sibutramine (5 mg/kg PO)	18.4±1.3*	0.179±0.03**	1,164±115	10.07±1.73***

Notes:

* P<0.05

** P<0.01

*** P<0.001 (significant differences from the vehicle-treated group). Samples were taken after a 4-hour fast. Data are means and standard error (n=6–10). Baseline values are those determined shortly prior to the onset of drug treatment.

Abbreviations: PO, per os (by mouth); TAG, triacylglycerol; NEFA, nonesterified fatty acid; HOMA-IR, homeostasis-model assessment of insulin resistance; HbA_1c, glycated hemoglobin.

Notes: *P<0.05; **P<0.01; ***P<0.001; ^asignificant difference from the empagliflozin group (P<0.01); ^bsignificant difference from the sibutramine group (P<0.05); ^csignificant difference from the orlistat group (P<0.05) Data are means and standard error (n=8–10). For clarity, the glucose and insulin excursions are separated for the empagliflozin/sibutramine and empagliflozin/orlistat combinations (C and D). In addition, for clarity, significant differences from control and between individual groups are not illustrated in C and D (for differences, see E).
Abbreviations: PO, per os (by mouth); bid, bis in die (twice daily); AUC, area under the curve.

Table 3 The effect of empagliflozin, sibutramine, and orlistat both alone and in combination with empagliflozin on body composition of diet-induced obese rats at study conclusion

	Water (g)	Fat (g)	Protein (g)
Vehicle	211.0±2.1	116.4±7.1	68.2±0.9
Empagliflozin (10 mg/kg PO)	209.0±3.8	113.8±2.7	66.4±1.0
Sibutramine (5 mg/kg PO)	204.8±3.4	95.5±4.6*	67.1±1.2
Empagliflozin (10 mg/kg PO)/sibutramine (5 mg/kg PO)	207.6±2.8	75.2±6.0***,a,b	68.1±0.9
Orlistat (20 mg/kg PO BID)	216.3±3.5	93.7±4.4*	69.9±1.4
Empagliflozin (10 mg/kg PO)/orlistat (20 mg/kg PO BID)	206.9±2.1	88.4±7.8**,a	66.9±0.8

Notes:

* P<0.05

** P<0.01

*** P<0.001 (significant differences from the vehicle-treated group)

a P<0.01 (significant differences from the empagliflozin group)

b P<0.05 (significant difference from the sibutramine group). Data are means and standard error (n=9–10).

Abbreviations: PO, per os (by mouth); BID, bis in die (twice daily).

Table 4 The effect of empagliflozin, sibutramine, and orlistat both alone and in combination with empagliflozin on the plasma levels of various metabolic parameters on day 30 in diet-induced obese rats

	Glucose (mM)	Insulin (ng/mL)	HOMA-IR	Leptin (ng/mL)	TAG (mM)
Baseline	5.91±0.07	1.98±0.12	11.36±0.79	9.2±0.8	0.219±0.01
Vehicle	7.09±0.30	2.04±0.33	13.94±2.65	14.1±1.5	0.263±0.05
Empagliflozin (10 mg/kg PO)	6.75±0.15	1.34±0.15*	8.88±1.10	12.2±1.3	0.193±0.03
Sibutramine (5 mg/kg PO)	6.08±0.17***	0.95±0.12***	5.67±0.73***	10.2±1.3*	0.186±0.03
Empagliflozin (10 mg/kg PO)/sibutramine (5 mg/kg PO)	5.73±0.31***,a	0.82±0.12***,a	4.67±0.72***,a	7.8±1.1***,a	0.166±0.04*
Orlistat (20 mg/kg PO BID)	6.77±0.19	1.47±0.19	9.89±1.28	10.3±0.8*	0.323±0.04
Empagliflozin (10 mg/kg PO)/orlistat (20 mg/kg PO BID)	6.27±0.17**	0.94±0.15***,c	5.65±1.05***,c	6.3±0.9***,a,c	0.271±0.04

Notes:

* P<0.05

** P<0.01

*** P<0.001 (significant differences from the vehicle-treated group)

a P<0.05 (significant differences from the empagliflozin group)

c P<0.05 (significant differences from the orlistat group). Samples were taken after an overnight fast. Data are means and standard error (n=9–10). Baseline values are those determined shortly prior to the onset of drug treatment.

Abbreviations: TAG, triacylglycerol; HOMA-IR, homeostasis-model assessment of insulin resistance; PO, per os (by mouth); BID, bis in die (twice daily).