Table 1.

Summary of existing animal studies on neprilysin inhibitors with metabolic endpoints

Drug	Animal model/population	Route	Dose	Treatment duration	Experiment to evaluate glucose homeostasis	Effects on glucose homeostasis/metabolism	Ref
Thiorphan	Male Sprague Dawley rats (no information on age)	sc	30 and 100 mg/kg bw	Acute	Subcutaneous insulin tolerance test	↑ Insulin sensitivity	[19]
Racecadotril	8-week-old male Wistar rats	iv	2 mg/kg bw	Acute	Fasted plasma measures	↑ Plasma insulin and C-peptide ↓ Plasma glucose	[20]
Retrothiorphan	12- to 13-week-old male obese insulin-resistant Zucker rats	iv	25 mg/kg bw	Acute	Hyperinsulinaemic-euglycaemic clamp	↑ Insulin sensitivity	[18]
Candoxatril	LYY strain pigs (no information on sex)	iv	5 mg/kg bw	Acute	IVGTT + GLP-1 infusion	Improved glucose tolerance	[3]
	10-week-old male diabetic Goto-Kakizaki rats	po	10 mg/kg bw per day	12 weeks	OGTT HbA1c levels	No effect on glucose tolerance No change in HbA1c levels	[33]
	12-week-old high-fat-fed C57BL/6J mice	po	30 mg/kg chow	12 weeks	IPGTT	No effect on glucose tolerance No change in weight gain	[32]
	12-week-old high-fat fed/low-dose STZ-diabetic male Sprague Dawley rats	po	300 mg/kg chow	12 weeks	IPGTT HbAlc levels Tissue glucose uptake	No effect on glucose tolerance No change in HbA1c levels ↑ Glucose uptake by isolated soleus muscle No change in weight gain	[34]
	12-week-old high-fat-fed male Sprague Dawley rats	po	300 mg/kg chow	24 weeks	IPGTT	No effect on glucose tolerance ↑ Weight gain	[35]

bw, body weight; po, oral administration; STZ, streptozotocin