Table 3.

Current and emerging antihyperglycemic treatment options with the potential to reduce hyperfiltration in diabetes

Treatment	FDA-Approved Compounds	Route of Administration	Mode of Action	(Potential) Adverse Eventsa	Potential Hyperfiltration-Reducing Mechanismb
SGLT2 inhibitor	Canagliflozin	Oral	↑ Urinary glucose excretion	Genital mycotic infections, urinary tract infections, ketoacidosisc, breast/bladder cancerc, bone fracturesc, lower limb amputationsc	Weight loss, BP ↓
	Dapagliflozin				TGF activation, PBOW ↑
	Empagliflozin
Dual SGLT1/SGLT2 inhibitor	Phase-3 development	Oral	↑ Urinary glucose excretion	Largely uncertain. Genital mycotic infections, urinary tract infections, GI side effects (nausea, diarrhea), ketoacidosisc	Weight loss, BP ↓
			↓ GI glucose uptake		GI absorption rate ↓
					ANP ↓, GLP-1 ↑
					TGF activation, PBOW ↑
GLP-1 receptor agonist	Albiglutide (QW)	Injectable	↑ Insulin secretion (glucose-dependent)	GI side effects (nausea, vomiting, diarrhea), acute gallstone disease, pancreatitisc, pancreatic cancerc	Weight loss, BP ↓
	Dulaglutide (QW)		↓ Glucagon secretion (glucose-dependent)		Gastric emptying rate ↓d
	Exenatide (QW, BID)		↓ Gastric emptyingd		Glucagon ↓, RAS ↓172
	Liraglutide (QD)		↑ Satiety		TGF activation, PBOW ↑
	Lixisenatide (QD)
	Semaglutide (QD)
DPP-4 inhibitor	Alogliptin	Oral	↑ Insulin secretion (glucose-dependent)	Nasopharyngitis, heart failurec,	Weight loss, BP ↓
	Linagliptin		↓ Glucagon secretion (glucose-dependent)	pancreatitisc, pancreatic cancerc	Ultrafiltration coefficient ↓173
	Saxagliptin				Glucagon ↓, RAS ↓172
	Sitagliptin				TGF activation, PBOW ↑
Thiazolidinedione	Pioglitazone	Oral	↑ Insulin sensitivity	Edema and heart failure, weight gain, bone fractures, bladder cancerc, CV eventsc	NO-bioavailability efferent arteriole ↑
	Rosiglitazone		↓ Hepatic glucose production		TGF signaling ↑
Insulin	Insulin lispro	Injectable		Hypoglycemia, weight gain	Postprandial IGF-1–dependent renal vasodilation ↓
			↑ Glucose disposal
			↓ Hepatic glucose production
Glucagon receptor antagonist	Phase-2 development	Oral/injectable	↓ Glucagon action	Uncertain	TGF activation

FDA, Food and Drug Administration; ↑, increase; P_BOW, hydraulic pressure in Bowman’s space; ↓, decrease; GI, gastro-intestinal; ANP, atrial natriuretic peptide; QW, once weekly; BID, twice daily; QD, once daily; CV, cardiovascular; NO, nitric oxide; IGF, insulin-like growth factor.

^aThe list of adverse events does not aim to be exhaustive.

^bPotential mechanisms beyond glucose reduction are listed.

^cUncertain safety issues.

^dEffect on gastric emptying is only sustained with short-action GLP-1 receptor agonists.