Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease

Table 1 Effects of anti-diabetic medications on insulin resistance and cardiovascular outcome with precautions for patients with chronic kidney disease

	Insulin resistance	CV effects[44]		CKD group
		ASCVD	HF
Metformin	Liver gluconeogenesis (increased). Peripheral tissue glucose utilizing (increased). Net glucose absorption (decreased). Insulin resistance (markedly decreased) may benefit PCOS	Potential benefit	Neutral	eGFR < 30: Lactic acidosis
TZDs	Insulin signaling (increased). FFA (increased). Insulin resistance (markedly decreased)	Potential benefit	Increase risk	No dose adjustment required. Fluid retention
SUs and meglitinides	Glucotoxicity (decreased). GLUT4 expression (increased). Insulin resistance, mainly by decreasing glucotoxicity (decreased)	Neutral	Neutral	Low dose initiation to prevent hypoglycemia
Alpha-glucosidase inhibitors	Glucotoxicity (decreased). Insulin resistance, mainly by decreasing glucotoxicity (decreased)	Potential benefit	Neutral	Contraindication in CrCl < 25 (lack of data). Liver injury?
DPP-4 inhibitors	Improved islet beta cell function. Inflammation (decreased)? Insulin resistance (decreased)	Neutral	Potential risk: Saxagliptin and alogliptin	Generally safe. They can be used in CKD group (no dose adjustment for linagliptin)
GLP-1RAs	Oxidative stress, inflammation (decreased). GLUT4 expression (increased). Insulin signaling (increased). Body weight (decreased): Insulin resistance (markedly decreased)	Benefit	Neutral	No dose adjustment required
SGLT2Is	Peripheral tissue glucose utilization (increased). Energy expenditure (increased). Induce M2 macrophage polarization: Insulin resistance (markedly decreased)	Benefit	Benefit	Decrease sugar lowering effect in CKD group. Do not initiate when eGFR < 20

CKD: Chronic kidney disease; CV: Cardiovascular; ASCVD: Atherosclerotic cardiovascular disease; HF: Heart failure; PCOS: Polycystic ovary syndrome; eGFR: Estimated glomerular filtration rate; FFA: Free fatty acid; TZDs: Thiazolidinediones; SUs: Sulfonylureas; GLUT4: Glucose transporter 4; DPP-4: Dipeptidyl peptidase-4; GLP-1RAs: Glucagon-like peptide-1 receptor agonists; SGLT2Is: Sodium-glucose co-transporter-2 inhibitors.