Table 16.

Profiles of Antihyperglycemic Medications

	Antihyperglycemic efficacy (as monotherapy)c	Hypoglycemia (as monotherapy)e	Weight	ASCVD events	HF	Effect on CKD worsening/other issues in presence of CKD	GI S/S
METFORMIN	++	Low risk	Neutral/slight loss	Neutral/slight benefit	Neutral	Neutral/contraindicated if eGFR <30 mL/min/ 1.73 m2; should not be initiated if eGFR <45 mL/min/1.73 m2. But once started, can continue to be used if stable eGFR >30 mL/min/1.73 m2, although reduction in dose is prudent if eGFR between 30 and 45 mL/min/1.73 m2.	Moderate
GLP-1 RA	+++	Low risk	Loss	Demonstrated benefit reducing risk of MACE (dulaglutide; liraglutide; semaglutide SQ); Demonstrated reduced risk for stroke with semaglutide and dulaglutide	Neutral	Renal benefit demonstrated in CVOTs (dulaglutide, liraglutide, SQ semaglutide) largely due to decreased albuminuria; Worsening kidney function or AKI can occur in presence of volume depletion due to severe adverse GI S/S. Exenatide not recommended if eGFR below 45 mL/min/1.73 m2 or ESKD or if CrCl <30 mL/min	Moderate
DUAL GIP/GLP-1 RA	+++	Low risk	Loss	CVOT being conducted	Neutral	One exploratory analysis showed slowing of eGFR decline in those with T2D and increased CV risk; Worsening kidney function or AKI can occur in presence of volume depletion due to severe adverse GI S/S	Moderate
SGLT2i	++	Low risk	Loss	Demonstrated benefit reducing risk of MACE (empagliflozin; canagliflozin); empagliflozin demonstrated benefit reducing risk of CV death and all-cause mortality	Demonstrated benefit reducing risk of HHF (see legenda)	Demonstrated benefit reducing risk for CKD progression (see legendb)	Neutral
DPP-4i	+	Low risk	Neutral	Noninferior to placebo	CVOT showed increased risk for HHF with saxagliptin; alogliptin should be used with caution in patients with CHF of NYHA functional classes III and IV.	Neutral/all but linagliptin require dose adjustment if decreased kidney function.	Neutral
AGI	+	Low risk	Neutral	Neutral	Neutral	Neutral/not recommended if serum creatinine >2.0 mg/dL	Moderate
TZD	++	Low risk	Gain	Potential reduced risk of MACE/stroke (pioglitazone)	Increased risk secondary to fluid retentiond	Neutral/potential for increased fluid accumulation	Neutral
SU/GLINIDE	++/+	Moderate-to-severe/mild-to-moderate increased risk for both with CKD	Gain	Neutral	Neutral	Neutral/increased risk of hypoglycemia	Neutral
COLSVL	+	Low risk	Neutral	Lowers LDL-C; Can increase TG levels; Contraindicated if serum TG >500 mg/dL or if history of hypertriglyceridemia-induced pancreatitis	Neutral	Neutral	Mild to Moderate
BCR-QR	+	Low risk	Neutral	No increased risk	Neutral	Neutral	Moderate
INSULIN (basal/basal bolus)	+++/++++	Moderate-to-severe increased risk with CKD	Gain	Neutral	Monitor for fluid retention	Neutral/increased risk of hypoglycemia	Neutral
PRAMLINTIDE	+	Increased risk because indicated in those with T1D and T2D using mealtime insulin	Modest loss	Neutral	Neutral	Neutral	Moderate

Abbreviations: AGI = alpha-glucosidase inhibitors; AKI = acute kidney injury; ASCVD = atherosclerotic cardiovascular disease; BCR-QR = bromocriptine quick release; CHF = congestive heart failure; CKD = chronic kidney disease; COLSVL = colesevelam; CrCl = creatinine clearance; CV = cardiovascular; CVD = CV disease; CVOT = CV outcome trial; DPP-4i = dipeptidyl peptidase 4 inhibitor; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; GFR = glomerular filtration rate; GI = gastrointestinal; GIP = glucose-dependent insulinotropic polypeptides; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HDL-C = high-density lipoprotein cholesterol; HF = heart failure; HHF = hospitalization for heart failure; HFrEF = heart failure with reduced ejection fraction; LDL-C = low-density lipoprotein cholesterol; MACE = major adverse cardiovascular event; S/S = signs & symptoms; SGLT2i = sodium glucose cotransporter 2 inhibitor; SU = sulfonylurea; T1D = type 1 diabetes; T2D = type 2 diabetes; TG = triglyceride; TZD = thiazolidinedione Disclaimer: The designated row of a medication class does not imply or indicate any preference or hierarchy. In addition, prescribers should always refer to the most recent published prescribing information for medications as well as consideration of local resources and individual patient circumstances. The evidence base content in the guideline has much more comprehensive information about antihyperglycemic medications including potential adverse events and how to reduce their risk and/or treat them.

^aDecreased HHF was seen in CVOTs with canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. Some subsequent studies had HF as primary outcomes and led to dapagliflozin receiving an indication to reduce risk of HHF in adults with T2D and either established CVD or multiple CV risk factors AND to reduce risk of CV death and HHF in adults (with or without T2D) with HFrEF (NYHA classes II-IV). Empagliflozin has indication to reduce the risk of CV death in adult patients with T2D and established CV disease AND to reduce the risk of CV death and HHF in adults (with or without T2D) with HF (not limited to HFrEF). Because of recent publication of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) trial,^1054a it is likely that the dapagliflozin HF indication will lose the limitation to HFrEF.

^bCanagliflozin has indication to reduce risk of ESKD, doubling of serum creatinine, CV death, in adults with T2D and diabetic nephropathy with albuminuria; HHF in those with a history of HF. Dapagliflozin has indication to reduce the risk of sustained eGFR decline, ESKD, CV death, in adults with CKD at risk of progression and HHF in those with history of HF. The EMPA-KIDNEY trial has been stopped early due to evidence of efficacy.

^cEfficacy dependent on baseline A1C and duration of diabetes.

^dTZDs are contraindicated in persons with NYHA Class III/IV CHF.

^eAgents with “low risk” for hypoglycemia may have that risk increased when combined with antihyperglycemic agents that themselves can cause hypoglycemia. The latter agents may need to have a lower dose in order to reduce hypoglycemia risk.