Medication	Mechanism of action	Clinical outcomes	Practical tips
Dipeptidyl-peptidase-4 inhibitors^19–21	Increase and prolong incretin activity, thus increasing insulin release from pancreatic beta cells; reduce glucagon secretion Decrease albuminuria independent of effects on glucose and blood pressure Synergistic with telmisartan (Micardis)	Decreased albuminuria at 24 weeks (even at 12 weeks) in a retrospective study; more recent prospective RCTs did not show the same benefit²⁰ Urinary albumin/creatinine ratio reduced by 32% in the treatment group compared with 6% in the placebo group SAVOR-TIMI trial showed increased rates of hospitalization for heart failure with use of saxagliptin (Onglyza; particularly those with known heart failure, elevated natriuretic peptide levels, or chronic kidney disease)²¹	Increase risk of hypoglycemia when used in combination with insulin or sulfonylureas Not studied for patients with type 1 diabetes mellitus Caution in patients with known heart failure
Glucagon-like peptide-1 receptor agonists^22–24	Increase insulin secretion by pancreatic beta cells in presence of hyperglycemia; delay gastric emptying Reduce renal oxidative stress Protect renal endothelial cells Suppress renal inflammatory cytokines	LEADER trial showed decreased rate of DKD as secondary outcome (decreased proteinuria; no effect on advanced disease outcomes)²² SUSTAIN-6 trial showed decreased rate of progression to macroalbuminuria²⁴ Trials showed fewer cardiac events; lower all-cause mortality	Adverse effects: mostly gastrointestinal; associated with increased risk of pancreatitis and acute gallbladder disease May not prevent progression of retinopathy FDA boxed warning: contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
Metformin²⁵	Improves insulin sensitivity First-line agent for patients with type 2 diabetes No risk for hypoglycemia Can safely be used in patients with type 1 diabetes	Improves glucose control Long-term use impairs vitamin B₁₂ absorption The U.K. Prospective Diabetes Study showed metformin was associated with lower risk of renal failure, lower diabetes mortality, and lower overall mortality in overweight patients with diabetes (specific mechanisms not defined)²⁶	Consider reduced dose if GFR declines to < 45 mL per minute; discontinue if estimated GFR < 30 mL per minute Should be avoided in situations where a high risk for acute kidney injury could occur; however, absolute risk for lactic acidosis is low Monitor vitamin B₁₂ level for patients taking metformin for more than five years, especially in patients with neuropathy
Sodium-glucose cotransporter-2 inhibitors^27,28	Reduce reabsorption of filtered glucose, leading to increased urinary excretion May have direct renovascular effects	EMPA-REG OUTCOME trial included patients with type 2 diabetes and high cardiovascular risk; approximately 65% had CKD²⁷ Results showed decreased progression of renal disease and decreased need for renal replacement therapy	Reduce the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease Lower weight and blood pressure Caution in patients with recurrent urinary tract infection Increased urinary excretion of glucose can increase risk of candidal infections Avoid using if estimated GFR < 45 mL per minute
Thiazolidine-diones (e.g., pioglitazone [Actos])²⁹	Increase insulin sensitivity Decrease gluconeogenesis	Reduce urinary albumin excretion; decrease vascular inflammatory markers²⁹ May decrease albuminuria, but degree of effect may not be clinically relevant	Monitor for edema and weight gain Not for use in patients with type 1 diabetes Monitor alanine transaminase level regularly Can cause or worsen heart failure in some patients; do not initiate in patients with symptomatic heart failure