Drug class	STEPS component
Drug class	Safety	Tolerability	Effectiveness*	Price†	Simplicity
Biguanides (e.g., Glucophage)	Historical concern for lactic acidosis, but Cochrane review of 347 studies found no cases in 70,490 patient-years, with lactate levels similar between patients receiving metformin (Glucophage) and a control group⁴ Should not be used in patients with estimated GFR <30 mL per minute per 1.73 m²; use caution in patients with estimated GFR of 30 to 45 mL per minute per 1.73 m² Long-term use may be associated with vitamin B₁₂ deficiency⁵ Safe in patients with stable CHF	GI effects (e.g., diarrhea, nausea, vomiting) in <10% of patients; discontinuation rate is <1%⁶	Outcomes: benefit In 1,704 overweight patients newly diagnosed with diabetes mellitus, metformin improved rates of all-cause mortality (13.5 vs. 20.6 per 1,000 patient-years; NNT = 14), MI (11 vs. 18 per 1,000 patient-years; NNT = 14), microvascular complications (6.7 vs. 9.2 per 1,000 patient-years; NNT = 40), and any diabetes-related end point (29.8 vs. 43.3 per 1,000 patient-years; NNT = 7)⁷	1,000 mg twice daily: $5 ($130) Extended-release, four 500-mg tablets once daily: $10 ($130) Extended-release, two 1,000-mg tablets once daily: $730 ($6,650)	Twice-daily oral dosing (once daily for extended-release formulation)
Sulfonylureas (e.g., Glucotrol, Amaryl)	Hypoglycemia Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency⁸ First generation (chlorpropamide, tolbutamide): systematic review shows increased CV mortality (N = 553; RR = 2.63)⁹	Weight gain¹⁰	Outcomes: • First generation: harm • Second generation (glipizide [Glucotrol], glyburide): neutral • Third generation (glimepiride [Amaryl]): unknown First generation: increased CV mortality rates^9,11 Second generation: two large systematic reviews showed no benefit or harm for mortality, MI, and stroke^9,11 Third generation: no long-term outcomes data⁹	Glipizide: $5 ($50 to $100, depending on dosage) Glyburide: $5 (NA) Glimepiride: $5 ($80 to $250, depending on dosage)	Once- or twice-daily oral dosing (depending on dosage; once daily for extended-release formulation)
Insulins (e.g., Lantus, Humalog)	Hypoglycemia, worse with intensive or complicated regimens	Injection, lipodystrophy, weight gain	Outcomes: neutral (when known) Glargine (Lantus): when used to normalize fasting glucose levels in 12,537 patients with diabetes or prediabetes for 6.2 years, mortality, CV events, and cancers neither increased nor decreased¹² No long-term outcome studies for other insulins or insulin regimens	Isophane (NPH): NA ($100 per 10-mL vial) Glargine: NA ($190 per 10-mL vial) Lispro (Humalog): NA ($180 per 10-mL vial) Preloaded pens more expensive	Subcutaneous injections one to four times daily, depending on formulation Injection is challenging for some patients; preloaded pens simplify injection
TZDs (e.g., Actos, Avandia)	Pioglitazone (Actos): CHF, serious fracture,¹³ bladder cancer (rare)¹⁴ Rosiglitazone (Avandia): CHF, MI¹⁵	Edema	Outcomes: •Pioglitazone: mixed •Rosiglitazone: harm Pioglitazone: in 5,238 patients treated for 9.5 years, no difference in primary CV outcome (CV events plus CV interventions); improved composite secondary CV outcome‡ of all-cause mortality, nonfatal MI, and nonfatal stroke (11.6% vs. 13.6%; NNT = 49); and increased CHF (10.8% vs. 7.5%; NNH = 31) and CHF hospitalizations (5.7% vs. 4.1%; NNH = 61)¹⁶ Rosiglitazone: systematic review of 56 trials (N = 35,531) showed no difference in all-cause mortality and CV mortality, but worse MI odds (odds ratio = 1.28 to 1.38)¹⁵	Pioglitazone: $10 ($600) Rosiglitazone: NA ($180)	Once-daily oral dosing
Alpha-glucosidase inhibitors (e.g., Precose)	Should not be used in patients with cirrhosis or chronic kidney disease (serum creatinine <2.0 mg per dL [177 μmol per L])	Severe GI effects (e.g., bloating, diarrhea, flatulence) in ≥50% of patients; variable but high discontinuation rates¹⁷	Outcomes: benefit (when known) Acarbose (Precose): systematic review of seven trials not limited to monotherapy (N = 2,180) showed reduced MI risk (RR = 0.36) and reduced risk of any CV event (RR = 0.65)¹⁸ All alpha-glucosidase inhibitors: systematic review of 41 monotherapy trials (N = 8,130) showed no mortality or diabetic end point benefit¹⁹ Acarbose: in 1,429 patients with prediabetes, reduced CV events (2.2% vs. 4.7%; NNT = 41) and MI (0.3% vs. 2.8%; NN T = 41) over 3.2 years²⁰ Acarbose: in 6,522 patients with CHD and prediabetes, no benefit or harm for mortality, individual, or combined CV outcomes over five years²¹	Acarbose: $25 ($100) Miglitol (Glyset): $60 ($250)	Oral dosing before meals (three times daily)
GLP-1 receptor agonists (e.g., Victoza, Ozempic)	Gallstones²² Occurrence <1%: acute kidney injury, angioedema, pancreatitis (insufficient data to indicate causal relationship; 16 cases among 14,562 patients in randomized controlled trials)²³	Headache, diarrhea, nausea, weight loss²⁴	Outcomes: benefit (some agents) Liraglutide (Victoza): in 9,340 patients with diabetes and high CV risk treated for 3.8 years, improved all-cause mortality (8.2% vs. 9.6%; NNT = 71), CV mortality (4.7% vs. 6.0%; NNT = 77), and CV events (13.0% vs. 14.9%; NNT = 53)²² Semaglutide (Ozempic): in 3,297 patients with diabetes treated for 2.1 years, improved CV events (6.6% vs. 8.9%; NNT = 43), worsened retinal complications (RR = 1.76), and no difference in all-cause or CV mortality ²⁵ Exenatide weekly (Bydureon): in 14,752 patients with diabetes and high CV risk treated for 3.2 years, improved all-cause mortality (6.9% vs. 7.9%; NNT = 100); other individual and combined CV outcomes narrowly missed statistical significance for improvement²⁶ Lixisenatide (Adlyxin): in 6,068 patients with diabetes and CHD treated for 2.1 years, no benefit or harm²⁷ All agents in this class independently produce direct weight loss	Liraglutide: NA ($920) Exenatide weekly: NA ($700) Exenatide twice daily (Byetta): NA ($750) Lixisenatide: NA ($620)	Subcutaneous injection twice daily, once daily, or once weekly
DPP-4 inhibitors (e.g., Januvia, Onglyza)	Pancreatitis (insufficient data to indicate causal relationship), hypoglycemia, slightly higher rates of CHF²⁸	Rare severe arthralgias	Outcomes: neutral Sitagliptin (Januvia): in 14,671 patients with diabetes treated for 3 years, no CV or mortality benefit or harm²⁹ Saxagliptin (Onglyza) and alogliptin (Nesina): short randomized controlled trials showed no CV benefit or harm^30,31	Alogliptin: NA ($90) Saxagliptin: NA ($410) Sitagliptin: NA ($450)	Once-daily oral dosing
Meglitinides (e.g., Prandin, Starlix)	Hypoglycemia, especially with concurrent use of insulin or sulfonylureas (meglitinides are also insulin secretagogues) Slight increase in serum uric acid levels	GI effects in <10% of patients (e.g., bloating, constipation, cramps, diarrhea, flatulence), dizziness³²	Outcomes: neutral (when known) Nateglinide (Starlix): in 9,306 patients with prediabetes and high CV risk treated for 5 years, no increase or decrease in mortality, combined CV outcomes, or individual CV outcomes³³	Repaglinide (Prandin): $30 ($570) Nateglinide: $50 ($340)	Oral dosing before meals (three times daily)
Amylin analogue (i.e., Symlin)	Serious hypoglycemia risk (U.S. Food and Drug Administration boxed warning; preemptive insulin dosage decreases warranted)³⁴ Should not be used in patients with gastroparesis (slows gastric emptying)	Nausea (slows gastric emptying)	Outcomes: unknown No studies with patient-oriented outcomes	Pramlintide (Symlin): NA ($1,100)	Subcutaneous injection before meals (three times daily) Always used with insulin, which necessitates numerous injections
SGLT-2 inhibitors (e.g., Jardiance, Invokana)	Hypotension of osmotic diuresis, hyperkalemia in patients with chronic kidney disease, diabetic ketoacidosis, urosepsis, decreased bone mineral density, acute kidney injury (rare) Canagliflozin (Invokana) taken for 3.6 years increases the risk of fracture (NNH = 79), amputation (NNH = 96), genital infections in men (NNH = 11), and yeast vaginitis in women (NNH = 5)³⁵	Slightly more urinary tract infections, many more genital infections	Outcomes: • Empagliflozin (Jardiance): benefit • Canagliflozin: mixed • Other agents: unknown Empagliflozin: in 7,020 patients with diabetes and high CV risk treated for 3 years, improved all-cause mortality (5.7% vs. 8.3%; NNT = 38), CV mortality (3.7% vs. 5.9%; NNT = 45), CHF hospitalizations (2.7% vs. 4.1%; NNT = 71), doubling of serum creatinine level (1.5% vs. 2.6%; NNT = 91), and need for dialysis (0.3% vs. 0.6%; NNT = 333)^36,37 Canagliflozin: in 10,142 patients with diabetes and high CV risk treated for 3.6 years, no difference in all-cause mortality, and improved rates of fatal and nonfatal MI and stroke (26.9 vs. 31.5 per 1,000 patient-years; NNT = 60; no individual outcome different), renal combined endpoints of disease- and patient-oriented evidence (5.5 vs. 9.0 per 1,000 patient-years; NNT = 79), and CHF hospitalization (5.5 vs. 8.7 per 1,000 patient-years; NNT = 87)³⁵	Canagliflozin: NA ($500) Empagliflozin: NA ($480) Dapagliflozin (Farxiga): NA ($490)	Once-daily oral dosing