Type 2 Diabetes Therapies: A STEPS Approach


Am Fam Physician. 2019 Feb 15;99(4):237-243.

Author disclosure: No relevant financial affiliations.

Only a few years ago, lifestyle modification, sulfonylureas, metformin, and insulin were the only treatment options for type 2 diabetes mellitus. Now, family physicians have approximately 40 medications in 10 categories to manage hyperglycemia in patients with type 2 diabetes. However, the availability of so many choices makes therapeutic decisions more complex. Although all 40 medications will improve blood glucose levels, that is not sufficient. As family physicians, we seek to treat the whole person, not just blood glucose levels, insulin resistance, and islet cell dysfunction. Our patients with diabetes depend on us to help reduce their long-term risk of myocardial infarction, stroke, amputation, dialysis, and premature mortality.

Several recent large randomized controlled trials have significantly improved our knowledge about the impact of diabetes medications on patient-oriented outcomes. After the thiazolidinedione (TZD) rosiglitazone (Avandia) was found to increase the risk of myocardial infarction,1 the U.S. Food and Drug Administration required newly approved diabetes drugs to undergo rigorous postmarketing studies of long-term cardiovascular harm.2 Studies evaluating harms, such as major cardiovascular events and cardiovascular mortality, also have the potential to show us which agents confer long-term benefits for those outcomes. The results of these studies can be used to make better choices for our patients with type 2 diabetes.

A concise and organized way to evaluate pharmacotherapy options for diabetes is to use the five patient-oriented STEPS criteria: safety, tolerability, effectiveness, price, and simplicity.3  Table 1 presents the STEPS approach for each category of diabetes medication.437 It permits side-by-side comparisons of the pros and cons, and reveals some insights for clinical decision making.

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Type 2 Diabetes Therapies: A STEPS Approach

Drug classSTEPS component

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


• First generation: harm

• Second generation (glipizide [Glucotrol], glyburide): neutral

• Third generation (glimepiride [Amaryl]): unknown

First generation: increased CV mortality rates9,11 Second generation: two large systematic reviews showed no benefit or harm for mortality, MI, and stroke9,11 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


The Authors

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JOSHUA STEINBERG, MD, is a faculty member at United Health Services Wilson Family Medicine Residency, Johnson City, NY, and a clinical assistant professor of family medicine at State University of New York Upstate Medical University, Binghamton Clinical Campus....

LYNDSAY CARLSON, PharmD, BCACP, is an ambulatory care clinical pharmacy specialist at United Health Services, Johnson City, NY.

Address correspondence to Joshua Steinberg, MD, United Health Services Wilson Family Medicine Residency, 507 Main St., Johnson City, NY 13790 (e-mail: jds91md@gmail.com). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


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