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.4–37 It permits side-by-side comparisons of the pros and cons, and reveals some insights for clinical decision making.
Type 2 Diabetes Therapies: A STEPS Approach
|Drug class||STEPS 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
• First generation: harm
• Second generation (glipizide [Glucotrol], glyburide): neutral
• Third generation (glimepiride [Amaryl]): unknownFirst 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)
Referencesshow all references
1. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs— insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285–1287....
2. U.S. Department of Health and Human Services; U.S. Food and Drug Administration. Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Accessed August 17, 2018.
3. Shaughnessy AF. STEPS drug updates. Am Fam Physician. 2003;68(12):2342–2348.
4. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;(4):CD002967.
5. Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754–1761.
6. Glucophage (metformin hydrochloride) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf. Accessed August 17, 2018.
7. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) [published correction appears in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854–865.
8. Glucotrol (glipizide) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017783s019lbl.pdf. Accessed August 17, 2018.
9. Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;(4):CD009008.
10. Phung OJ, Scholle JM, Talwar M, et al. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303(14):1410–1418.
11. Rados DV, Pinto LC, Remonti LR, Leitão CB, Gross JL. Correction: the association between sulfonylurea use and all-cause and cardiovascular mortality: a meta-analysis with trial sequential analysis of randomized clinical trials. PLoS Med. 2016;13(6):e1002091.
12. Gerstein HC, Bosch J, Dagenais GR, et al.; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–328.
13. Kernan WN, Viscoli CM, Furie KL, et al.; EMPA-REG OUTCOME Investigators. Pioglita-zone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–1331.
14. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645.
15. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med. 2010;170(14):1191–1201.
16. Dormandy JA, Charbonnel B, Eckland DJ, et al.; EMPA-REG OUTCOME Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–1289.
17. Catalan VS, Couture JA, LeLorier J. Predictors of persistence of use of the novel antidiabetic agent acarbose. Arch Intern Med. 2001;161(8):1106–1112.
18. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J. 2004;25(1):10–16.
19. Van de Laar FA, Lucassen PL, Akkermans RP, et al. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(2):CD003639.
20. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290(4):486–494.
21. Holman RR, Coleman RL, Chan JC, et al.; EMPA-REG OUTCOME Investigators. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet Diabetes Endocrinol. 2017;5:877–886]. Lancet Diabetes Endocrinol. 2017;5(11):877–886.
22. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322.
23. Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.
24. Victoza (liraglutide [rDNA origin] injection), solution for subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022341lbl.pdf. Accessed November 8, 2018.
25. Marso SP, Bain SC, Consoli A, et al.; EMPA-REG OUTCOME Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844.
26. Holman RR, Bethel MA, Mentz RJ, et al.; EMPA-REG OUTCOME Investigators. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–1239.
27. Pfeffer MA, Claggett B, Diaz R, et al.; EMPA-REG OUTCOME Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl JMed. 2015;373(23):2247–2257.
28. Rehman MB, Tudrej BV, Soustre J, et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab. 2017;43(1):48–58.
29. Green JB, Bethel MA, Armstrong PW, et al.; EMPA-REG OUTCOME Investigators. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes [published correction appears in N Engl J Med. 2015;373(6):586]. N Engl J Med. 2015;373(3):232–242.
30. Scirica BM, Bhatt DL, Braunwald E, et al.; EMPA-REG OUTCOME Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–1326.
31. White WB, Cannon CP, Heller SR, et al.; EMPA-REG OUTCOME Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl JMed. 2013;369(14):1327–1335.
32. Prandin (repaglinide) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020741s035lbl.pdf. Accessed November 8, 2018.
33. Holman RR, Haffner SM, McMurray JJ, et al.; EMPA-REG OUTCOME Investigators. Effect of nateglinide on the incidence of diabetes and cardiovascular events [published correction appears in N Engl J Med. 2010;362(18): 1748]. N Engl J Med. 2010;362(16):1463–1476.
34. Symlin (pramlintide acetate) injection for subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021332s007_S016.pdf. Accessed November 8, 2018.
35. Neal B, Perkovic V, Mahaffey KW, et al.; EMPA-REG OUTCOME Investigators. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657.
36. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
37. Wanner C, Inzucchi SE, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–334.
38. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(suppl 1):S1–S135.
39. ClinicalTrials.gov. Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes mellitus. Identifier NCT02465515. https://clinicaltrials.gov/ct2/show/NCT02465515?id=NCT02465515. Accessed February 5, 2018.
40. ClinicalTrials.gov. Researching cardiovascular events with a weekly incretin in diabetes (REWIND). Identifier NCT01394952. https://clinicaltrials.gov/ct2/show/NCT01394952?id=NCT01394952. Accessed February 5, 2018.
41. American Diabetes Association. Standards of medical care in diabetes – 2018 abridged for primary care providers. Clin Diabetes. 2018;36(1):14–37.
42. Qaseem A, Barry MJ, Humphrey LL, Forciea MA. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279–290.
43. U.S. Department of Veterans Affairs; U.S. Department of Defense. VA/DoD clinical practice guideline for the management of type 2 diabetes mellitus in primary care, version 5.0. April 2017. https://www.healthquality.va.gov/guidelines/CD/diabetes/VADoDDMCPGFinal508.pdf. Accessed August 17, 2018.
Copyright © 2019 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact firstname.lastname@example.org for copyright questions and/or permission requests.
Want to use this article elsewhere? Get Permissions