Joshua Steinberg, MD, United Health Services Wilson Family Medicine Residency, Johnson City, New York Lyndsay Carlson, PharmD, BCACP, United Health Services, Johnson City, New York
Only a few years ago, lifestyle modification, sulfony- lureas, metformin, and insulin were the only treatment options for type 2 diabetes mellitus. Now, family physicians have approximately 40 medications in 10 categories to man- age hyperglycemia in patients with type 2 diabetes. How- ever, 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, amputa- tion, 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 stud- ies of long-term cardiovascular harm.2 Studies evaluating harms, such as major cardiovascular events and cardiovas- cular 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 pharmacother- apy 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.
The American Diabetes Association recommends the biguanide metformin (Glucophage) as first-line pharma- cotherapy for type 2 diabetes.38 The STEPS criteria show why: it is safe and fairly well-tolerated, has excellent long- term effectiveness on patient-oriented outcomes, is mod- erately priced, and has a simple dosing regimen. No other diabetes medication excels in the STEPS criteria as well as metformin.
This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz on page 255
Author disclosure: No relevant financial affiliations.
However, most patients with type 2 diabetes require more than one medication. The STEPS approach can help us choose subsequent medications if metformin does not provide adequate glycemic control for our patients.
Focusing first on effectiveness, the table shows evidence of improved patient-oriented outcomes from glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter-2 (SGLT-2) inhibitors in patients who are at high cardiovascular risk or have known cardiovascular dis- ease. (22,36,37) Such improvements are likely to be significantly more modest in patients who are not at high cardiovascu- lar risk. No long-term improvement in patient-oriented outcomes has been demonstrated for the dipeptidyl- peptidase-4 (DPP-4) inhibitors or for the amylin analogue pramlintide (Symlin). The high prices and lack of favorable long-term outcomes leave the use of agents such as sita- gliptin (Januvia) and pramlintide hard to justify. The alpha- glucosidase inhibitor acarbose (Precose) has evidence to support improved patient-oriented outcomes,18 and as with metformin, its price is quite low.
Focusing next on price, the table shows that metformin and, to a lesser extent, acarbose have evidence of a favor- able effect on long-term outcomes and are relatively inex- pensive. Likewise, inexpensive generic pioglitazone (Actos) is an option with a mix of potential benefits and harms.16 Sulfonylureas and older insulins are also inexpensive, and although there is no evidence from randomized trials of long-term patient-oriented benefits, there is also no evi- dence of long-term end-organ harm. (9,11,12)
Focusing next on safety, the table shows that several agents are concerning because they increase hypoglycemia risk (e.g., sulfonylureas, insulins, meglitinides, pramlintide) or require monitoring, dose adjustments, or discontinuation in patients with chronic kidney disease (e.g., metformin, acarbose).
Focusing last on simplicity, the table shows that several agents may be challenging for some patients because of the need for frequent or complicated dosing or injections. Poor memory, eyesight, or health literacy may make such a chal- lenging regimen a poor option for some patients.
Although agents within a drug category are more similar than different, a STEPS table comparing each insulin would highlight differences in safety, price, and simplicity. A table comparing each GLP-1 receptor agonist would show that only some (liraglutide [Victoza], semaglutide [Ozempic],
Drug class | Safety | Tolerability | Effectiveness* | Price† | Simplicity |
---|---|---|---|---|---|
Biguanides (e.g., Glucophage) | Historical concern for lactic acidosis, but Cochrane review of 347 stud- ies found no cases in 70,490 patient-years, with lactate levels similar between patients receiving metformin (Glucophage) and a control group (4) 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 deficiency (5) Safe in patients with stable CHF | GI effects (e.g., diarrhea, nausea, vomiting) in < 10% of patients; dis- continuation 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), microvascu- lar 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 deficiency (8) First generation (chlorpropamide, tolbutamide): systematic review shows increased CV mortality (N = 553; RR = 2.63) (9) | Weight gain (10) | 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 data (9) | 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 decreased (12) 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, MI (15) | 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 discon- tinuation rates (17) | Outcomes: benefit (when known) Acarbose (Precose): systematic review of seven trials not limited to monother- apy (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 benefit (19) 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 years (20) Acarbose: in 6,522 patients with CHD and prediabetes, no benefit or harm for mortality, individual, or combined CV outcomes over five years (21) | Acarbose: $25 ($100) Miglitol (Glyset): $60 ($250) | Oral dosing before meals (three times daily) |
GLP-1 receptor agonists (e.g., Victoza, Ozempic) | Gallstones (22) Occurrence < 1%: acute kidney injury, angioedema, pancreatitis (insuffi- cient data to indicate causal relationship; 16 cases among 14,562 patients in randomized controlled trials) (23) | Headache, diarrhea, nausea, weight loss (24) | 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 improvement (26) Lixisenatide (Adlyxin): in 6,068 patients with diabetes and CHD treated for 2.1 years, no benefit or harm (27) 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 CHF (28) | Rare severe arthralgias | Outcomes: neutral Sitagliptin (Januvia): in 14,671 patients with diabetes treated for 3 years, no CV or mortality benefit or harm (29) 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), dizziness (32) | 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 outcomes (33) | 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), dou- bling 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 |
CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; DPP-4 = dipeptidyl-peptidase-4; GFR = glomerular filtration rate; GI = gastrointestinal; GLP-1 = glucagon-like peptide-1; MI = myocardial infarction; NA = not available; NNH = number needed to harm; NNT = number needed to treat; RR = relative risk; SGLT-2 = sodium glucose cotransporter-2; STEPS = simplicity, tolerability, effectiveness, price, simplicity; TZDs = thiazolidinediones.
*—Based on patient-oriented evidence from randomized controlled trials.
†—Estimated retail price for one month of therapy unless otherwise noted, based on prices obtained from http://www.goodrx.com (accessed January 22, 2019). Generic price listed first; brand name price in parentheses.
‡—Although composite outcome improved, no improvement was noted for any individual outcome.
Information from references 4 through 37.
exenatide) have proven cardiovascular benefit, (22,25,26) whereas others have no evidence of benefit and still others have out- come studies that have not been completed. (39,40)
Major guidelines are increasingly aligned with a STEPS approach to pharmacotherapy for type 2 diabetes. Although it has traditionally focused on disease-oriented outcomes, the American Diabetes Association was more patient- oriented in 2018, strongly recommending metformin as first-line therapy, with additional agents added after con- sideration of hypoglycemia risk, comorbidities, potential adverse effects, effectiveness, price, and delivery method.41 The American Academy of Family Physicians–endorsed 2017 guideline on pharmacotherapy for type 2 diabetes from the American College of Physicians shares an empha- sis on safety, tolerability, effectiveness, and price when making initial choices about monotherapy and combina- tion therapy, while focusing on improving patient-oriented outcomes amidst a dearth of evidence regarding specific combinations of hypoglycemic drugs.42 Likewise, the 2017 guideline from the Department of Veterans Affairs and Department of Defense also recommends metformin first, then additional agents according to evidence of effective- ness and consideration of safety, adverse effects, cost, and comorbidities.43 All of these guidelines are consistent with an evidence-based STEPS approach.
Data Sources: Essential Evidence Plus and the Cochrane data- base were searched using the keywords type 2 diabetes and medication therapy. Trials and systematic reviews referenced in the 2017 American Diabetes Association guideline and package inserts of newer medications, and selected relevant references were used. Search dates: August 2017 to October 2018.
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.
The Authors
LYNDSAY CARLSON, PharmD, BCACP, is an ambulatory care clinical pharmacy specialist at United Health Services, John- son 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.
References
- 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.
- 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.
- Shaughnessy AF. STEPS drug updates. Am Fam Physician. 2003;68(12): 2342-2348.
- 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.
- Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Out- comes study. J Clin Endocrinol Metab. 2016;101(4):1754-1761.
- Glucophage (metformin hydrochloride) tablets. https://www.access data.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202 s021s023lbl.pdf. Accessed August 17, 2018.
- 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.
- Glucotrol (glipizide) tablets. https://www.accessdata.fda.gov/drugs atfda_docs/label/2008/017783s019lbl.pdf. Accessed August 17, 2018.
- Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;(4):CD009008.
- 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.
- 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.
- 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.
- Kernan WN, Viscoli CM, Furie KL, et al.; IRIS Trial Investigators. Pioglita- zone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-1331.
- 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.
- 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.
- Dormandy JA, Charbonnel B, Eckland DJ, et al.; PROactive Investiga- tors. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clini- cal Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
- 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.
- 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.
- 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.
- 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.
- Holman RR, Coleman RL, Chan JC, et al.; ACE Study Group. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a ran- domised, double-blind, placebo-controlled trial [published correction appears in Lancet Diabetes Endocrinol. 2017;5:877-886]. Lancet Diabe- tes Endocrinol. 2017;5(11):877-886.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovas- cular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
- 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.
- Victoza (liraglutide [rDNA origin] injection), solution for subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022341lbl. pdf. Accessed November 8, 2018.
- Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Sema- glutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
- Holman RR, Bethel MA, Mentz RJ, et al.; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239.
- Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.
- 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.
- Green JB, Bethel MA, Armstrong PW, et al.; TECOS Study Group. 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.
- Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Com- mittee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14): 1317-1326.
- White WB, Cannon CP, Heller SR, et al.; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
- Prandin (repaglinide) tablets. https://www.accessdata.fda.gov/drugsatf da_docs/label/2009/020741s035lbl.pdf. Accessed November 8, 2018.
- Holman RR, Haffner SM, McMurray JJ, et al.; NAVIGATOR Study Group. 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.
- Symlin (pramlintide acetate) injection for subcutaneous use. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2014/021332s007_ S016.pdf. Accessed November 8, 2018.
- Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 dia- betes. N Engl J Med. 2017;377(7):644-657.
- Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investi- gators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
- Wanner C, Inzucchi SE, Lachin JM, et al.; EMPA-REG OUTCOME Inves- tigators. Empagliflozin and progression of kidney disease in type 2 dia- betes. N Engl J Med. 2016;375(4):323-334.
- American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(suppl 1):S1-S135.
- ClinicalTrials.gov. Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in sub- jects with type 2 diabetes mellitus. Identifier NCT02465515. https:// clinicaltrials.gov/ct2/show/NCT02465515?id=NCT02465515&rank=1. Accessed February 5, 2018.
- ClinicalTrials.gov. Researching cardiovascular events with a weekly incretin in diabetes (REWIND). Identifier NCT01394952. https:// clinicaltrials.gov/ct2/show/NCT01394952?id=NCT01394952&rank=1. Accessed February 5, 2018.
- American Diabetes Association. Standards of medical care in diabetes – 2018 abridged for primary care providers. Clin Diabetes. 2018;36(1):14-37.
- 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.
- U.S. Department of Veterans Affairs; U.S. Department of Defense. VA/ DoD clinical practice guideline for the management of type 2 diabe- tes mellitus in primary care, version 5.0. April 2017. https://www.health quality.va.gov/guidelines/CD/diabetes/VADoDDMCPGFinal508.pdf. Accessed August 17, 2018.