Acarbose INITIAL: 25 mg PO TID ($45) Miglitol INITIAL: 25 mg PO TID ($145)

PL Detail-Document #310601 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER June 2015 Drugs for Type 2 Diabetes (Last modified September 2015) Diabetes is a worldwide problem affecting millions of people. Glucose control is the mainstay of therapy in these patients. In recent years, a variety of new agents with novel mechanisms of action have been approved for the treatment of type 2 diabetes. While this provides more options for the treatment of these patients, the wide array of medications can lead to confusion as to which agents should be used. In general, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) recommend that in addition to lifestyle modification, metformin is first-line for the treatment of type 2 diabetes in most patients. 1,2 In general, the target A1C concentrations are 7% (ADA) or 6.5% (AACE), but the goal may be individualized in patients with other illnesses and in those at risk for hypoglycemia. 1,2 Therapy can be started with more than one agent in patients with an A1C >9% (ADA) or >7.5% (AACE). However, for patients who fail metformin monotherapy, a broad variety of agents can be used in combination with metformin, or as monotherapy in those who cannot use metformin. 1,2 The choice of secondline and third-line agents varies based on patient characteristics, patient preferences, and properties of the medications such as the risk of hypoglycemia or weight gain. The table below summarizes the agents available for the treatment of type 2 diabetes, including expected A1C reduction, mechanism of action, dosing, and advantages and disadvantages of each class of medication. Abbreviations: BID - twice ; CVD - cardiovascular disease; MOA - mechanism of action; PO - by mouth; SC - subcutaneously; TID - three times. Alpha-glucosidase inhibitor 0.5% to 1% 3 Slows intestinal carbohydrate digestion/ absorption. Acarbose (Precose, others) Miglitol (Glyset) Acarbose INITIAL: 25 mg PO TID ($45) Miglitol INITIAL: 25 mg PO TID ($145) Lack of hypoglycemia when used as monotherapy Weight neutral Reduces postprandial glucose values Not absorbed Likely reduces CVD events (acarbose) Beneficial in the treatment of prediabetes (acarbose) 9 Modest effect on A1C Flatulence Diarrhea Need for frequent dosing.com

(PL Detail-Document #310601: Page 2 of 11) Amylin analog 0.5% to 1% 5 Slows gastric emptying, increases the feeling of fullness, reduces postprandial glucagon secretion. Pramlintide (Symlin) Pramlintide INITIAL: 60 mcg SC prior to major meals (>250 kcal or containing >30 g carbohydrate) ($590) Lack of hypoglycemia when used as monotherapy Weight loss Reduces postprandial glucose values Increases feeling of fullness after meal Modest effect on A1C Nausea Vomiting Hypoglycemia if insulin dose is not reduced Need for frequent dosing Injectable Biguanide 1% to 1.5% 3 Inhibits hepatic glycogenolysis and gluconeogenesis. Enhances insulin sensitivity in muscle and fat. Metformin (Glucophage, Glucophage XR) Available in combination with alogliptin, glimepiride, glipizide, glyburide, linagliptin, pioglitazone, rosiglitazone, saxagliptin, sitagliptin, repaglinide, and canagliflozin. See specific agents. Metformin INITIAL: 500 mg PO BID or 850 mg PO once (less than $20/month) Lack of hypoglycemia Weight neutral Likely reduces CVD events Beneficial in the treatment of prediabetes 10 Diarrhea Abdominal cramping B12 deficiency Lactic acidosis (rare) in patients with cardiovascular, renal, or hepatic dysfunction

(PL Detail-Document #310601: Page 3 of 11) Dipeptidyl peptidase-4 (DPP-4) inhibitor ( gliptins ) or incretin enhancer 0.5% to 1% 3 (However, some experts feel that the actual range is lower [e.g., <0.7%].) Inhibits degradation of endogenous incretins resulting in increased insulin secretion in response to elevated blood glucose, decreased glucagon secretion, slowed gastric emptying, and increased satiety. Alogliptin (Nesina) (Kazano) With pioglitazone (Oseni) Linagliptin (Tradjenta) (Jentadueto) With empagliflozin (Glyxambi) Saxagliptin (Onglyza) (Kombiglyze XR) Sitagliptin (Januvia) (Janumet, Janumet XR) Alogliptin INITIAL: 25 mg PO once ($310) Linagliptin INITIAL: 5 mg PO once ($330) Saxagliptin INITIAL: 2.5 or 5 mg PO once ($325) Sitagliptin INITIAL: 100 mg PO once ($330) No hypoglycemia when used as monotherapy Weight neutral Generally well tolerated Dosage modification with renal impairment needed (sitagliptin, saxagliptin, alogliptin) CYP3A4 interactions (saxagliptin, linagliptin) May be associated with pancreatitis 6 May worsen heart failure (saxagliptin) 7,13 May cause severe joint pain 12

(PL Detail-Document #310601: Page 4 of 11) Glucagon-like, peptide-1 (GLP-1) agonist or incretin mimetic 1% to 1.5% 3 Stimulation of GLP-1 receptors results in increased insulin secretion in response to elevated blood glucose, decreased glucagon secretion, slowed gastric emptying, and increased satiety. (GLP-1 is an incretin hormone.) For more information, see our PL Chart, Comparison of GLP-1 Agonists. Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide extendedrelease (Bydureon) Liraglutide (Victoza) Albiglutide INTIAL: 30 mg SC once weekly ($325) Dulaglutide INITIAL: 0.75 mg SC once weekly ($490) Exenatide INITIAL: 5 mcg SC BID ($480) Exenatide extended-release INITIAL: 2 mg SC once weekly ($475) Liraglutide INITIAL: 0.6 mg SC once x 1 week, then increase to 1.2 mg SC once ($430) Lack of hypoglycemia when used as monotherapy Weight loss Reduces postprandial glucose values In patients who need more than one or two antidiabetes agents, combination injectable therapies of basal insulin and a GLP-1 agonist is an efficient, emerging strategy. Headache Nausea (often transient) Diarrhea Dosage modification with renal dysfunction needed (albiglutide, dulaglutide) Avoid in severe renal impairment (exenatide) May be associated with pancreatitis 6 Associated with thyroid cell cancer in rodents May be associated with renal insufficiency 8 Injectable

(PL Detail-Document #310601: Page 5 of 11) Insulin 1.5% to 3.5% 5 Meglitinide 0.5% to 1% 3 Stimulates pancreatic insulin secretion. Various. See our PL Chart, Comparison of Insulins and Injectable Diabetes Meds. Nateglinide (Starlix) Repaglinide (Prandin, others) (PrandiMet) See our PL Charts, Initiation and Adjustment of Insulin Regimens for Type 2 Diabetes and Comparison of Insulins and Injectable Diabetes Meds. Nateglinide INITIAL: 60 to 120 mg PO TID with meals ($105) Repaglinide INITIAL: 0.5 mg PO TID with meals if A1C <8%, 1 or 2 mg TID with meals if A1C >8% ($50) Effective in all patients Reduced microvascular complications Consider starting insulin, in combination with metformin therapy with or without other noninsulin therapies when the blood glucose is >300 mg/dl to 350 mg/dl and/or the A1C >10%. Insulin may be more effective than other therapies when hyperglycemia is severe, especially if the patient is symptomatic or has any catabolic features (e.g., weight loss, ketosis). Reduces postprandial glucose values Can be used in place of sulfonylureas in patients with irregular meal schedules or in those who develop late hypoglycemia with a sulfonylurea Hypoglycemia Weight gain Injectable Hypoglycemia if taken without food or if severe renal impairment Weight gain Frequent dosing Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started 3

(PL Detail-Document #310601: Page 6 of 11) Sodium-glucose cotransporter 2 (SGLT2) inhibitor or flozins 0.5% to 1% 1 Blocks glucose reabsorption in kidney, increases glucosuria. Canagliflozin (Invokana) (Invokamet) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) With linagliptin (Glyxambi) (Synjardy) Canagliflozin INITIAL: 100 mg PO once ($340) Dapagliflozin INITIAL: 5 mg PO once ($340) Empagliflozin INITIAL: 10 mg PO once ($340) Lack of hypoglycemia Weight loss May reduce blood pressure Genital fungal infections (male and female) Urinary tract infection Increased urination Hypotension Increase LDL Do not use if egfr <45 ml/min/1.73m 2 (canagliflozin, empagliflozin) or <60 ml/min/1.73m 2 (dapagliflozin) Fractures (rare, in susceptible patients). 4 Decrease in BMD (canagliflozin). 11 May be associated with increased risk of bladder cancer (dapagliflozin) Possible association with ketoacidosis 14

(PL Detail-Document #310601: Page 7 of 11) Sulfonylurea first generation 1% to 1.5% 3 Stimulates pancreatic insulin secretion. Chlorpropamide (Diabinese, others) Tolazamide (Tolinase, others) Tolbutamide (Orinase, others) Chlorpropamide INITIAL: 100 to 250 mg PO once (less than $20/month) Tolazamide INITIAL: 250 mg PO once ($48) Tolbutamide INITIAL: 1 g PO once ($70) Initially, good efficacy Inexpensive Hypoglycemia more common compared with second-generation sulfonylureas 5 Weight gain 5 Reduced efficacy over time 5 Avoid in patients with renal dysfunction or the elderly (chlorpropamide) Use of second-generation sulfonylureas preferred over first-generation sulfonylureas Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started 1

(PL Detail-Document #310601: Page 8 of 11) Sulfonylurea-second generation 1% to 1.5% 3 Stimulates pancreatic insulin secretion. Glyburide (Diabeta, Glynase, Micronase, others) (Glucovance) Glipizide (Glucotrol, Glucotrol XL, others) (Metaglip) Glimepiride (Amaryl, others) (Amaryl M) With pioglitazone (Duetact) With rosiglitazone (Avandaryl) Glyburide INITIAL: 2.5 mg PO once (less than $10/month) Glipizide INITIAL: 5 mg PO once (less than $10/month) Glimepiride INITIAL: 1 mg PO once (less than $10/month) Initially, good efficacy Inexpensive Hypoglycemia, especially with renal dysfunction (less with glimepiride versus glyburide) 5 Weight gain (glyburide more than glipizide, glimepiride) Reduced efficacy over time For the elderly and those with hepatic or renal dysfunction, start with low doses and titrate up Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started 1

(PL Detail-Document #310601: Page 9 of 11) Thiazolidinedione (TZD) 1% to 1.5% 3 Increases insulin sensitivity in muscle and fat. Others bile acid sequestrant 0.5% to 1% 3 May reduce hepatic glucose production, may increase incretin levels, and decreases GI glucose absorption. Others dopamine agonist 0.5% to 1% 3 Pioglitazone (Actos) (Actoplus Met or Actoplus Met XR) With glimepiride (Duetact) With alogliptin (Oseni) Rosiglitazone (Avandia) (Avandamet) With glimepiride (Avandaryl) Colesevelam (Welchol) Bromocriptine (Cycloset) Pioglitazone INITIAL: 15 mg PO once (less than $20) Rosiglitazone INITIAL: 4 mg PO once ($115) Colesevelam INITIAL: 3.75 g PO per day (taken as six tablets once, or three tablets BID, with meals) ($470) Bromocriptine INITIAL: 0.8 mg PO once ($90) Lack of hypoglycemia when used as monotherapy Improves HDL cholesterol Reduced triglycerides (pioglitazone) May reduce CVD (pioglitazone) No hypoglycemia Weight neutral Safe in CVD Lowers LDL cholesterol No hypoglycemia Weight neutral Weight gain Volume retention, congestive heart failure Increased fracture risk Increases LDL (rosiglitazone) May possibly increase the risk of bladder cancer (pioglitazone) Constipation Nausea, bloating Increased triglycerides Drug interactions Dizziness/syncope Nausea May centrally regulate metabolism, increase insulin sensitivity.

(PL Detail-Document #310601: Page 10 of 11) a. Information based on most current U.S. product information unless otherwise noted: Precose (March 2015), Glyset (February 2015), Symlin (March 2015), Glucophage (March 2015), Onglyza (May 2013), Januvia (March 2015), Tradjenta (May 2014), Byetta (February 2015), Bydureon (March 2015), Victoza (March 2015), Starlix (January 2013), Prandin (March 2012), Diabeta (October 2013), Glucotrol (February 2011), Amaryl (February 2012), Actos (August 2012), Avandia (May 2012), Welchol (January 2014), Cycloset (March 2011), Diabinese (October 2013), tolazamide (Mylan; December 2009), tolbutamide (Mylan; February 2009), Invokana (March 2015), Nesina (June 2013), Farxiga (March 2015), Jardiance (August 2014), Tanzeum (March 2015), Invokamet (March 2015), Trulicity (March 2015). b. Approximate prices based on WAC for 30-day supply (of generic product if available, generic prices may vary considerably). If WAC not available (chlorpropamide, tolazamide, tolbutamide), AWP for 30-day supply used. c. A1C reductions are estimates using monotherapy. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(PL Detail-Document #310601 Page 11 of 11) Project Leader in preparation of this PL Detail- Document: Neeta Bahal O Mara, Pharm.D., BCPS References 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Diabetes Care 2015;38:140-9. 2. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology-Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan 2015. Endo Pract 2015;21(Suppl 1):1-87. 3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35:1364-79. 4. Hackethal V. SGLT2 inhibitors and fracture risk: a review of what we know. Endocrinology Network, March 30, 2015. http://www.endocrinologynetwork.com/sglt2/sglt2- inhibitors-and-fracture-risk-review-what-we-know. (Accessed April 13, 2015). 5. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203. 6. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-fda and EMA assessment. N Engl J Med 2014;370:794-7. 7. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26. 8. PL Detail-Document, Comparison of GLP-1 Agonists. Pharmacist s Letter/Prescriber s Letter. December 2014. 9. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP- NIDDM randomized trial. Lancet 2002;359:2072-7. 10. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012;35:731-7. 11. FDA. Invokana and Invokamet (canagliflozin): drug safety communication new information on bone fracture risk and decreased bone mineral density. September 10, 2015. http://www.fda.gov/safety/medwatch/safetyinformatio n/safetyalertsforhumanmedicalproducts/ucm461876. htm. (Accessed September 13, 2015). 12. FDA. FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. August 28, 2015. http://www.fda. gov/drugs/drugsafety/ucm459579.htm. (Accessed September 13, 2015). 13. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care 2015;38:696-705. 14. FDA. SGLT2 inhibitors: drug safety communication FDA warns medicines may result in a serious condition of too much acid in the blood. May 15, 2015. http://www.fda.gov/safety/medwatch/safetyinformatio n/safetyalertsforhumanmedicalproducts/ucm446994. htm. (Accessed May 26, 2015). Cite this document as follows: PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist s Letter/Prescriber s Letter. June 2015. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2015 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com

PL Detail-Document #280601 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER June 2012 Stepwise Approach to Selecting Treatments for Type 2 Diabetes (ADA) (2012 American Diabetes Association and European Association for the Study of Diabetes) Diagnosis of type 2 diabetes in nonpregnant adults 1,a,b Counsel patients regarding lifestyle modification such as healthy diet, weight loss, exercise At or soon after diagnosis, add metformin c monotherapy ( A1C 1%-1.5%) unless contraindicated If target A1C not achieved after approximately 3 months, consider ADDING a second agent (based on patient and drug characteristics) Sulfonylurea d TZD f DPP-4 inhibitor GLP-1 agonist insulin (usually basal) e ( A1C 1%-1.5%) ( A1C 1%-1.5%) ( A1C 0.5%-1%) ( A1C 1%-1.5%) ( A1C 1.5%-3.5%) 2 (2nd generation) -pioglitazone (Actos) -sitagliptin (Januvia) -exenatide (Byetta) -glyburide (not preferred) -saxagliptin (Onglyza) -exenatide extended-release (Bydureon) -glipizide (Glucotrol) -linagliptin (Tradjenta) -liraglutide (Victoza) -glimepiride (Amaryl) If target A1C not achieved after approximately 3 months, consider ADDING a third agent TZD f or SU d or SU d or SU d or TZD f or DPP-4 inhibitor or DPP-4 inhibitor or TZD f or TZD f or DPP-4 inhibitor or GLP-1 agonist or GLP agonist or insulin (usually basal) e insulin (usually basal) e GLP-1 agonist insulin (usually basal) e insulin (usually basal) e If a 3-drug combination (including basal insulin) does not achieve target A1C after 3 to 6 months, move to more complex insulin regimen (multiple doses), with 1 or 2 non-insulin agents. Sulfonylureas and meglitinides are generally avoided in patients who require more complex insulin regimens including prandial insulins. 1 See our PL Chart, Drug Classes for Type 2 Diabetes, for more information about the pros and cons of the drugs used for type 2 diabetes. Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SU = sulfonylurea; TZD = thiazolidinedione. Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

(PL Detail-Document #280601: Page 2 of 3) The above algorithm does not include pramlintide (Symlin), alpha-glucosidase inhibitors (acarbose [Precose], miglitol [Glyset]), bile acid sequestrant (colesevelam [Welchol]), or dopamine agonists (bromocriptine [Cycloset]), because of modest efficacy and/or intolerable side effects. However, these may be used in selected patients. Insulin is likely to be more effective than other third-line agents, especially in patients with high A1C (e.g., 9% or greater). In patients with severe hyperglycemia (e.g., A1C 10% or greater), a more rapid progression from a two-drug combination directly to a regimen of multiple insulin doses is indicated. a. This algorithm provides a summary of the 2012 position statement of the American Diabetes Association and European Association for the Study of Diabetes created for the treatment of adult, nonpregnant patients with type 2 diabetes. Of note, it is based on evidence, where it exists, but also relies on the opinions of experts. The recommendations should be considered within the context of the needs, preferences, and tolerance of the individual patient. b. While the American Diabetes Association Standards of Medical Care in Diabetes recommends lowering the A1C to less than 7% in most patients, some patients may benefit from less stringent A1C goals. For example, an A1C goal of 7.5% to 8.0% or slightly higher may be acceptable in patients with a history of severe hypoglycemia, those with a limited life expectancy, those with advanced complications such as moderate to severe renal dysfunction, or those with extensive comorbid conditions. Conversely, some patients may benefit from more stringent goals (e.g., A1C 6.0% to 6.5%) such as those with a short duration of disease, long life expectancy, and no significant cardiovascular disease. c. Metformin is contraindicated in patients at risk of lactic acidosis such as those with significant renal dysfunction (e.g., serum creatinine values >1.5 mg/dl [males] and >1.4 mg/dl [females]) or alcoholism. For more information about contraindications for metformin, see our PL Detail- Document, Clinical Use of Metformin in Special Populations - Chronic Renal Insufficiency, Heart Failure, and Hepatic Dysfunction. d. Consider rapid-acting secretagogues or the meglitinides (repaglinide [Prandin], nateglinide [Starlix]) in place of sulfonylurea agents in certain patients. For example, meglitinides may be safer in patients with irregular meal schedules or in those who develop late postprandial hypoglycemia while on sulfonylurea agents. e. Basal insulin: insulin glargine (Lantus), insulin detemir (Levemir), or NPH insulin. f. Rosiglitazone use is restricted. It is only available by mail order from specially certified pharmacies. Health care providers and patients must enroll in the Avandia-Rosiglitazone Medicines Access Program. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

(PL Detail-Document #280601: Page 3 of 3) Project Leader in preparation of this PL Detail- Document: Neeta Bahal O Mara, Pharm.D., Drug Information Consultant References 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care Published on-line ahead of print, April 19, 2012; doi:10.2337/dc12-0413. 2. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203. Cite this document as follows: PL Detail-Document, Stepwise Approach to Selecting Treatments for Type 2 Diabetes. Pharmacist s Letter/Prescriber s Letter. June 2012. Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2012 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com