Comparison of GLP-1 Agonists

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in January 2017 ~ Resource # Comparison of GLP-1 Agonists Ozempic (semaglutide) and Bydureon BCise (extended-release exenatide) are the newest glucagon-like peptide-1 (GLP-1) receptor agonists approved for type 2 diabetes. The first GLP-1 agonist, exenatide (Byetta), marketed in 2005, required twice-daily dosing. Since then, newer agents with longer half-lives and extended-release formulations have been developed allowing for once-daily, and even once-weekly, dosing. While all GLP-1 receptor agonists reduce A1C and fasting blood glucose concentrations, only some have evidence of improved cardiovascular outcomes. See our chart, Diabetes Medications and Cardiovascular Impact, for more on their cardiovascular impact. All of the agents carry a warning about the risk of worsening renal function, the rare occurrence of pancreatitis, and a possible association with thyroid C-cell tumors in rodents. Some carry an additional precaution about the potential for gallbladder disease. The exact role in therapy for the GLP-1 receptor agonists is evolving as we learn more about potential cardiovascular benefits. For most patients, GLP-1 agonists should be reserved for those who require two or more diabetes medications to maintain a desired A1C. See our algorithm, Management of New-Onset Type 2 Diabetes, for more information. The chart below compares the GLP-1 receptor agonists for type 2 diabetes currently available in the U.S. Abbreviations: BID = twice daily; ESRD = end-stage renal disease; g = gauge; GI = gastrointestinal; SQ = subcutaneously. Drug e Cost/month a A1C reduction b Dulaglutide (Trulicity) ~$675 (0.75 mg and 1.5 mg doses) A1C: ~1.5% Dosing Start with 0.75 mg SQ once weekly, with or without meals. Increase to 1.5 mg once weekly, if needed for additional A1C lowering. Delayed doses: o If 3 days until the next scheduled dose, give right away. o If <3 days until next scheduled dose, skip and give at next scheduled weekly dose. Availability and Storage Requirements Single-dose pens and prefilled syringes (includes needles): 0.75 mg 1.5 mg Reconstitution not necessary. Keep refrigerated. May store at room temperature for up to 14 days, if needed. Rates of Nausea c and Injection Site Reactions Nausea: 0.75 mg: 12.4% 1.5 mg: 21.1% (placebo-controlled trials, monotherapy or add-on therapy) Injection site reactions: 0.5% Use in Renal/Hepatic Impairment No dosage changes necessary in patients with renal impairment. Monitor renal function in patients with significant GI adverse effects. Hepatic impairment is not expected to affect blood concentrations. Avg. Shortterm Weight Loss b ~2.5 kg

2 (Clinical Resource #330104: Page 2 of 8) Drug e Cost/month a A1C reduction b Exenatide (Byetta) ~$710 (5 mcg and 10 mcg doses) A1C: ~1% Exenatide extendedrelease (Bydureon, Bydureon BCise) ~$660 A1C: 1,4 ~1.5% (Bydureon) ~1.4% (Bydureon BCise) Continued Dosing Start with 5 mcg SQ BID. Increase to 10 mcg BID after one month, if needed for additional A1C lowering. Inject within 60 minutes prior to morning and evening meals (or before the two main meals of the day, 6 hours apart). Delayed doses: Give missed dose as soon as able and resume normal dosing. 2 mg SQ once weekly at any time of day, with or without meals. Delayed doses: o If 3 days until the next scheduled dose, give right away. o If <3 days until next scheduled dose, skip and give at next scheduled weekly dose. Availability and Storage Requirements Multi-dose pens (60 doses per pen): 5 mcg/dose 10 mcg/dose Pen needles not supplied with pens. No mixing needed. Keep refrigerated. After first use, can be kept at room temperature. Discard 30 days after first use. Bydureon Single-dose vial: 2 mg (Comes with prefilled diluent syringe, vial connector, and 23 g needle.) Single-dose dual chamber pen: 2 mg (One chamber with medication and one with diluent, comes with 23 g needle.) Both the vial and the pen dosage forms must be reconstituted immediately prior to use. Keep refrigerated. Can be kept at room temperature for up to four weeks, if needed. Rates of Nausea c and Injection Site Reactions Nausea: Monotherapy: 8% Add-on therapy: 44% Injection site reactions: <2% Nausea (pooled rate of monotherapy or as add-on to other agents): 11.3% (Bydureon) 8.2 % (Bydureon BCise) Injection site reactions (postmarketing reports of serious injection site reactions with or without SQ nodules): 17.1% (Bydureon) Use in Renal/Hepatic Impairment Not recommended in ESRD or severe renal impairment. Use with caution in patients with renal transplantation or moderate renal impairment. Hepatic impairment is not expected to affect blood concentrations. Not recommended in severe renal impairment or ESRD. Use with caution in patients with renal transplantation or moderate renal impairment. Hepatic impairment is not expected to affect blood concentrations. Avg. Shortterm Weight Loss b ~2 kg Bydureon: ~2.5 kg Bydureon BCise: ~1.4 kg

3 (Clinical Resource #330104: Page 3 of 8) Drug e Cost/month a A1C reduction b Exenatide extendedrelease, continued Dosing Availability and Storage Requirements Bydureon BCise Single-dose autoinjector: Keep refrigerated. Can be kept at room temperature for up to four weeks, if needed (unmixed). Store flat in original packaging, protected from light. Remove from refrigerator about 15 minutes prior to mixing. Shake vigorously to mix for at least 15 seconds. Rates of Nausea c and Injection Site Reactions Injection site reactions: 23.9% (Bydureon BCise) Use in Renal/Hepatic Impairment Avg. Shortterm Weight Loss b Liraglutide (Victoza) ~$540 for 1.2 mg daily ~$805 for 1.8 mg daily A1C: ~1.5% Start with 0.6 mg SQ once daily for one week (to reduce nausea, not effective for glycemic control), increase to 1.2 mg once daily. Can increase to 1.8 mg once daily if needed for additional A1C lowering. Administer at any time of day, with or without meals. Delayed doses: Give missed dose as soon as able and resume normal dosing. Multi-dose pens (6 mg/ml, 3 ml): Each pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg Needles not supplied with pens. No mixing needed. Keep refrigerated. After first use, can be stored at room temperature. Discard 30 days after first use. Nausea: 20% (pooled data from placebo- and activecontrolled trials) Injection site reactions: 2% (injection site rash, erythema) Use caution when initiating or escalating doses in patients with renal impairment. Use caution in patients with hepatic impairment. ~2.5 kg

4 (Clinical Resource #330104: Page 4 of 8) Drug e Cost/month a A1C reduction b Insulin degludec/ liraglutide (Xultophy 100/3.6) ~$990 for max daily dose A1C: ~1% more than insulin degludec Dosing Start with 16 units insulin degludec/0.58 mg liraglutide SQ once daily, with or without food. Adjust dose by 2 units (2 units of insulin degludec and mg of liraglutide) every three to four days Maximum daily dose is 50 units insulin degludec/1.8 mg liraglutide. d Delayed doses: Give missed dose as soon as able and resume normal dosing schedule. Availability and Storage Requirements Multi-dose pens (3 ml): Insulin degludec (100 units/ml) and liraglutide (3.6 mg/ml) Each pen delivers doses from 10 units to 50 units with each injection Keep refrigerated. After first use, store at room temperature. Discard 21 days after first use. Rates of Nausea c and Injection Site Reactions Nausea: 7.8% Injection site reactions: 2.6% (hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, mass) Use in Renal/Hepatic Impairment Use caution when initiating or escalating doses in patients with renal impairment. Has not been studied in patients with hepatic impairment. Avg. Shortterm Weight Loss b ~2.5 kg versus insulin degludec 3 Lixisenatide (Adlyxin) ~$590 for the 20 mcg daily dose A1C: ~1% Start with 10 mcg SQ once daily for 14 days. Increase to 20 mcg once daily. Administer within one hour prior to the first meal of the day. Delayed doses: Give missed dose as soon as able and resume normal dosing schedule. Multi-dose pens (14 doses per pen): 10 mcg 20 mcg Needles not supplied with pen. No mixing needed. Keep refrigerated prior to first use. After first use, store at room temperature. Discard 14 days after first use. Nausea: 25% Injection site reactions: 4% (pain, pruritus, erythema) Monitor for GI adverse effects and changes in renal function in patients with severe renal impairment. Hepatic impairment is not expected to affect blood concentrations. ~ 2 kg

5 (Clinical Resource #330104: Page 5 of 8) Drug e Cost/month a A1C reduction b Insulin glargine/ lixisenatide (Soliqua 100/33) ~$815 for max daily dose A1C: 0.5% more than insulin glargine alone Dosing Uncontrolled on <30 units of basal insulin or lixisenatide: Start with 15 units (15 units insulin glargine/5 mcg lixisenatide) SQ once daily. Uncontrolled on 30 units to 60 units of basal insulin: Start with 30 units (30 units insulin glargine/10 mcg lixisenatide) SQ once daily. Adjust dose by 2 units (2 units insulin glargine/ 0.66 mcg lixisenatide) to 4 units (4 units insulin glargine/1.32 mcg lixisenatide) each week. Maximum daily dose is 60 units insulin glargine/ 20 mcg lixisenatide per day. d Administer within one hour before the first meal of the day. Delayed doses: Give missed dose as soon as able and resume normal dosing schedule. Availability and Storage Requirements Multi-dose pens (3 ml): Insulin glargine (100 units/ml) and lixisenatide (33 mcg/ml). Each pen delivers doses from 15 to 60 units per injection. Needles not supplied with pen. No mixing needed. Keep refrigerated prior to first use. After first use, store at room temperature. Discard 14 days after first use. Rates of Nausea c and Injection Site Reactions Nausea: 10% Injection site reactions: 1.7% (hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, injection-site mass) Use in Renal/Hepatic Impairment Monitor for GI adverse effects and changes in renal function in patients with severe renal impairment. Increase the frequency of glucose monitoring in patients with renal or hepatic impairment. Avg. Shortterm Weight Loss b ~1.4 kg versus insulin glargine 2

6 (Clinical Resource #330104: Page 6 of 8) Drug e Cost/month a A1C reduction b Semaglutide (Ozempic) ~$675 (0.5 mg and 1 mg doses) A1C: f ~1.5% Dosing Start with 0.25 mg SQ once weekly at any time of day with or without meals. Increase to 0.5 mg once weekly after four weeks. May increase to 1 mg once weekly, if needed after at least four weeks. Delayed doses: o If within 5 days of missed dose, give right away. o If >5 days since the dose was missed, skip and give at next scheduled weekly dose. Availability and Storage Requirements Multi-dose pens (1.34 mg/ml, 1.5 ml): Carton with 1 pen intended for 0.25 mg and 0.5 mg doses. Carton with 2 pens intended for 1 mg doses. No mixing needed. Keep refrigerated prior to first use. After first use, can be stored at room temperature. Discard 56 days after first use. Rates of Nausea c and Injection Site Reactions Nausea: 0.5 mg: 15.8% 1 mg: 20.3% (placebo-controlled trials, monotherapy or add-on therapy) Injection site reactions: 0.2% Use in Renal/Hepatic Impairment No dosage changes necessary in patients with renal impairment. Monitor renal function in patients with significant GI adverse effects. Hepatic impairment is not expected to affect blood concentrations. Avg. Shortterm Weight Loss b ~4 kg Because clinical trials are conducted under widely varying conditions, rates of efficacy and adverse effects seen in the clinical trials of a medication cannot be directly compared to those of another medication and may not reflect the rates seen in clinical practice. a. Wholesale average cost of 30-day supply. Medication pricing by Elsevier, accessed January b. A1C reduction and weight loss based on results of FDA-approval clinical trials. A1C reduction and weight loss are average values and will vary among patients. c. Nausea is transient and usually dissipates within the first few weeks of therapy. Incidence of nausea is the rate reported in placebo-controlled trials used for FDA approval, unless otherwise noted. d. GLP-1 agonist and insulin fixed-dose combination products (e.g., Soliqua, Xultophy) have shown comparable rates of hypoglycemia compared to similar doses of basal insulin alone. 2,3 e. Albiglutide (Tanzeum) removed from chart due to discontinuation in late f. Unpublished results from SUSTAIN 7, a head-to-head trial comparing semaglutide and dulaglutide, found semaglutide 1 mg may reduce A1C by as much as 1.8%. Watch for more about this when the data are published in early

7 (Clinical Resource #330104: Page 7 of 8) Information from U.S. prescribing information, unless otherwise noted: Trulicity (March 2015); Bydureon (September 2015); Bydureon BCise (December 2017); Byetta (February 2015); Victoza (April 2016); Xultophy 100/3.6 (November 2016); Adlyxin (July 2016); Soliqua 100/33 (November 2016); Ozempic (December 2017). Users of this resource 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.

8 (Clinical Resource #330104: Page 8 of 8) Project Leader in preparation of this clinical resource (330104): Beth Bryant, Pharm.D., BCPS, Assistant Editor; last modified January 2018 References 1. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010;376: Rosenstock J, Diamant M, Aroda VR, et al. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of lixisenatide and insulin glargine, versus insulin glargine in type 2 diabetes inadequately controlled on metformin monotherapy: the LixiLan proof-of-concept randomized trial. Diabetes Care 2016;39: Buse JB, Vilsboll T, Thurman J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014;37: Wysham CH, Rosenstock J, Vetter ML, et al. Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes. Diabetes Obes Metab 2018;20: Novo Nordisk. Semaglutide superior to dulaglutide on glucose control and weight loss in people with type 2 diabetes. August 16, df. (Accessed January 12, 2018). Cite this document as follows: Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist s Letter/Prescriber s Letter. January Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

9 This Professional Resource gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER August 2016 ~ Resource # Diabetes Medications and Cardiovascular Impact Type 2 diabetes is a known risk factor for cardiovascular disease. 1,2 In addition, the combination of diabetes and cardiovascular disease increases the risk of death. 3 When considering glucose-lowering potential, side effects, cost, and outcomes; metformin remains the optimal first-line oral agent in the management of type 2 diabetes for most patients. 4,5 For a complete listing of available diabetes medications including expected A1C lowering and adverse effects see our charts, Drugs for Type 2 Diabetes (U.S.) and Stepwise Treatment of Type 2 Diabetes (Canada). In 2008, the FDA issued guidance for evaluating cardiovascular risk of medications used to manage type 2 diabetes. 19 Since then, studies are evaluating cardiovascular outcomes associated with diabetes medications. These studies will assist in prioritizing add-on medications choices for diabetes management. The chart below summarizes the existing cardiovascular outcome data for medications used to treat type 2 diabetes. Cardiovascular impact definitions listed in the chart include: Unknown = cardiovascular outcome data is currently unavailable. Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes. Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes. Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes. Abbreviations: ACS = acute coronary syndrome; CV = cardiovascular; DM = diabetes mellitus; MI = myocardial infarction. Medications a Alpha-glucosidase inhibitors Acarbose (e.g., Precose [U.S.], Glucobay [Canada]) Miglitol (e.g., Glyset [U.S.]) Cardiovascular Impact Cardiovascular Outcomes Data Unknown: Acarbose: The ACE (Acarbose Cardiovascular Evaluation) trial (NCT ) Acarbose is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients Miglitol with impaired glucose tolerance and established coronary heart disease or ACS. 18 Amylin analog Pramlintide (SymlinPen [U.S.]) Unknown: Pramlintide Pramlintide: Unable to identify any published or ongoing trials evaluating CV impact. Copyright 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

10 (Professional Resource #320804: Page 2 of 7) Medications a Biguanide Metformin (e.g., Glucophage, Glycon [Canada]) Cardiovascular Impact Cardiovascular Outcomes Data Improves Outcomes: Metformin: A subanalysis of the UKPDS trial found good glycemic control with Metformin metformin with about 10 years of use MAY reduce the risk of CV mortality, especially in obese patients, NNT = 14 [Evidence level A; high-quality RCT]. 21 o Pooled data demonstrate possible reduced CV mortality with a NNT = 56, compared to other DM medications or placebo [Evidence level A; high-quality meta-analysis]. 15 Dipeptidyl peptidase-4 (DPP-4) inhibitors Alogliptin (e.g., Nesina) Linagliptin (e.g., Tradjenta [U.S.]; Trajenta [Canada]) Saxagliptin (e.g., Onglyza) Sitagliptin (e.g., Januvia) Neutral: Alogliptin* Saxagliptin* Sitagliptin Unknown: Linagliptin *based on CV morbidity and mortality outcomes, but note increased risk of heart failure-related admissions. Alogliptin: The EXAMINE trial found alogliptin use in patients with type 2 DM and a history of a recent ACS, did not increase major adverse CV events, compared to placebo [Evidence level A; high-quality RCT]. 10 o Alogliptin is associated with an increased risk of heart failure-related admissions, NNH = 167 [Evidence level A; high-quality RCT]. 10 Saxagliptin: The SAVOR-TIMI 53 found saxagliptin use in patients with type 2 DM at high risk for CV events; neither reduced nor increased the risk of CV death, MI, or ischemic stroke, compared to standard therapy [Evidence level A; highquality RCT]. 11 o Saxagliptin was associated with an increased risk of heart failure-related admissions, NNH = 143 [Evidence level A; high-quality RCT]. 11 Sitagliptin: The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events, hospitalization for heart failure, or other adverse events compared to placebo [Evidence level A; high-quality RCT]. 12 Linagliptin: CAROLINA, CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM (NCT ) is ongoing to evaluate the long-term impact of linagliptin versus glimepiride on CV morbidity and mortality. 14 Glucagon-like peptide-1 (GLP-1) receptor agonists Albiglutide (Discontinued end of 2017) Dulaglutide (e.g., Trulicity) Exenatide (e.g., Byetta, Bydureon, Bydureon BCise [U.S.]) Continued Unknown: Albiglutide Dulaglutide Improves Outcomes: Liraglutide Semaglutide Albiglutide: HARMONY Outcomes (NCT ) is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on major cardiovascular events. 22 Dulaglutide: The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial (NCT ) is ongoing to evaluate if dulaglutide can reduce major CV events in patients with type 2 diabetes. 23 Exenatide: The EXSCEL trial found adding exenatide to conventional therapy in type 2 DM patients with or without CV disease had a neutral effect on CV outcomes. 24 Copyright 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

11 (Professional Resource #320804: Page 3 of 7) Medications a GLP-1 agonists, continued Liraglutide (e.g., Victoza, Saxenda b ) Lixisenatide (pending FDA approval; Lyxumia) Semaglutide (e.g., Ozempic) Insulin Cardiovascular Impact Cardiovascular Outcomes Data Neutral: Liraglutide: The LEADER trial [Evidence level A; high-quality RCT] found Exenatide adding liraglutide to standard care in patients with type 2 DM with CV disease or at Lixisenatide high CV risk over almost four years may reduce: 13 o Death from CV causes, nonfatal MI, or nonfatal stroke, NNT = 53. o Death from CV causes, NNT = 77. Neutral: Glargine o Death from any cause, NNT = 71. o Liraglutide did not reduce the individual rates of MI, nonfatal stroke, or hospitalization for heart failure. Lixisenatide: The ELIXA trial found adding lixisenatide to conventional therapy in type 2 DM patients with a recent ACS had a neutral effect on CV outcomes. 29 Semaglutide: The SUSTAIN-6 trial [Evidence level A; high-quality RCT] found adding semaglutide to conventional therapy in type 2 DM patients with CV disease, chronic kidney disease, or CV risk factors for about two years may reduce the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (NNT=44). 30 However, when evaluated individually, only nonfatal stroke was significant. 30 Glargine: The ORIGIN trial found use of basal insulin glargine for over six years had a neutral effect on CV outcomes [Evidence level A; high-quality RCT]. 6 Meglitinides Nateglinide (e.g., Starlix [U.S.]) Repaglinide (e.g., Prandin [U.S.], GlucoNorm [Canada]) Unknown: Nateglinide Repaglinide Nateglinide: No outcome data for inpatients with type 2 DM. However, the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascular outcomes [Evidence level A; high-quality RCT]. 25 Sodium-glucose cotransporter 2 (SGLT2) inhibitors Canagliflozin (e.g., Invokana) Dapagliflozin (e.g., Farxiga [U.S.], Forxiga [Canada]) Continued Unknown: Dapagliflozin Ertugliflozin Improves Outcomes: Canagliflozin Empagliflozin Canagliflozin: CANVAS (CANagliflozin cardiovascular Assessment Study) [Evidence level A; high-quality RCT] found canagliflozin use for about 3.5 years when added to standard glucose-lowering therapy in patients with type 2 diabetes and very high CV risk (>70% of patients had atherosclerotic CV disease), may reduce the combined endpoint of CV mortality, nonfatal MI, or nonfatal stroke (NNT=333). However, when evaluated individually, these endpoints were no longer significantly reduced. 20 Dapagliflozin: DECLARE-TIMI58 (NCT ) is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI, ischemic stroke, and Copyright 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

12 (Professional Resource #320804: Page 4 of 7) Medications a SGLT2 inhibitors, continued Empagliflozin (e.g., Jardiance) Ertugliflozin (e.g., Steglatro [U.S.]) Cardiovascular Impact Cardiovascular Outcomes Data CV death. 26 Empagliflozin: The EMPA-REG OUTCOME trial [Evidence level A; highquality RCT] found empagliflozin use for about three years, when added to standard glucose-lowering therapy in patients with type 2 DM and underlying CV disease, may reduce: 7 o Hospitalization due to heart failure (NNT = 71). o CV death rates (NNT = 45). o Overall death rates (NNT = 39). o Empagliflozin did not reduce the individual rates of MI or stroke. Ertugliflozin: The VERTIS CV Study (NCT ) is ongoing to evaluate the impact of adding ertugliflozin in patients with existing vascular disease to current DM therapy on cardiovascular death, nonfatal MI, and nonfatal stroke in patients with type 2 diabetes. 31 Sulfonylureas (first generation) Chlorpropamide Tolazamide Tolbutamide Sulfonylureas (second generation) Gliclazide (Canada) Glipizide Glimepiride Glyburide Unknown: Chlorpropamide Tolazamide Worsens Outcomes: Tolbutamide Unknown: Gliclazide Glipizide Glimepiride Glyburide Tolbutamide: use has been associated with increased CV mortality compared to diet alone or diet plus insulin. 16 Glimepiride: CAROLINA, CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM (NCT ) is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality. 14 Thiazolidinediones Pioglitazone (e.g., Actos) Rosiglitazone (e.g., Avandia) Continued Improves Outcomes:* Pioglitazone Neutral:* Rosiglitazone *based on CV morbidity and Pioglitazone: The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or transient ischemic attack may reduce the risk of a future stroke or MI (NNT = 36) [Evidence level A; high-quality RCT]. 8 Pioglitazone: The primary endpoint in the PROactive trial was not improved with pioglitazone. A secondary endpoint found use of pioglitazone for about three years Copyright 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

13 (Professional Resource #320804: Page 5 of 7) Medications a Thiazolidinediones, continued Cardiovascular Impact Cardiovascular Outcomes Data mortality outcomes, but note increased risk of heart failure associated with use. in patients with type 2 DM and macrovascular disease (e.g., MI, stroke, PCI) may reduce the risk of all-cause mortality, non-fatal MI, and stroke (NNT = 50) [Evidence level A; high quality RCT]. 27 o Subgroup analysis found use of pioglitazone for about three years in patients with type 2 diabetes and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A; high quality RCT]. 28 Rosiglitazone: The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality [Evidence level A; high-quality RCT]. 9 Pioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treated with either agent for approximately two years [Evidence level A; high-quality meta-analysis]. 17 a. Many of these are also available as combination products with other medications like metformin or pioglitazone with different brand names. b. Saxenda contains the same active ingredient as Victoza, but at higher doses and is indicated for weight loss, NOT the treatment of diabetes. Users of this resource 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 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

14 (Professional Resource #320804: Page 6 of 7) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Project Leader in preparation of this professional resource (320804): Beth Bryant, Pharm.D., BCPS, Assistant Editor; last modified January References 1. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative metaanalysis of 102 prospective studies. Lancet 2010;375: Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287: Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38: Goldenburg R, Clement M, Hanna A, et al. Pharmacologic management of type 2 diabetes: 2016 interim update. Can J Diabetes 2016;40: ORIGIN trial investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367: Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. New Engl J Med 2016;374: Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in an oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomized, open-label trial. Lancet 2009;373: White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369: 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: Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373: Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016 Jun 13. [Epub ahead of print]. Doi: /NEJMoa ClinicalTrials.gov. CAROLINA: cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. June 21, (Accessed June 29, 2016). 15. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 2008;168: Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. mortality results. Diabetes 1970;19:S Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo analysis. Diabetes Care 2007;30: ClinicalTrials.gov. Acarbose cardiovascular evaluation trial (ACE). March (Accessed June 30, 2016). 19. FDA. Guidance for Industry. Diabetes mellitus evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December Drugs/GuidanceComplianceRegulatoryInformation/G uidances/ucm pdf. (Accessed July 11, 2016). 20. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 June 12. Doi: /NEJMoa [Epub ahead of print]. 21. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: ClinicalTrials.gov. Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes. March Copyright 2016 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com

15 (Professional Resource #320804: Page 7 of 7) =albiglutide+cardiovascular&rank=1. (Accessed July 12, 2016). 23. ClinicalTrials.gov. Researching cardiovascular events with a weekly incretin in diabetes (REWIND). May =dulaglutide+cardiovascular&rank=1. (Accessed July 12, 2016). 24. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377: Holman RR, Haffner SM, McMurray JJ, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362: ClinicalTrials.gov. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). June ?term=dapagliflozin+cardiovascular&rank=1. (Accessed July 12, 2016). 27. Dormandy JA, Charbonnel B, Eckland DJ, et al. 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: Wilcox R, Bousser MG, Betteridge OJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitazone Clinical Trial In macrovascular Events 04). Stroke 2007;38: Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373: Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375: ClinicalTrials.gov. Cardiovascular outcomes following ertugliflozin treatment in type 2 diabetes mellitus participants with vascular disease, The VERTIS CV Study (MK ). April 7, (Accessed January 7, 2018). Cite this document as follows: Professional Resource, Diabetes Medications and Cardiovascular Impact. Pharmacist s Letter/Prescriber s Letter. August Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2016 by Therapeutic Research Center Subscribers to the Letter can get professional resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, or PharmacyTechniciansLetter.com

16 This Clinical Resource gives subscribers additional insight related to the Recommendations published in July 2017 ~ Resource # Drugs for Type 2 Diabetes Glucose control is the mainstay of therapy diabetes management. 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, it may 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. 1,2,21 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. 1,2,21 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. 1,2,21 The choice of second-line and third-line agents varies based on patient characteristics, patient preferences, potential adverse effects (e.g., hypoglycemia, weight gain), and cost. The table below summarizes the agents available in the U.S. for the treatment of type 2 diabetes, including expected A1C reduction when added to metformin, cost, adverse effects, and other pertinent information (e.g., frequency of dosing, cardiovascular benefits). For additional details on cardiovascular benefits associated with drugs for type 2 diabetes, see our chart, Diabetes Medications and Cardiovascular Impact. Abbreviations: BID = two times daily; CVD = cardiovascular disease; egfr = estimated glomerular filtration rate; GI = gastrointestinal; MOA = mechanism of action; TID = three times daily; UTI = urinary tract infection. i Drug or Drug Class Alpha-glucosidase inhibitors Acarbose (Precose, generics) Miglitol (Glyset, generics) Expected A1C drop when added to metformin 23 MOA 0.6% (acarbose) 0.7% (miglitol, when added to sulfonylurea, not metformin) 36 MOA: slows intestinal carbohydrate digestion/absorption 21,24 Maximum daily dose 24 (Cost/30 days) a Acarbose 300 mg, divided TID (~$45) Miglitol 300 mg, divided TID (~$200) Notable Adverse Effects GI (e.g., flatulence, diarrhea) 23 Low risk of hypoglycemia when used as monotherapy 23 Comments Weight neutral as monotherapy 23 Taken with meals 24 Reduces postprandial glucose 21 Requires frequent dosing (e.g., TID) 21 Beneficial in the treatment of prediabetes (acarbose) 9 Ongoing trial to assess potential for CVD benefit in patients with impaired glucose tolerance 22

17 (Clinical Resource #330711: Page 2 of 10) Drug or Drug Class Expected A1C drop when added to metformin 23 Maximum daily dose 24 (Cost/30 days) a Notable Adverse Effects Comments Amylin analog Pramlintide (Symlin) MOA ~0.36% when added to insulin with or without metformin and/or a sulfonylurea 33 MOA: slows gastric emptying, increases the feeling of fullness, and reduces postprandial glucagon secretion 21,24 Pramlintide 120 mcg/dose (usually 360 mcg/day; divided, prior to major meals) (~$2,000) GI (e.g., nausea, vomiting) 21 Hypoglycemia rare, unless insulin dose not reduced 21 Weight loss 21 Increased feeling of fullness after meal 21 Injectable 21 Taken immediately before meals 24 Reduces postprandial glucose 21 Requires frequent dosing 21 Biguanide Metformin (Glucophage, Glucophage XR) Available in combination with alogliptin, canagliflozin, glimepiride, glipizide, glyburide, linagliptin, pioglitazone, rosiglitazone, saxagliptin, sitagliptin, and repaglinide. See specific agents. 1% to 1.5% as monotherapy MOA: inhibits production of glucose, intestinal absorption of glucose, and increases insulin sensitivity in muscle and fat 21,24 Metformin 2,000 to 2,550 mg, divided BID to TID (~$10) Metformin XR 2,000 mg to 2,500 mg, divided BID (~$120) B12 deficiency 23 GI (e.g., diarrhea, nausea, cramping) 21,23 Lactic acidosis (rare) in patients with cardiovascular, renal, or hepatic dysfunction 21,24 Low risk of hypoglycemia when used as monotherapy 23 Weight neutral 21,23 Ameliorates insulin-associated weight gain 23 First-line after diet and exercise for most patients 21 Beneficial in the treatment of prediabetes 10 May reduce cardiovascular mortality, especially in obese patients [Evidence level A, highquality RCT] 23 Safe in patients with stable heart failure and moderate renal impairment: 3,16,25,26 o Can be initiated in patients with an egfr >45 ml/min/1.73m 2 o Discontinue if egfr falls below 30 ml/min/1.73m 2

18 (Clinical Resource #330711: Page 3 of 10) Drug or Drug Class Expected A1C drop when added to metformin 23 Maximum daily dose 24 (Cost/30 days) a Notable Adverse Effects Comments Dipeptidyl peptidase-4 (DPP-4) inhibitor ( gliptins ) or incretin enhancer Alogliptin (Nesina, others, with metformin [Kazano], with pioglitazone [Oseni]), Linagliptin (Tradjenta, with metformin [Jentadueto], with empagliflozin [Glyxambi]) Saxagliptin (Onglyza, with metformin [Kombiglyze XR]) MOA 0.7% MOA: increases insulin secretion in response to elevated blood glucose, decreases glucagon secretion, increases sense of fullness, and slows gastric emptying 21,24 Alogliptin 25 mg (~$195) Linagliptin 5 mg (~$380) Saxagliptin 5 mg (~$385) Sitagliptin 100 mg (~$380) May be associated with pancreatitis 6,21 New or worsening heart failure (saxagliptin and alogliptin)[evidence level A, high-quality RCT] 7,8,13,17,21,23 May cause severe joint pain 12 Low risk of hypoglycemia when used as monotherapy 21,23 Dosage modification with renal impairment needed (sitagliptin, saxagliptin, alogliptin) 24 CYP3A4 interactions (saxagliptin, linagliptin) 24 Reduces postprandial glucose 23 Weight neutral 23 Generally well tolerated 21 Sitagliptin (Januvia, with metformin [Janumet, Janumet XR]) Glucagon-like, peptide-1 (GLP-1) agonist or incretin mimetic Dulaglutide (Trulicity) Exenatide (Byetta) and exenatide extendedrelease (Bydureon, Bydureon BCise) Continued ~1% (See GLP-1 agonist chart for individual agents) MOA: increases insulin secretion in response to elevated blood glucose, decreases glucagon secretion, leading to See our chart, Comparison of GLP-1 Agonists, for dosing and cost info GI (diarrhea, nausea) 21 May be associated with pancreatitis (rare) 6,21 May be associated with gallbladder disease (liraglutide, exenatide) 18,19 Low risk of hypoglycemia when used as monotherapy 21 Weight loss 21 Injectable 21 Linked to thyroid cell cancer in rats 21 Dosage modification with renal dysfunction needed (albiglutide, dulaglutide) Avoid in severe renal impairment (exenatide) Reduces postprandial glucose 21

19 (Clinical Resource #330711: Page 4 of 10) Drug or Drug Class GLP-1 agonists, continued Liraglutide* (Victoza, with insulin degludec [Xultophy]) Lixisenatide (Adlyxin, with insulin glargine [Soliqua]) Semaglutide (Ozempic) Insulin Various Expected A1C drop when added to metformin 23 MOA reduced hepatic glucose production and slowed gastric emptying 21,24 0.9% to 1.1% MOA: promotes storage of glucose in muscle and fat tissues, and inhibits production of glucose 21,24 Maximum daily dose 24 (Cost/30 days) a No maximum dose 23 See our chart, Comparison of Insulins and Injectable Diabetes Meds, for cost info Notable Adverse Effects May lead to retinopathy complications (semaglutide) 41 Hypoglycemia (educate patient to prevent, recognize, and manage) 21 Highest risk of weight gain 21,23 Comments CV benefit: liraglutide use in patients with high CV risk or CV disease for about four years may reduce [Evidence level A; highquality RCT]: 19 o Death from CV causes (NNT = 77) o Death from any cause (NNT = 71) CV benefit: semaglutide use in patients with CV disease, chronic kidney disease, or CV risk factors for about two years may reduce the combined endpoint of CV death, nonfatal MI, or nonfatal stroke (NNT=44) [Evidence level A; highquality RCT]. 40 When evaluated individually, only nonfatal stroke was significant. 40 In patients who need more than one or two diabetes meds, combination therapy with basal insulin and a GLP-1 agonist is an emerging strategy 1 Consider initial therapy within insulin plus metformin if blood glucose is 300 mg/dl and/or A1C is 10% 21

20 (Clinical Resource #330711: Page 5 of 10) Drug or Drug Class Expected A1C drop when added to metformin 23 Maximum daily dose 24 (Cost/30 days) a Notable Adverse Effects Comments Meglitinide Nateglinide (Starlix, generics) Repaglinide (Prandin, others, with metformin [PrandiMet]) MOA 0.7% MOA: stimulates pancreatic insulin secretion 21,24 Nateglinide 360 mg, divided TID (~$120) Repaglinide 16 mg, divided TID (~$75) Hypoglycemia (educate patient to prevent, recognize, and manage) 21 Weight gain 21 Requires frequent dosing 21 Reduces postprandial glucose 21 Provides flexible dosing (e.g., can hold dose if skipping meal) 21,23 Consider over sulfonylureas (less hypoglycemia, better postprandial control) 2 Sodium-glucose cotransporter 2 (SGLT2) inhibitors or flozins Canagliflozin (Invokana, with metformin [Invokamet]) Dapagliflozin (Farxiga) Empagliflozin (Jardiance, with linagliptin [Glyxambi], with metformin [Synjardy]) Ertugliflozin* (Steglatro, with metformin [Segluromet], with sitagliptin [Steglujan]) *expected to be available early 2018 Continued 0.7% to 1% MOA: blocks glucose reabsorption in the kidney, and increases urinary excretion of glucose 21,24 Canagliflozin 300 mg (~$465) Dapagliflozin 10 mg (~$465) Empagliflozin 25 mg (~$465) Ertugliflozin 15 mg (~$270) Genital fungal (yeast) infections (male/female) 2 UTI (may be severe), ketoacidosis (rare) 14 Dizziness, hypotension, hypoglycemia (rare), increased LDL/urination 21 Hyperkalemia, especially in patients with renal impairment 35 Fractures (rare, in susceptible patients) 4 Decrease in BMD (canagliflozin) 11 May be associated with increased risk of bladder cancer (dapagliflozin) 39 Acute kidney injury, may require dialysis (canagliflozin, dapagliflozin) 15 Amputations may occur in about 6 of every 1,000 patients treated with canagliflozin over 1 year, Weight loss 21 Do not use if egfr <45 ml/min/1.73m 2 (canagliflozin, empagliflozin) or <60 ml/min/1.73m 2 (dapagliflozin, ertugliflozin) CV benefit: empagliflozin use in patients with CVD for about three years may reduce [Evidence level A, high-quality RCT]: 20 o Hospitalizations due to heart failure (NNT = 71) o CV death (NNT = 45) o Overall death (NNT = 39) o Empagliflozin use has NOT been shown to reduce individual rates of MI or stroke 20 CV benefit: CANVAS (CANagliflozin cardiovascular Assessment Study)[Evidence level A; high-quality RCT] found canagliflozin use for about 3.5 years when added to standard glucose-lowering therapy in patients with type 2 diabetes and very high CV risk (>70% of patients had

21 (Clinical Resource #330711: Page 6 of 10) Drug or Drug Class Expected A1C drop when added to metformin 23 Maximum daily dose 24 (Cost/30 days) a Notable Adverse Effects Comments SGLT2 inhibitors, continued Sulfonylurea first generation Chlorpropamide (Diabinese, generics) Tolazamide (Tolinase, generics) Tolbutamide (Orinase, generics) MOA 0.8% MOA: stimulates pancreatic insulin secretion 21,24 Chlorpropamide 750 mg 24 (~$230) Tolazamide 1,000 mg (doses >500 mg divide BID) 24 (~$630) Tolbutamide 3,000 mg (given once daily or divided up to TID) 24 (~$215) compared to about 3 in every 1,000 patients on other diabetes meds 27,37 Canagliflozin use in patients at high CV risk for about 3.5 years may increase risk of amputations, NNH ~77 [Evidence level A; highquality RCT] 37,38 Hypoglycemia (educate patient to prevent, recognize, and manage) 21 o More common than with secondgeneration sulfonylureas 5 Weight gain 5 Increased CV mortality (tolbutamide) 29 atherosclerotic CV disease), may reduce the combined endpoint of CV mortality, nonfatal MI, or nonfatal stroke (NNT=333). However, when evaluated individually, these endpoints were no longer significantly reduced. 37 Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started 1 Second-generation sulfonylureas preferred over first-generation sulfonylureas, due to lower risk of hypoglycemia 5 Relatively short-lived efficacy 1 Avoid chlorpropamide in patients with renal dysfunction or the elderly 24 Sulfonylurea-second generation Glyburide (Diabeta, Glynase, Micronase, generics, with metformin [Glucovance]) Continued 0.8% MOA: stimulates pancreatic insulin secretion 21,24 Glimepiride 8 mg (less than $10) Glipizide IR 40 mg (doses >30 mg should be divided BID) (less than $10) Hypoglycemia, especially with renal dysfunction (educate patient to prevent, recognize, and manage) 21 o Less with glimepiride versus glyburide 5 Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started 1 Relatively short-lived efficacy 1 For the elderly and those with hepatic or renal dysfunction, start with low doses and titrate up 21

22 (Clinical Resource #330711: Page 7 of 10) Drug or Drug Class Expected A1C drop when added to metformin 23 Maximum daily dose 24 (Cost/30 days) a Notable Adverse Effects Comments Sulfonylureas, continued Glipizide (Glucotrol, Glucotrol XL, generics, with metformin [Metaglip]) Glimepiride (Amaryl, generics, with metformin [Amaryl M], with pioglitazone [Duetact], with rosiglitazone [Avandaryl]) MOA Glipizide XL 20 mg (less than $10) Glyburide 20 mg (standard; doses >10 mg can divide BID); 12 mg (micronized product; once daily or in divided doses) (~$11) Weight gain o Less with glipizide and glimepiride versus glyburide 5 Thiazolidinedione (TZD) Pioglitazone (Actos, generics, with metformin [Actoplus Met or Actoplus Met XR], with glimepiride [Duetact], with alogliptin [Oseni]) Rosiglitazone (Avandia, with metformin [Avandamet], with glimepiride [Avandaryl]) 0.8% MOA: increases insulin sensitivity in muscle and fat 21,24 Pioglitazone 45 mg (~$14) Rosiglitazone 8 mg (~$325) Low risk of hypoglycemia when used as monotherapy 21 Edema 21 Weight gain 21 Heart failure 21 Increased fracture risk 21 Increased LDL (rosiglitazone) 21 Possible increased risk of bladder cancer (pioglitazone). Assess risk factors and counsel patients to report hematuria. 31,34 Glycemic control better sustained over diabetes course than metformin or sulfonylureas 21 Pioglitazone may improve lipid profile (e.g., lowers triglycerides) 21 Avoid in patients with symptomatic heart failure 21 CV benefit: pioglitazone use for about three years in patients with type 2 diabetes and macrovascular disease may reduce the risk of allcause mortality, nonfatal MI and stroke (NNT = 50)[Evidence level A; high-quality RCT] 30