1. Review of Type 2 Oral Agents: The Old and The New MEDS July 29, 2011 Ellen D. Mandel, DMH, MPA, MS, PA-C, RD, CDE Associate Professor, Seton Hall University Physician Assistant Program Clinical Associate Professor, Pace University Physician Assistant Program Summit Medical Group, Internal Medicine

2. Timeline Quiz 1921 1946 1995 1997 2005 2006 2009 2008

3. Typical A1C Reduction by Treatment Regimen Approved Antidiabetes Medications in the United States MedicationRoute of Administration Year of Introduction or FDA Approval Insulininjection1921 SulfonylureasOral1946 Metformin*Oral1995 AGIOral1995 TZDsOral1997 GlinidesOral1997 GLP-1 agonistsinjection2005 DPP-4 inhibitorsOral2006 ColsevelamOral2008 BromocriptineOral2009 *Metformin has been available in other countries since 1957 but was approved in the United States in 1995. Adapted from Unger J et al. Postgrad Med. 2010;122:145-157.

4. General Considerations What do your patients think about? – Cost – Weight Gain – Hypoglycemia – Needles – Ease of use – Other side effects – Do I still have to watch my diet and exercise if I take this medication?

5. A Few Things Considered Drug~A1c Reduction Cost/30 d Varies Hypoglycemia Risk Weight Change Sulfonylureas~1.5%US $15Small, significant + 1 – 2 kg Metformin1.0 – 1.5%US $36No- 0 – 2 kg TZD1.0 – 1.5%US $254No+ 2 – 4 kg AGI0.5 – 1.0%US $90No- 0 –1 kg DPP-4s0.5 – 0.8%US $220NoNo Change GLP-1s0.4 – 1.5%US $300No- 1 – 3 kg Colesevelam0.5%US $250NoNo Change Adapted from D’Allesio DA and Hirsch IB. glycemic Management of Type 2 DM. Translational Endocrinology & Metabolism. 2011;2(1):75. www.drugstore.comwww.drugstore.com price checker Accessed 20110623

6. General Considerations Medication’s expected glucose-lowering is not simple pharmacokinetics Diabetes is progressive and glycemic control often decreases over time Factors effecting results of use include: – Baseline glycemia – Previous therapies

7. Medication Adherence Direct Method Observe directly, measure concentration in the blood, measure a biological marker Observe Indirectly Patient diaries Measure physiologic response Electronic medication monitors Measure clinical response Refill Rate Pill count Factors effecting use: Individual patient needs Side effects & tolerability Ease of use Costs Non-glycemic benefits

8. Fasting vs Postprandial Glucose Relationship to A1C Contribution (%) A1C Range (%) 0 20 40 60 80 100 Fasting plasma glucose (FPG) Postprandial plasma glucose (PPG) > 10.2 70% 30% 9.3–10.2 60% 40% 8.5–9.2 55 % 45% 7.3–8.4 50% < 7.3 30% 70% Monnier L, et al. Diabetes Care. 2003;26:881-885.

9. Typical A1C Reduction by Treatment Regimen Approved Antidiabetes Medications in the United States Medication Efficacy as Monotherapy, Measured as a Reduction in the Glycated Hemoglobin Concentration (A1C; %) Lifestyle: Weight/Exercise1.0 – 2.0 Insulin  2.5 Sulfonylureas1.0 – 2.0 Metformin*1.5 – 2.0 Alpha Glucosidase Inhibitors0.5–0.8 TZDs0.5–1.4 Glinides0.5–1.5 GLP-1 agonists0.4–1.5 DPP-4 inhibitors0.5–0.8 Colesevelam0.5 – 1.0 Bromocriptine0.6 *Metformin has been available in other countries since 1957 but was approved in the United States in 1995. Adapted from Unger J et al. Postgrad Med. 2010;122:145-157.and Nyenwe et al. Metabolism Clinical Experimental. 2011;60:1-23. http://www.uspharmacist.com/content/s/165/c/28092/

10. Correlation of HbA1c w/Average Blood Glucose HbA1cAverage Blood Glucose 6126 7154 8183 9212 10240 11269 12298 Estimated Blood Glucose from A1c is: (28.7 X A1c) – 46.7

11. 11 Sulfonylureas Meglitinides DPP-4 Inhibitors Liver Metformin TZDs Pancreas Alpha-glucosidase Inhibitors Metformin, GLP-1RA Colesevelam Gut Muscle TZDs  Hyperglycemia Holst JJ, Ørskov C. Diabetes. 2004;53:S197-S204; Lebovitz HE. Diabetes Rev. 1999;7:139-153; Prescribing Information for Actos ® (pioglitazone HCl), Amaryl ® (glimepiride), Avandia ® (rosiglitazone maleate), Glyset ® (miglitol tablets), Glucophage ® (metformin), Januvia ™ (sitagliptin), Prandin ® (repaglinide), Precose ® (acarbose tablets). Target Sites of Action of Oral Antidiabetic Agents (OADs) DPP-4 = dipeptidyl peptidase-4; TZDs – thiazolidinediones, GLP-1RA = glucagon like peptide – Receptor Agonists Adipose Tissue GLP-1RA Bromocriptine

13. A1C 6.5 – 7.5% ** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 2 - 3 Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if  PPG 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C 7.6 – 9.0% Dual Therapy 8 2 - 3 Mos. *** Triple Therapy 9 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1TZD 2 AGI 3 Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

14. A1C 6.5 – 7.5% ** Monotherapy MET+ GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD+GLP-1 or DPP4 1 MET+ Colesevelam AGI 3 2 - 3 Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 INSULIN ± Other Agent(s) 6 Triple Therapy MET † DPP4 1 GLP-1TZD 2 AGI 3 2 - 3 Mos. *** *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if  PPG 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL

15. MET+ GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 A1C 7.6 – 9.0% LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE Dual Therapy 8 MET+ GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 2 - 3 Mos. *** Triple Therapy 9 2 - 3 Mos. *** INSULIN ± Other Agent(s) 6 *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered

16. No Symptoms Drug Naive Under Treatment Symptoms MET+ GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C > 9.0% LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4

18. Tier Zero Monotherapy: Broad Benefits Lifestyle to decrease weight and increase activity Expected decrease in A1c is 1 – 2 % Low cost and self-actualizing No associated nausea, vomiting, diarrhea, hypoglycemia, osteoporosis, URI, UTI, pancreatitis, peripheral edema, CHF, or established long term risks! FDA approved - date too far back to track!

19. ADOPT Trial: Primary Failure Rates Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy Steven E. Kahn, M.B et al.F.R.C.P. for the ADOPT Study Group. N Engl J Med 2006; 355:2427-2443

20. Sulfonylureas Mode of Action: Lowers glycemia by enhancing insulin secretion Work quickly Qd long acting, bid older agents – Generics include glipizide, glyburide, and glimepiride Lower A1c by ~1.5% Weight gain ~2kg is common with initiation Hypoglycemia risks

21. Sulfonylureas Control of glycemic targets diminishes and eventually lost over time based on UKPDS and ADOPT STUDIES Early on concerns over increased CVD mortality with their use – not substantiated with later studies (UKPDS and ADVANCE) Maximal benefit is achieved at ~50% of maximal doses and higher doses may be of limited benefit

22. The Glinides Amino Acid Derivative: Nateglinide (Starlix) Meglitinides: Repaglinide (Prandin) MOA: Stimulate insulin secretion while binding to a different sulfonylurea receptor Shorter ½ life than sulfonylureas – Require more frequent dosing – Generally given ac up to tid – More flexibilty and safer, esp if pt skips meal(s) – Decreases A1C by ~1.5%

23. Biguanides Metformin or Metformin ER – (Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet) Essentially the only biguanide available worldwide MOA – Decreases hepatic glucose (insulin sensitizer at the liver) output and lower fasting glycemia minimal effect on pp BS, improves peripheral glucose uptake and utilization (minimal) Rarely associated with hypoglycemia As monotherapy lowers A1C by ~1.5%

24. Biguanides Interferes with the B 12 – intrinsic factor complex absorption in the terminal ileum Consider checking Vit B 12 level and supplementing 7% had decreases below normal (Package insert) Varying presentations include megaloblastic anemia, peripheral neuropathy, and increase in homocysteine Benefit: Often associated with weight loss or weight neutral as compared to other hypoglycemic meds – Weight losses of ~ 1 -2 lbs you could just mention the amount of weight since it is negligible Bell, D. Metformin-induced vitamin D deficiency presenting as a peripheral neuropathy. Southern Med Journal. March 2010;103(3):pp 265-267. deJagerJ et al. Long term treatment w/metformin in patients with t2D and risk of vitamin B12 deficiency: randomized placebo controlled trial. BMJ May 20, 2010. 340.

25. Biguanides Most common side effects are GI discomfort and diarrhea Generally well tolerated, brand products with extended release appear better tolerated Discontinuation of all metformin products is low – Dose low and titrate up over 2 week increments

26. Biguanide Concerns and Procedures: Hold metformin if receiving contrast CT for 48 hours after procedure and ensuring S. creatinine normal before restart as contrast can cause renal compromise Caution with ETOH abuse - risk for lactic acidosis Temporarily suspend for non-minor surgical procedures until food and fluids resume and renal function evaluated as normal

27. Biguanides Contraindicated: – Renal dysfunction as may increase the rare outcome of lactic acidosis – suggested by S.creatinine of >1.4 in males and >1.3 in females or creat. clearance <60 ml/min, or the ULN for age Elderly: particularly ≥80 years of age, renal function should be monitored regularly

28. Alpha-Glucosidase Inhibitors Acarbose (Precose), Miglitol (Glyset) MOA: Reduce rate of digestion of polysaccharides in the proximal small intestine – Do not induce weight gain or hypoglycemia as most CHO is absorbed distal to the drug’s action Increased CHO delivery results in flatulence and GI side effects – High discontinuation rates due to the side effects

29. Alpha-Glucosidase Inhibitors Primarily lowers post prandial hyperglycemia Reduce A1C by 0.5 – 0.8% Dose with meals – 3 times/day Must treat hypoglycemia with glucose products

30. Effects of TZDs on the 3 primary insulin-responsive tissues. Lee C et al. Endocrinology 2003;144:2201-2207 ©2003 by Endocrine Society

31. Thiazoladinediones (TZD) Pioglitazone (Actos), Rosiglitazone (Avandia) MOA: Increases insulin sensitivity of the muscle, to endogenous and exogenous insulin – improves glucose disposal into skeletal muscle

32. Thiazoladinediones (TZD) Monotherapy A1C results in reduction of 0.5- 1.4% ADOPT (with rosiglitazone) study showed more durability as compared to sulfonylureas and metformin Most common side effect are weight gain and fluid retention, peripheral edema – Increased risk for CHF with NYHA class 3 and 4 or known risk factors Increased adiposity, mostly sub Q and some possible reduction in visceral fat

33. Thiazoladinediones (TZD) Concerns for Rosiglitazone include increased risk for MI, but not consistently shown Exercise caution with TZDs in general due to fluid retention, CHF and – increased incidence of fracture in women and possibly men (ongoing studies underway) – Pioglitazone recently shown to have a small increased incidence of bladder CA – Dosing – depends upon agent – either QD or bid

34. FDA & Rosiglitazone FDA Drug Safety Communication: Avandia (rosiglitazone) issued on 2-03-2011 Cardiovascular risks (including heart attack) added to physician labeling May now only be used in patients already being treated with it or Patients whose blood sugar cannot be controlled with other anti-diabetic medicines and who do not wish to use pioglitazone http://www.fda.gov/Drugs/DrugSafety/ucm241411.htmhttp://www.fda.gov/Drugs/DrugSafety/ucm241411.htm Accessed 20110530

35. Incretin Hormones 2 hormones secreted from the intestines are primarily responsible for the incretin effect, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) Normally secreted into the intestines in response to the ingestion of a meal: Impaired in T2 DM The word incretin is derived from INtestinal seCRETion of INsulin

36. GLP -1 Reduced food intake due to enhanced satiety Insulin secretion enhanced Improved fasting and post-prandial glucose Gastric emptying delayed Decreased hepatic glucose production 32. Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2009;43:1433-1444.

37. Glucagon Like Peptide – 1 Receptor Agonists GLP-1 is naturally occurring peptide made by the L- cells of small intestine with short half-life of 1 to 2 minutes MOA: Potentiates glucose-stimulated insulin secretion and suppresses glucagon in a glucose dependant manner Binds to GLP-1 receptor on pancreatic beta cell and augments glucose mediated insulin secretion Suppresses glucagon secretion Slows gastric motility, regulates gastric emptying rate

38. Glucagon Like Peptide – 1 Receptor Agonists May improve sensitivity of beta cells to glucose At high levels can delay gastric emptying to facilitate insulin’s action Improves beta cell differentiation in animal models Improves satiety from the GI through delayed gastric emptying rate and centrally

39. Glucagon Like Peptide – 1 Receptor Agonists Exenatide (Byetta) FDA approved 2005 as twice/day sub Q injection before meals (Incretin mimetic) Liraglutide (Victoza) FDA approved January 2010 for a once-daily injection not in relation to meals (GLP-1 receptor agonist) Lowers A1c by 0.4 to 1.5% primarily via drop in post-prandial glucose values http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm198638.htmhttp://www.fda.gov/newsevents/newsroom/pressannouncements/ucm198638.htm Accessed 20110530 http://www.uspharmacist.com/content/s/165/c/28092/http://www.uspharmacist.com/content/s/165/c/28092/ Accessed 20110626

40. Glucagon Like Peptide – 1 Receptor Agonists No associated hypoglycemia when used as monotherapy but risk increases with sulfonyureas Nausea, vomiting or diarrhea – abates with time - <8 weeks Increased reports of Pancreatitis with this class

41. Glucagon Like Peptide – 1 Receptor Agonists Liraglutide: FDA - Causes thyroid C-cell tumors in rats and mice exposed to levels of the drug similar to those used clinically – 15 year cancer registry for this class of agents Contraindicated in patients with a personal or family history of medullary thyroid cancer or a personal history of multiple endocrine neoplasia syndrome type 2. – FDA recommended against its first-line use until more evidence is available (http://www.medpagetoday.com/ProductAlert/Prescriptions/27053. Published 20110614. Accessed 20110628http://www.medpagetoday.com/ProductAlert/Prescriptions/27053

42. Dipeptidyl Peptidase – 4 Inhibitors Sitagliptin (Januvia – FDA approval 2006), Saxigliptin (Onglyza), Linagliptin (Tradjenta) MOA: prevents the enzymatic inactivation of endogenous GLP-1, thus allowing enhanced GLP-1 actions that Increase glucose mediated insulin secretion and suppress glucagon secretion DPP-4 inhibitors – found in many tissues including immune cells, enhance the effects of GLP-1 and GIP

43. Dipeptidyl Peptidase – 4 Inhibitors Lower A1c by 0.5 – 0.8% Weight neutral Generally well-tolerated Rare mild hypoglycemia as monotherapy Risk of pancreatitis http://www.januvia.com/sitagliptin/januvia/hcp/januvia/mechanism_of_action/mechanism_of_action.jsphttp://www.januvia.com/sitagliptin/januvia/hcp/januvia/mechanism_of_action/mechanism_of_action.jsp Accessed 20110626

44. Dipeptidyl Peptidase – 4 Inhibitors Concerns: Increased URI/UTI/nasopharyngitis Immune system – DPP enzyme is ubiquitous – Found on surface of endothelial cells and T- lymphocytes and circulates freely Long term effects in general have not been established Dosing – oral medication QD

45. Bile Acid Sequestrant Colesevelam (Welchol) FDA approved January 2008 to improve glycemic control First and only medication that lowers LDL-C and glucose levels MOA unclear – Likely more than “binding” http://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose-adults-type-2- diabetes-810.htmlhttp://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose-adults-type-2- diabetes-810.html Accessed 20110530

46. Bile Acid Sequestrant Reduce A1c by 0.5% when added to metformin, sulfonylurea or insulin Side effects: up to 10% experience constipation, dyspepsia, abdominal pain and nausea Contraindicated with bowel obstruction, TG>500mg/dL or history of hypertriglyceridemia- induced pancreatitis May increase TG when used with sulfonylureas or insulin – Use caution with TG>300mg/dL http://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose- adults-type-2-diabetes-810.htmlhttp://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose- adults-type-2-diabetes-810.html Accessed 20110530

47. Bile Acid Sequestrant May decrease absorption of fat-soluble vitamins A, D, E and K May interfere with absorption of other drugs – Separate vitamin intake >4 hours Dosing: 2 formulations – Tablets QD or bid or – Powder for oral suspension QD or bid http://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose- adults-type-2-diabetes-810.htmlhttp://www.drugs.com/newdrugs/welchol-colesevelam-hcl-receives-fda-approval-reduce-blood-glucose- adults-type-2-diabetes-810.html Accessed 20110530

48. Bromocriptine mesylate Bromocriptine mesylate (Cycloset) FDA approved May, 2009 Dopamine receptor agonist is indicated as an adjunct to diet and exercise to improve glycemic control in adults with diabetes Not a new drug —used in different formulations to treat conditions such as Parkinson’s disease and prolactin secreting pituitary tumors

49. Bromocriptine mesylate MOA: manages blood glucose via brain signals and targets the central nervous system Researched as hibernating animals become more insulin resistant during certain times of the year – Exact mechanism is unknown: “resets” biological clock affecting circadian rhythms in the hypothalamus – A1C reduction of ~0.7% when added to metformin and sulfonylurea

50. Bromocriptine mesylate Most common adverse events were nausea, fatigue, dizziness, vomiting and headache Minimal hypoglycemia and not associated with increased cardiovascular risk Contraindicated with ergot medicines and syncopal migraines as may cause hypotension, and breast feeding Weight neutral Once daily dosing within 2 hours after awakening in the morning with dose titration

51. *The abbreviations used here correspond to those used on the algorithm (Fig. 1). **The term ‘glinide’ includes both repaglinide and nateglinide. Benefits are classified according to major effects on fasting glucose, postprandial glucose, and nonalcoholic fatty liver disease (NAFLD). Eight broad categories of risks are summarized. The intensity of the background shading of the cells reflects relative importance of the benefit or risk.* Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

52. Anti-Diabetes Agents ClassGeneric (Brand) Name BiguanideMetformin (Glucophage) (Glumetza) (Fortamet) ThiazolidinedionePioglitazone (Actos); Rosiglitazone (Avandia) SulfonylureaGlimepiride (Amaryl); Glipizide (Glucotrol); Glyburide (Dia  eta, Glynase, Micronase); GlinideNateglinide (Starlix); Repaglinide (Prandin) Dipeptidyl Peptidase-4 InhibitorSitagliptin (Januvia); Saxagliptin (Onglyza); Linagliptin (Tradjenta); Vildagliptin (Galvus – Europe)  -Glucosidase Inhibitor Acarbose (Precose); Miglitol (Glyset) Glucagon-like Peptide-1 AgonistExenatide (Byetta); Liraglutide (Victoza) Bile Acid SequestrantsColesevelam (Welchol) Dopamine AgonistBromocriptine (Cycloset)

53. Generics and Brands for Combination Anti-Diabetes Agents ClassGeneric (Brand) Name Biguanide & DPP4 InhibitorSaxagliptin/metformin (Kombiglyze XR) Sitagliptin/metformin (Janumet) Biguanide & MeglitinideRepaglinide/metformin (Prandimet) Biguanide & SulfonylureaGlipizide/metformin (Metaglip) Glyburide/metformin (Glucovance); Biguanide & TZDPioglitazone/metformin (ACTOplus met, ACTOplus met RX) Rosiglitazone/metformin (Avandamet) Sulfonylurea & TZDPioglitazone/glimepiride (Duotact) Rosiglitazone/glimepiride (Avandaryl)

54. Thank you for your kind attention!