The Role of Oral Antidiabetic Therapy 4/14/2017 3:46 PM The Role of Oral Antidiabetic Therapy Jane Weinreb, MD Chief, Diabetes Program VA Greater Los Angeles Healthcare System Clinical Professor of Medicine David Geffen School of Medicine at UCLA

Objectives 4/14/2017 3:46 PM To review major pathophysiologic defects in Type 2 Diabetes and targeted sites for medications To review available classes as well as specific oral antidiabetic medications: mechanism of action, efficacy, adverse effects Discuss role of combination therapy Discuss AACE Diabetes Roadmap and case presentation

Defective insulin secretion Overview of Glucose Regulation Alpha glucosidase inhibitors Glucose Defective insulin secretion Sulfonylureas Meglitinides b-cell insulin secretion Persistent Hepatic Glucose Output In nondiabetic individuals, glucose is absorbed from the gut and stimulates beta cell insulin secretion. Insulin then acts on its three main target tissues: the liver, where it blunts hepatic glucose output; the muscle, where it stimulates glucose disposal; and the adipocyte, where it diminishes lipolysis and enhances lipogenesis. There are three main defects in diabetes, and these include diminished insulin secretion; resistance to insulin action in insulin responsive tissues, and persistent elevation of glucagon with resultant persistent hepatic glucose output Insulin action DPP-IV Inhibitors Thiazolidinediones Resistance to insulin action Metformin Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. 3

Overview of Available Agents 4/14/2017 3:46 PM Overview of Available Agents Biguanides Metformin Secretagogues Sulfonylureas: Glipizide, Glyburide, Glimepiride Glinides: Nateglinide, Repaglinide Thiazolidinediones Pioglitazone, Rosiglitazone Alpha Glucosidase Inhibitors Acarbose, Miglitol Dipeptidyl-Peptidase 4 Inhibitors Sitagliptin Bile Acid Sequestrant Colesevalam AACE Diabetes Melllitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

Biguanide Agent in Class: Metformin 4/14/2017 3:46 PM Agent in Class: Metformin Mechanism of action: poorly understood, but its primary effect is to reduce hepatic glucose production in the presence of insulin Efficacy: lowers A1C by 1 to 2%, maximum effective dose is 2 grams/d Major advantages: Lack of weight gain or modest weight loss Absence of or infrequent hypoglycemia AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11 2008

4/14/2017 3:46 PM Biguanide Adverse effects mainly GI: abdominal pain, bloating, nausea, and diarrhea (minimize by slow titration) Contraindication: renal dysfunction, Cr >1.5 mg/dL in men and Cr > 1.4 mg/dL in women Avoid in patients with hepatic dysfunction, CHF, metabolic acidosis, dehydration, and alcoholism Available combinations with sulfonylureas, thiazolidinediones, repaglinide, and sitagliptin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Secretagogues: Sulfonylureas 4/14/2017 3:46 PM Agents in Class: Glipizide, Glyburide, and Glimepiride Mechanism of action: increase insulin secretion from pancreatic beta cells Efficacy: lower A1C by 1-2%; glucose-lowering effect usually plateaus at one half of the maximum recommended dose Nonglycemic effects: weight gain is common Major Advantages: Long track record of safety Low price of generic preps AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Secretagogues: Sulfonylureas 4/14/2017 3:46 PM Adverse effect: mainly hypoglycemia, which can be prolonged and more frequent in elderly or with impaired renal function (glipizide and glimepiride may be preferred in elderly patient) Avoid in hepatic and renal impairment Available combinations with metformin, both thiazolidinediones, and acarbose AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Secretagogues: Glinides 4/14/2017 3:46 PM Agents in Class: Nateglinide, Repaglinide Mechanism of action: stimulate a rapid but short-lived release of insulin that lasts for 1-2 hours, therefore should be used to target postprandial glucose levels Efficacy: similar to SU’s for repaglinide; nateglinide is less efficacious in A1C lowering (0.5-0.8%) Nonglycemic effect: weight gain similar to SU AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Secretagogues: Glinides 4/14/2017 3:46 PM Adverse effect: Much less hypoglycemia than SU Many drug-drug interactions. Most concerning is gemfibrozil which increases repaglinide concentration and may result in prolonged lows. Used with caution in patients with hepatic impairment Nateglinide is renally cleared, whereas this is minimal for repaglinide latter can be used with renal impairment Available combination: repaglinide with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Thiazolidinediones Agents in class: Pioglitazone, Rosiglitazone 4/14/2017 3:46 PM Agents in class: Pioglitazone, Rosiglitazone Mechanism of action: Enhancing peripheral insulin sensitivity, especially at the muscle and adipose tissue, via activation of PPAR (peroxisome proliferator-activated receptor gamma). Efficacy: lower A1C 0.8 to 1.5% (decrease in glucose may not be apparent for 4 weeks and maximum efficacy of dose may not be observed for 4-6 months) Nonglycemic effects: weight gain - modestly reduce blood pressure enhances fibrinolysis - improve endothelial dysfunction AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Thiazolidinediones Major advantages: 4/14/2017 3:46 PM Thiazolidinediones Major advantages: absence of hypoglycemia when used as monotherapy no reliance on renal excretion. Adverse effects: weight gain, edema, anemia, and peripheral fractures in women Contraindications: should not be used in patients with CHF (New York Heart Association class III or IV cardiac disease and functional capacity) or hepatic impairment with ALT > 2.5 times the upper normal limits Available combinations with metformin and sulfonylurea AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Alpha-Glucosidase Inhibitors 4/14/2017 3:46 PM Alpha-Glucosidase Inhibitors Agents in Class: Acarbose, Miglitol Mechanisms of action: decrease the rate of digestion for polysaccharides in the proximal small intestine, primarily lowering postprandial glucose levels Efficacy: lower A1C by 0.5 to 1.0% Adverse effects: flatulence, diarrhea, and abdominal discomfort (minimize by slow titration). Available combination with sulfonylurea AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Dipeptidyl-Peptidase 4 Inhibitors 4/14/2017 3:46 PM Agent in Class: Sitagliptin, Saxagliptin Mechanism of action: slows the inactivation of incretin hormones (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) Increases glucose-stimulated insulin secretion Causes glucose-stimulated glucagon suppression primarily lowers postprandial glucose levels but has also been shown to reduce fasting plasma glucose AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

Inhibition of DPP-IV Increases Active Portal GLP-1 and GIP DPP-IV inhibitors exhibit both short term and long term actions of GLP-1 Augment glucose induced insulin secretion Inhibit glucagon secretion Slow gastric emptying Increase insulin biosynthesis Promote beta cell differentiation T ½=1-2mins

Dipeptidyl-Peptidase 4 Inhibitors 4/14/2017 3:46 PM Dipeptidyl-Peptidase 4 Inhibitors Efficacy: Lower HbA1C by 0.8% Nonglycemic effect: weight neutral Adverse effects: well tolerated, no hypoglycemia when used as monotherapy. More recently reported to be associated with pancreatitis, ?causative? Available combination with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

Bile Acid Sequestrant Agent in Class: Colesevalam 4/14/2017 3:46 PM Bile Acid Sequestrant Agent in Class: Colesevalam Mechanism of action uncertain Efficacy: Lowers the A1C 0.5-8% when added to metformin, sulfonylurea or insulin Not studied as monotherapy or in combination with incretins or TZD’s Significant LDL-C reductions of 12.3-16.1% vs. placebo Bays HE, et al. Arch Intern Med. In press. Fonseca VA, et al. Diabetes Care. 2008; 31: 1479-1484. Goldberg RB, et al. Arch Intern Med. 2008; 168: 1531-1540.

4/14/2017 3:46 PM Colesevelam Take with meals and liquid either 6 tablets once daily or 3 tablets twice daily No special considerations or dosage adjustments with hepatic impairment or renal disease Contraindications: History of bowel obstruction Serum triglycerides >500 mg/dL History of hypertriglyceridemia-induced pancreatitis Welchol® (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January 2008. 18

Colesevelam: Drug Interactions 4/14/2017 3:46 PM Colesevelam: Drug Interactions Drugs with a known interaction with colesevelam- administer 4 hours prior to colesevalam Glyburide, levothyroxine, and oral contraceptives containing ethinyl estradiol and norethindrone Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with colesevelam Phenytoin- Should be administered 4 hrs before colesevalam Warfarin- No noted problem with colesevalam coadministration, but study did not eval INR Drugs that do not interact with colesevelam based on in vitro or in vivo testing Cephalexin, ciprofloxacin, digoxin, warfarin, fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil Key Message: In tests determining in vitro binding or in vivo drug interaction studies or through postmarketing experience, Welchol has been shown to interact with certain drugs. Supporting/Background Information The following drugs are known to interact with Welchol and therefore should be administered at least 4 hours before taking Welchol: glyburide, levothyroxine, and oral contraceptives containing ethinyl estradiol and norethindrone. The following drugs have shown interaction in postmarketing reports: phenytoin and warfarin. It is suggested that phenytoin be administered at least 4 hours prior to Welchol. An in vitro study showed that there was no significant change in warfarin concentrations when Welchol was coadministered. However, the study did not evaluate warfarin pharmacodynamics. In postmarketing reports, concomitant use of Welchol and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, INR should be monitored before initiating Welchol and frequently enough during early Welchol therapy to ensure that no significant alteration in INR occurs. Once INR is stable, continue to monitor INR at intervals usually recommended for patients on warfarin. The following drugs do not interact with Welchol based on premarket testing: cephalexin, ciprofloxacin, digoxin, warfarin, fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, and verapamil. Orally administered drugs that have not been tested for interaction with Welchol, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to the administration of Welchol. Alternatively, the physician should monitor drug levels of the coadministered drug. Reference Welchol™ (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January 2008. 19

Colesevelam in Type 2 DM: Adverse Reactions* 4/14/2017 3:46 PM Colesevelam in Type 2 DM: Adverse Reactions* Event Description Number of Patients (%) Colesevalam N = 566 Placebo N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea Hypertension 16 (2.8) 9 (1.6) Key Message: In clinical trials of patients with type 2 diabetes, the most common adverse reactions associated with Welchol included constipation, nasopharyngitis, and dyspepsia. Hypoglycemia was reported in 3% of patients receiving Welchol compared with 2.3% of patients receiving placebo. Supporting/Background Information The safety of Welchol was evaluated in patients with type 2 diabetes in 4 double-blind, 12-26 week, placebo-controlled trials. The trials included 566 and 562 patients in the Welchol and placebo arms, respectively. All patients had inadequate glycemic control on a metformin-, sulfonylurea-, or insulin-based therapy. Upon completion of the 4 trials, 492 patients entered a 52-week open-label uncontrolled extension where all patients received Welchol (3.8 g/day) and continued with their preexisting anti-diabetic therapy. The chart reports adverse reactions that were reported in ≥2% of patients and were more common than in patients receiving placebo. The adverse reactions were also reported regardless of causality as assessed by each investigator. The most common adverse reactions were constipation, nasopharyngitis, and dyspepsia. A total of 6.7% and 3.2% of patients discontinued treatment because of adverse reactions in the Welchol and placebo treatment groups, respectively. Discontinuation of treatment was mostly associated with gastrointestinal reactions. None of the patients treated with Welchol developed severe hypoglycemia. Reference Welchol™ (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January 2008. *Placebo-Controlled Clinical Studies of Colesevelam Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality. Colesevelam HCl prescribing information, January 2008. 20

4/14/2017 3:46 PM Considerations in the Management of Type 2 Diabetes Monotherapy vs. Combination Therapy Considerations in the Management of Type 2 Diabetes

Traditional Monotherapies Do Not Maintain A1C Control Over Time 4/14/2017 3:46 PM United Kingdom Prospective Diabetes Study (UKPDS) 10 9 8 Median A1C (%) 7 Conventional* ADA Goal Insulin Glibenclamide (glyburide) 6 Metformin 3 6 9 12 15 Time From Randomization (Years) *Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dL, then patients were re-randomized to receive non-intensive metformin, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, then those on SU would have metformin added. If FPG exceeded 270 mg/dL after this, then insulin was substituted. Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.

Two Year Efficacy of Pioglitazone: 4/14/2017 3:46 PM Two Year Efficacy of Pioglitazone: Time Course of A1C Pioglitazone Type 2 diabetes is a progressive disease. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that an improvement in glycemic control (decrease in A1C) during the first year was followed by progressive deterioration (increase in A1C). Long-term efficacy in the treatment of type 2 diabetes is demonstrated when there is a sustained improvement in glycemic control. Failure to maintain adequate glycemic control can be measured by A1C at the time of the visit at which a level greater than or equal to a failure threshold was recorded. A 2-year efficacy study of ACTOS demonstrated sustained glycemic control. During this study, failure to maintain glycemic control was defined as inability to maintain an A1C level <9% on two consecutive visits during the parent study. During the extension study, failure to maintain glycemic control was defined as the inability to maintain an A1C level <8% on any visit after the first. Mean A1C at baseline was 8.62% for ACTOS. A1C showed a mean reduction of 1.42% and 1.29% for ACTOS at Week 52 and Week 104, respectively. Takeda Pharmaceuticals North America, Inc. Data on file. Tan MH, et al. Diabetes Care. 2005;28:544-550.

4/14/2017 3:46 PM ADOPT: A Diabetes Outcome Progression Trial Rosiglitazone Sustained A1C Over Time* 8.0 Treatment Difference at 4 Years RSG vs MET –0.13 (–0.22 to –0.05), P=.002 RSG vs GLYB –0.42 (–0.50 to –0.33), P<.001 1 2 3 4 5 Time (years) HbA1C (%) 6.0 7.0 6.5 7.5 RSG GLYB MET Number of patients: 4012 3308 2991 2583 2197 822 * Mean A1C values per visit are based on a repeated measures mixed model. Kahn SE et al. N Engl J Med. 2006;355:2427-2443.

Why Combination Therapy Make Sense Treat to Fail vs. Treat to succeed 4/14/2017 3:46 PM Why Combination Therapy Make Sense Treat to Fail vs. Treat to succeed

Major Targeted Sites of Oral Drug Classes 4/14/2017 3:46 PM Major Targeted Sites of Oral Drug Classes Pancreas Beta-cell dysfunction Sulfonylureas Muscle and fat Glinides Liver DPP-4 inhibitors ↓Glucose level Hepatic glucose overproduction Insulin resistance Major Targeted Sites of Various Oral Drug Classes Speaker Notes The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycemia.1,2 Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1 Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells. They are used to control postprandial hyperglycemia.1 TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2 Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1 Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1,3,4 Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product. The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and help regulate insulin production and secretion.5 This glucose-dependent mechanism targets 2 key defects: insulin release and hepatic glucose production. Purpose: To provide a broad overview of the key mechanisms and targeted sites of available antihyperglycemic classes and to introduce the concept that DPP-4 inhibitors have an effect on both the pancreas and the liver. Takeaway: Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve A1C control. The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. Biguanides Gut TZDs TZDs Biguanides Alpha-glucosidase inhibitors DPP-4 inhibitors Glucose absorption Biguanides DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. References: 1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004. 3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. 4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004. 5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.

Rosiglitazone/Metformin Combination: Additive Glycemic Control vs Metformin Alone 4/14/2017 3:46 PM Placebo + Met RSG 4 mg QD + Met RSG 8 mg QD + Met 1.0 0.5 0.0 Mean Change in HbA1c (%) -0.5 -1.0 -1.5 -1.0* -1.2* -2.0 Compared to Baseline Treatment Effect *P<0.0001 vs. metformin

Pioglitazone Added to Metformin 4/14/2017 3:46 PM Pioglitazone Added to Metformin HbA1c 1 0.5 * * * -0.5 - 0.8% points P£0.05 vs Metformin + placebo Change From Baseline (% points) * * -1 * * -1.5 -2 ACTOS 30 mg added to a stable dose of metformin (slightly greater than 2,000 mg/day mean dose) demonstrated a difference in HbA1c of -0.8 percentage points compared with metformin plus placebo. Studies are under way to evaluate the effect of the 45-mg once-daily dose in a similarly designed trial. Takeda Pharmaceuticals America, Inc. Data on file, Study 027. -2.5 -6 8 12 16 Weeks LOCF Met + Placebo Met + pio 30 mg * P£0.05 vs baseline .

4/14/2017 3:46 PM Sitagliptin A1C Reductions From Baseline When Added to Metformin or Pioglitazone 24-week change from baseline Add-on to metformin study1 Add-on to pioglitazone study2 Mean Baseline A1C: 8.0% Mean Baseline A1C: 8.0%, 8.1% Metformin + Placebo Metformin sitagliptin Pioglitazone + Placebo Pioglitazone + sitagliptin n=224 n=453 n=174 n=163 –0.2 –0.0% –0.2 –0.2% JANUVIA™ (sitagliptin): Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone Speaker Notes In patients with type 2 diabetes inadequately controlled with metformin or pioglitazone, adding JANUVIA significantly reduced A1C compared with placebo.1,2 In the add-on to metformin study, the average baseline A1C for all patients was 8.0%. At Week 24, patients receiving metformin plus JANUVIA achieved significant (P<0.001) mean placebo-subtracted A1C reductions (–0.7%) compared with those receiving metformin plus placebo.1 In the add-on to pioglitazone study, the average baseline A1C was 8.1% for patients randomized to JANUVIA and 8.0% for patients randomized to placebo. At Week 24, patients receiving pioglitazone plus JANUVIA achieved significant (P<0.001) mean placebo-subtracted A1C reductions (–0.7%) compared with those receiving pioglitazone plus placebo.2 These data represent mean changes. Treatment with JANUVIA may result in higher or lower changes in A1C in some patients. –0.4 –0.4 Purpose: To demonstrate the A1C reductions at 24 weeks in the add-on to metformin and add-on to pioglitazone studies. Takeaway: JANUVIA provided significant improvements in A1C when added to treatment for patients inadequately controlled on metformin or pioglitazone. Mean Change in A1C From Baseline, % Mean Change in A1C From Baseline, % P<0.001* –0.6 –0.6 –0.7% –0.8 P<0.001* –0.8 0.7% placebo- subtracted result –0.9% –1.0 –1.0 0.7% placebo- subtracted result *Compared with placebo. 1. Charbonnel B et al. Diabetes Care. 2006;29:2638–2643. 2. Rosenstock J et al. Clin Ther. 2006;28:1556–1568. References: 1. Charbonnel B, Karasick A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–2643. 2. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–1568.

RSG/Met Reductions in A1C in Drug-Naïve Patients 4/14/2017 3:46 PM RSG/Met Reductions in A1C in Drug-Naïve Patients D -0.4 P<.001* D -0.6 P<.0001* Mean change from baseline in A1C (%) at Week 32 –1.6% –1.8% –2.3% RSG/Met RSG MET Baseline A1C (%) 8.9 8.8 8.8 n= 152 155 150 Mean final dose 7.2 mg/1799 mg 7.7 mg 1847 mg . Rosenstock J et al. Diabetes Obes Metab. 2006;8:650–660.

AACE Diabetes Roadmap Guide to therapy base on A1C level 4/14/2017 3:46 PM AACE Diabetes Roadmap Guide to therapy base on A1C level Initiation as well as maintaining therapy AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) If ≤ 6.5% A1C Goal Not Achieved Initial A1C% Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C ) Continuous Titration of Rx ( 2 - 3 months ) Intervention 6 - 7 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Initial Therapy Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic*1 Alternatives Glinides SU (low dose) Prandial insulin5,8 Preferred: Metformin4 TZD10,11,12 AGI DPP-4 Inhibitor Modification Lifestyle Assess FPG and PPG If ≤ 6.5% A1C Goal Not Achieved 7 - 8 Target: PPG and FPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies 6,7 Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin Alternatives Prandial insulin5,8 Premixed insulin preparations5 Basal insulin analog9 Metformin Glinides AGI TZD12 SU DPP-4 Inhibitor + met Colesevelam + met, SU or insulin Modification Lifestyle * Available as exenatide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 4 Preferred first agent in most patients 5 Analog preparations preferred 6 Appropriate for most patients 7 2 or more agents may be required 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

8 - 9 9 - 10 Target: FPG and PPG Target: FPG and PPG 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Initial A1C% Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C ) If ≤ 6.5% A1C Goal Not Achieved Continuous Titration of Rx ( 2 - 3 months ) Intervention 8 - 9 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including prandial insulin5,8, incretin mimetic1, or amylin analog** (with prandial insulin5,8) Combine Therapies to Address FPG and PPG7 Prandial insulin5,8 Premixed insulin preparations5 NPH Other approved combinations Metformin TZD10,11,12 SU Glinides DPP-4 Inhibitor Basal insulin analog9 Modification Lifestyle Target: FPG and PPG If ≤ 6.5% A1C Goal Not Achieved 9 - 10 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Target: FPG and PPG Combine Therapies to Address FPG and PPG7 Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic1 Modification Lifestyle Prandial insulin5,8 Premixed insulin preparations5 NPH Other approved combinations Metformin TZD12 SU Glinides Basal insulin analog9 ** Available as pramlintide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 5 Analog preparations preferred 7 2 or more agents may be required 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) If ≤ 6.5% A1C Goal Not Achieved Initial A1C% Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C ) Continuous Titration of Rx ( 2 - 3 months ) Intervention > 10 Basal insulin analog9 or NPH + prandial insulin5,8 Premixed insulin preparations5 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Modification Lifestyle Insulin Therapy2,3 †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG 2 For selected patients presenting with an A1C of >10%, certain oral agent combinations may be effective 3 Insulin sensitizer (metformin preferred) may be combined with initial insulin therapy 5 Analog preparations preferred 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) Current A1C% Continuous Titration of Rx (2-3 months) Current Therapy Intervention Intensify Lifestyle Modification Initiate Combination Therapy 6.5 to 8.5 Incretin mimetic + metformin and/or TZD Basal3 or premixed insulin preparations1 Amylin analog** with prandial insulin2 Metformin + SU or Glinide Metformin + TZD4,5 or AGI TZD + SU DPP-4 + Metformin ± SU DPP-4 + TZD Colesevelam + met, SU or insulin Incretin mimetic* + metformin and/or SU Other approved combinations including approved oral agents with insulin6 Monotherapy : Glinides, SU, AGI, metformin, TZD, DPP-4, premixed insulin preparations1, prandial2 or basal insulin3 Monitor / adjust Rx to maintain ACE Glycemic Goals† Continue Lifestyle Modification Continuous Titration of Rx (2-3 months) Intensify Lifestyle Modification Maximize Combination Therapy Maximize Insulin Therapy Combination Therapy: Glinides, SU, DPP-4, AGI, metformin, TZD, colesevelam, incretin mimetic*, premixed insulin preparations1, prandial2 or basal insulin3 If elevated FPG, add or increase basal insulin3 If elevated PPG, add or increase prandial insulin2 If elevated FPG and PPG, add or intensify basal3 + prandial2 or premixed insulin therapy1 Combine with approved oral agents6 Amylin analog** with prandial insulin2 Add incretin mimetic to patients on SU, TZD, and/or metformin Monitor / adjust Rx to maintain ACE Glycemic Goals† * Available as exenatide ** Available as pramlintide 1 Analog preparations preferred 2 Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3 Available as glargine and detemir 4 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) Continuous Titration of Rx (2-3 months) Current A1C% Current Therapy Intervention >8.5 Intensify Lifestyle Modification Initiate Insulin Therapy (Basal-Bolus) Basal3 + prandial insulin2 Premixed insulin preparations1 Combine with approved oral agents4 Monitor / adjust Rx to maintain ACE Glycemic Goals† Monotherapy or Combination Therapy Continue Lifestyle Modification †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG 1 Analog preparations preferred 2 Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia Available as glargine and detemir According to the FDA, rosiglitazone not recommended with insulin ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

? Case Study: Mona Treatment option(s): Female, 60 years old, obese 4/14/2017 3:46 PM Case Study: Mona Female, 60 years old, obese Serum creatinine: 1.4 mg/dL A1C: 6.9% Treatment-naive for diabetes Antihypertensive therapy History of inflammatory bowel disease Recent myocardial infarction Case Study: Mona (cont) What treatment options would you consider? ? Treatment option(s):

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) If ≤ 6.5% A1C Goal Not Achieved Initial A1C% Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C ) Continuous Titration of Rx ( 2 - 3 months ) Intervention 6 - 7 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Initial Therapy Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic*1 Alternatives Glinides SU (low dose) Prandial insulin5,8 Preferred: Metformin4 TZD10,11,12 AGI DPP-4 Inhibitor Modification Lifestyle Assess FPG and PPG If ≤ 6.5% A1C Goal Not Achieved 7 - 8 Target: PPG and FPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies 6,7 Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin Alternatives Prandial insulin5,8 Premixed insulin preparations5 Basal insulin analog9 Metformin Glinides AGI TZD12 SU DPP-4 Inhibitor + met Colesevelam + met, SU or insulin Modification Lifestyle * Available as exenatide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 4 Preferred first agent in most patients 5 Analog preparations preferred 6 Appropriate for most patients 7 2 or more agents may be required 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

? Case Study: Nancy Treatment option(s): Female, 55 years old, obese 4/14/2017 3:46 PM Case Study: Nancy Female, 55 years old, obese Serum creatinine: 1.0 mg/dL A1C: 8.5% Treatment-naive for diabetes Antihypertensive therapy Case Study: Nancy (cont) What treatment options would you consider? ? Treatment option(s):

8 - 9 9 - 10 Target: FPG and PPG Target: FPG and PPG Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Initial A1C% Achieve ACE Glycemic Goals† ( FPG, PPG, and A1C ) If ≤ 6.5% A1C Goal Not Achieved Continuous Titration of Rx ( 2 - 3 months ) Intervention 8 - 9 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including prandial insulin5,8, incretin mimetic1, or amylin analog** (with prandial insulin5,8) Combine Therapies to Address FPG and PPG7 Prandial insulin5,8 Premixed insulin preparations5 NPH Other approved combinations Metformin TZD10,11,12 SU Glinides DPP-4 Inhibitor Basal insulin analog9 Modification Lifestyle Target: FPG and PPG If ≤ 6.5% A1C Goal Not Achieved 9 - 10 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Target: FPG and PPG Combine Therapies to Address FPG and PPG7 Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic1 Modification Lifestyle Prandial insulin5,8 Premixed insulin preparations5 NPH Other approved combinations Metformin TZD12 SU Glinides Basal insulin analog9 ** Available as pramlintide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 5 Analog preparations preferred 7 2 or more agents may be required 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

? Case Study: Archie Treatment option(s): Male, 54 years old, obese 4/14/2017 3:46 PM Case Study: Archie Male, 54 years old, obese Serum creatinine: 0.9 mg/dL A1C: 8.4% Has been receiving metformin 1,000 mg twice a day for past 6 months Case Study: Archie (cont) What treatment options would you consider? ? Treatment option(s):

Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 4/14/2017 3:46 PM Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) Current A1C% Continuous Titration of Rx (2-3 months) Current Therapy Intervention Intensify Lifestyle Modification Initiate Combination Therapy 6.5 to 8.5 Incretin mimetic + metformin and/or TZD Basal3 or premixed insulin preparations1 Amylin analog** with prandial insulin2 Metformin + SU or Glinide Metformin + TZD4,5 or AGI TZD + SU DPP-4 + Metformin ± SU DPP-4 + TZD Colesevelam + met, SU or insulin Incretin mimetic* + metformin and/or SU Other approved combinations including approved oral agents with insulin6 Monotherapy : Glinides, SU, AGI, metformin, TZD, DPP-4, premixed insulin preparations1, prandial2 or basal insulin3 Monitor / adjust Rx to maintain ACE Glycemic Goals† Continue Lifestyle Modification Continuous Titration of Rx (2-3 months) Intensify Lifestyle Modification Maximize Combination Therapy Maximize Insulin Therapy Combination Therapy: Glinides, SU, DPP-4, AGI, metformin, TZD, colesevelam, incretin mimetic*, premixed insulin preparations1, prandial2 or basal insulin3 If elevated FPG, add or increase basal insulin3 If elevated PPG, add or increase prandial insulin2 If elevated FPG and PPG, add or intensify basal3 + prandial2 or premixed insulin therapy1 Combine with approved oral agents6 Amylin analog** with prandial insulin2 Add incretin mimetic to patients on SU, TZD, and/or metformin Monitor / adjust Rx to maintain ACE Glycemic Goals† * Available as exenatide ** Available as pramlintide 1 Analog preparations preferred 2 Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3 Available as glargine and detemir 4 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” Cannot be used in NYHA CHF Class 3 or 4 According to the FDA, rosiglitazone not recommended with insulin †ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Revision April 2008 © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Endocr Pract. 2007;13:260-268

Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous Use of insulin sensitizers such as metformin and /or thiazolidinediones as part of the therapeutic regimen in most patients unless contraindicated or intolerance to these agents has been demonstrated Metformin, thiazolidinediones, and incretin mimetics do not cause hypoglycemia: when used in combination with secretagogues or insulin, these medications may need to be adjusted as blood glucose levels declined AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

Clinical Considerations The weight gain associated with thiazolidinediones in some patient may be partly offset by combination therapy with metformin Carefully assess postprandial glucose levels if the A1C level is elevated and preprandial blood glucose measurements are at target levels INDIVIDUALIZE TREATMENT REGIMENS! AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007