Please Complete the Pre-Activity Survey

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2 Please Complete the Pre-Activity Survey

3 This activity is supported through an educational grant from Novo Nordisk.

4 Learning Objectives Upon completion of this educational activity, the participant should be able to: 1. Outline differences and similarities in the mechanisms of action for both major classes of incretin-based therapies. 2. Describe the effects of DPP-4 inhibitors on glycemic targets, including A1c levels and postprandial glucose. 3. Discuss the effects of GLP-1 receptor agonists on glycemic targets, including A1c levels and postprandial glucose. 4. Review the effects of GLP-1 receptor agonists and DPP-4 inhibitors on cardiovascular risk factors including lipid levels, blood pressure, and body weight.

5 Pathophysiology of Type 2 Diabetes (T2DM) Obesity Accumulation of cellular energy Increased serum FFAs Altered adipocyte hormone production Decreased insulin action in: Muscle Liver Adipose tissue Other tissues Increased insulin secretion from betacells Abnormal insulin secretion Increased PPG Increased FPG Dyslipidemia Fatty liver Progressive beta cell dysfunction: Decreased insulin production Beta cell death Decreased incretin secretion/action Abnormal insulin processing FFA = free fatty acids FPG = fasting plasma glucose PPG = postprandial glucose Adapted by Lillian McVey from Campbell RK. Clin Ther. 2011;33(5):

6 The Importance of Glycemic Control in Type 2 Diabetes Good glycemic control associated with: - Delayed progression of disease and associated morbidity/mortality Decreased rates of microvascular and neuropathic complications Risk reduction for cardiovascular disease Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110.

7 Summary of ADA Glycemic Recommendations A1c Glycemic Recommendations for Nonpregnant Adults With Diabetes Preprandial capillary plasma glucose Peak postprandial capillary plasma glucose** <7.0% (53 mmol/mol)* mg/dl* ( mmol/l) <180 mg/dl* (10.0 mmol/l) * More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. ** Postprandial glucose (PPG) may be targeted if A1c goals are not met despite reaching preprandial glucose goals. PPG measurements should be made 1-2 hours after the beginning of the meal, generally peak levels in patients with diabetes. Only 37% of adults with T2DM achieve A1c <7.0% Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110. Saydah SH, et al. JAMA. 2004;291:

8 Individualizing Glycemic Targets Patient/Disease Features Risks potentially associated with hypoglycemia and other drug adverse effects more stringent low A1c 7% less stringent high Disease duration newly diagnosed long-standing Life expectancy long short Usually not modifiable Important comorbidities absent few/mild severe Established vascular complications absent few/mild severe Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities less motivated, nonadherent, poor self-care capacities Potentially modifiable Resources and support system readily available limited Cefalu WT, et al. Diabetes Care. 2016;39(Suppl 1):S1-S110. Copyright 2016 by the American Diabetes Association, Inc. All rights reserved. Used with permission. Inzucchi SE, Bergenstal RM, Buse JB, et al. Diabetes Care. 2015;38:

9 Incretins: History Incretin hormones were discovered during trials to identify the phenomenon that has been called the incretin effect La Barre 1930s - Used the term incretin to describe gut activity that stimulated pancreatic endocrine secretion - Identified that insulin response was greater if glucose was administered orally vs intravenously Nauck Demonstrated that a glucose infusion to achieve plasma glucose levels identical to those achieved with oral glucose led to an insulin response that was only one-quarter as high La Barre J, Still EU. Am J Physiol. 1930;91: Nauck MA, et al. J Clin Endocrinol Metab. 1986;63(2):

10 Incretins Secreted within minutes after meal ingestion in response to activation of neural circuits that connect the GI tract with the hypothalamus - Gastric inhibitory polypeptide (GIP) - Glucagon-like peptide-1 (GLP-1) Broken down in GI tract by enzyme dipeptidyl peptidase-iv (DPP-4) Cardioprotection Cardiac output Glucose production Appetite GLP-1 Glucose uptake DPP-4 causes breakdown of GLP-1 Gastric emptying Insulin secretion Beta cell neogenesis Beta cell apoptosis Glucagon secretion Image courtesy of Shannon Reedy Idzik, DNP, CRNP, FAANP. Used with permission.

11 The Incretin Effect In patients with T2DM: - The incretin effect is severely reduced Insulinotropic effects of GIP are virtually absent Insulinotropic effects of GLP-1 are at least partially preserved Endogenous GLP-1 mediated insulin secretion does not compensate for loss of insulinotropic activity of GIP Defective glucagon suppression produces hyperglucagonemia (fasting and post-nutrient state) - Defective incretin-mediated stimulation contributes to defective insulin secretion Nauck M. Diabetes Obes Metab. 2016;18(3):

12 Incretin-based Medications GLP-1 receptor agonists (RAs) - Produce effects similar to those of native GLP-1 Stimulate insulin secretion Suppress glucagon secretion, appetite, and food intake Slow gastric emptying Stimulate pancreatic beta cell proliferation - Resistant to DPP-4 degradation DPP-4 antagonists - Augment endogenous GLP-1 by inactivating the enzyme responsible for its degradation Nauck M. Diabetes Obes Metab. 2016;18(3):

13 Incretin-based Therapies GLP-1 RAs DPP-4 Inhibitors Drug Starting dose Drug Starting dose Exenatide INITIAL: 5 mcg SC twice daily Alogliptin INITIAL: 25 mg PO once daily Liraglutide Exenatide extendedrelease Albiglutide INITIAL: 0.6 mg SC once daily x 1 week, then increase to 1.2 mg SC once daily INITIAL: 2 mg SC once weekly INTIAL: 30 mg SC once weekly Linagliptin Saxagliptin Sitagliptin INITIAL: 5 mg PO once daily INITIAL: 2.5 mg or 5 mg PO once daily INITIAL: 100 mg PO once daily Dulaglutide INITIAL: 0.75 mg SC once weekly

14 Beneficial Effects of Incretin-based Therapies Effect GLP-1 RAs* DPP-4 Inhibitors** Reduction in A1c 0.5%-1.5% 0.5%-0.9% Reduction in FPG 7-74 mg/dl mg/dl Reduction in PPG mg/dl mg/dl Effect on weight 1-4 kg kg Improvement in markers of pancreatic beta cell function? Yes Yes *Exenatide 5-10 mcg SC twice daily, Liraglutide mg once daily **Sitagliptin 100 mg PO once daily, Saxagliptin mg PO once daily, Linagliptin 5 mg PO once daily Cobble M. Diabetol Metab Synd. 2012;4(1):8.

15 Incretin-based Therapies in Current Guidelines According to 2015 AACE/ACE guidelines: - GLP-1 RAs now second drug of choice in patients with A1c <7.5% - Metformin and GLP-1 RA combination is first line dual therapy for patients with A1c 7.5% Garber AJ, et al. Endocr Pract. 2015;21(4):

16 GLP-1 RAs Advantages Lack of hypoglycemia when used as monotherapy Weight loss Reduces PPG values Combination of injectable therapies of basal insulin and a GLP-1 RA is a strategy 1.AstraZeneca Pharmaceuticals. BYETTA (exenatide) injection prescribing information. Accessed July 1, Novo Nordisk. VICTOZA (liraglutide) injection prescribing information. Accessed July 1, GlaxoSmithKline. TANZEUM (albiglutide) perscribing information. Accessed July 1, Eli Lilly. TRULICITY (dulaglutide) injection prescribing information. Accessed July 1, Disadvantages Injectable AEs: headache, nausea (often transient), diarrhea Dosage modification with renal dysfunction needed (albiglutide, dulaglutide) Contraindicated in severe renal impairment (exenatide) May be associated with pancreatitis Associated with thyroid cell cancer in rodents May be associated with renal insufficiency

17 DPP-4 Inhibitors Advantages Oral No hypoglycemia when used as monotherapy Weight neutral Generally well tolerated 1.Takeda Pharmaceuticals. NESINA (alogliptin) prescribing information. Accessed July 1, Boehringer Ingelheim. TRADJENTA (linagliptin) prescribing information. Accessed July 1, AstraZeneca Pharmaceuticals. ONGLYZA (saxagliptin) prescribing information. Accessed July 1, Merck. JANUVIA (sitagliptin) prescribing information. Accessed July 1, Disadvantages Dosage modification required with renal impairment (sitagliptin, saxagliptin, alogliptin) CYP3A4 interactions (saxagliptin, linagliptin) May be associated with pancreatitis May worsen heart failure (saxagliptin) May cause severe joint pain

18 Nauck M. Diabetes Obes Metab. 2016;18(3): GLP-1 RAs vs DPP-4 Inhibitors: Head-to-Head Trials Parameter Greater glycemic control Greater reductions in body weight GLP-1 RAs X X DPP-4 Inhibitors Comments Compared with sitagliptin, liraglutide, exenatide once weekly, and dulaglutide produced significantly greater reductions in A1c and other glycemic parameters Compared with sitagliptin, GLP-1 RAs produced significantly greater reductions in body weight Greater tolerability X Higher incidence of mild-to-moderate gastrointestinal AEs associated with GLP-1 RAs Greater improvements in beta cell function Greater reduction in postprandial triglycerides Greater treatment satisfaction X X X Exenatide, liraglutide, and dulaglutide treatment resulted in more favorable improvements in beta cell function vs sitagliptin Exenatide twice daily produced greater reductions in postprandial triglycerides compared with sitagliptin Likely driven by weight reduction, despite need for injection with liraglutide vs oral sitagliptin

19 Effects of Incretin-based Therapies on Cardiovascular Risk Factors

20 Cardiovascular Disease and Diabetes Cardiovascular disease is the most common cause of death in adults with diabetes - Increased incidence of atherosclerosis - Increased incidence of hypertension and lipid abnormalities - Increased macrovascular complications such as stroke and myocardial infarction Higher cost of managing cardiovascular disease in diabetes than nondiabetic counterparts Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112.

21 Cardiovascular Risk Reduction Risk reduction strategies for cardiovascular disease in diabetes focus on: - Medical nutrition therapy - Improvement of glucose control - Weight loss and weight maintenance - Blood pressure control - Lipid-lowering strategies Lifestyle interventions are the cornerstone of cardiovascular risk reduction; however, many patients will need pharmacological help to maintain goals

22 Cardiovascular Risk Reduction: Body Weight Many conventional glucose-lowering medications associated with weight gain Studies show that weight maintenance is difficult with lifestyle alone Benefits of weight loss: - Weight loss of 5% to 10% associated with reduction in blood pressure, lipids, and improvement in glycemic control (Look AHEAD trial) - Modest weight loss linked to as much as a 28% risk reduction in cardiovascular disease and mortality - Additional benefits of weight loss include remission or reduced severity of obstructive sleep apnea Van Gaal L, Scheen A. Diabetes Care. 2015;38(6):

23 Incretin-based Therapies and Weight Loss GLP-1 RA (eg, exenatide, exenatide ER, liraglutide, albiglutide, dulaglutide) - Dose-dependent weight loss - Over 85% of patients lose weight DPP-4 (eg, sitagliptin, linagliptin, alogliptin, saxagliptin) - Meta-analysis results of 13 studies show weight neutrality or weight loss Davidson JA. Cleve Clin J Med. 2009;76(Suppl 5):S28-S38.

24 Exenatide and Weight Loss 0 Change in body weight (kg) in placebo-controlled trials, open-label extensions (10 µg exenatide twice daily) week completer (n=314) Intent-to-treat (n=551) ± 0.2kg -4.4 ± 0.3kg Treatment (weeks) Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Blonde L, et al. Diabetes Obes Metab. 2006;8(4):

25 Exenatide vs Insulin Glargine for Weight Loss Change in body weight (kg) during 26 week treatment with exenatide or insulin glargine Exenatide group (n=275) Insulin glargine group (n=260) * * * * * Weeks * * P <.0001 exenatide compared with insulin glargine Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Heine RJ, et al. Ann Intern Med. 2005;143(8):

26 Liraglutide and Weight Loss: LEAD Trials LEAD-3 trial: - Weight reduction of up to 2.5 kg with liraglutide compared with a weight gain of 1.1 kg with glimepiride (P = ) - Weight loss sustained throughout a 52-week study LEAD-5 trial: - Liraglutide produced a greater reduction in A1c and body weight (loss of 1.8 kg) than insulin glargine (gain of 1.6 kg) LEADER trial: - Compared with placebo, liraglutide treatment resulted in: 13% risk reduction for MACE (non-fatal MI, non-fatal stroke, and CV death) 22% risk reduction for CV death 15% reduction in all-cause mortality Sesti G. Diabetes Care. 2011;34(Suppl 2):S272-S275. Marso SP, et al. N Engl J Med Jun 13 [Epub ahead of print].

27 Cardiovascular Risk Reduction: Blood Pressure Increasing levels of systolic blood pressure (starting as low as 115 mmhg) linked with progressive increase in risk of macrovascular and microvascular events Current clinical recommendations for blood pressure goals in diabetes: - <140/90 mmhg (with some exceptions) Most patients with diabetes and hypertension will require multiple pharmacological agents to obtain adequate blood pressure control Fox CS, et al. Diabetes Care. 2015;38(9):

28 Incretin-based Therapies and Blood Pressure Effects of incretin-based therapies on blood pressure: - Small decreases in both systolic and diastolic blood pressure - Possible reduction in albuminuria, proteinuria, and glomerular injury - Increased urinary water and sodium secretion - Protective effects on endothelium in postprandial state - Shown to reduce postprandial oxidative stress and biomarkers of cardiovascular disease Cernea S, Raz I. Diabetes Care. 2011;34 Suppl 2:S264-S271.

29 Sitagliptin and Blood Pressure **After 12 weeks of monotherapy Systolic Blood Pressure Diastolic Blood Pressure Baseline Endpoint Baseline Endpoint Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Mistry GC, et al. J Clin Pharmacol. 2008;48(5):

30 Change in SBP (mm Hg) Liraglutide and Blood Pressure LEAD Liraglutide 1.8 mg (n=178) Placebo (n=173) Time (weeks) Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Gallwitz B, et al. Int J Clin Pract. 2010;64(2):

31 Cardiovascular Risk Reduction: Lipids Common lipid abnormalities in T2DM include elevated triglycerides, decreased HDL, and elevated LDL LDL particles are oftentimes small and dense Small/dense LDL particles are more atherogenic LDL lowering should be the primary target with reduction in triglycerides a secondary endpoint Moderate or high-intensity statin therapy should be initiated for adults 40 to 75 years of age Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112. Stone NJ, et al. J Am Coll Cardiol. 2014;63(25 Pt B):

32 Cardiovascular Risk Reduction: Lipids Major vascular events reduced by 21% with every 39 mg/dl reduction in LDL-C in people with T2DM (RR 0.79 [99% CI ]; P < ) All-cause mortality reduced by 9% with every 39 mg/dl reduction in LDL-C (RR 0.91 [99% CI ]; P = 0.02) Kearney PM, et al. Lancet. 2008;371(9607):

33 Incretin-based Therapies and Lipids GLP-1 RAs - Reduce postprandial triglycerides, FFA, and LDL DPP-4 inhibitors - Reduce fasting LDL and triglycerides - Small increase in HDL - Parallels weight loss Cefalu WT, et al. Diabetes Care. 2015;39(1):S1-S112.

34 Exenatide and Lipids Open label 3-year RCT to evaluate exenatide effect on cardiovascular markers (n=151) Triglycerides decreased 12% (P =.0003) Total cholesterol decreased 5% (P =.0007) LDL decreased 6% (P <.0001) HDL increased 24% (P <.0001) Klonoff DC, et al. Curr Med Res Opin. 2008;24(1):

35 mg/dl Sitagliptin and Lipids Baseline Endpoint 50 0 Total Cholesterol LDL Total Triglycerides HDL Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Mistry GC, et al. J Clin Pharmacol. 2008;48(5):

36 Considerations for Treatment Plans Containing Incretin-based Therapies

37 Clinical Case 58-year-old female with newly diagnosed T2DM presents for a 3-month follow-up Patient has been implementing lifestyle changes and weight loss for the past 3 months to improve her glycemic control Patient is motivated to improve nutritional choices and increase her physical activity levels; to date, she has lost a total of 10 pounds (4.4% TBW) and feels encouraged to continue with her weight loss program Comorbidities include: Class 2 obesity Hypertension Dyslipidemia Osteoarthritis Patient s A1c is 7.9% TBW = total body water

38 Clinical Case Physical Exam: BMI = 37 (5'5", 223 lbs) Waist circumference = 50" BP = 145/86 mmhg Pulse = 76 bpm FBG = 173 mmol/l A1c = 7.9% Total cholesterol = 187 mg/dl Triglycerides = 278 mg/dl HDL = 44 mg/dl LDL = 88 mg/dl Medications: Lisinopril 40 mg daily Norvasc 5 mg daily Meloxicam 15 mg daily Cyclobenzaprine 10 mg as needed Loratadine 10 mg daily Lifestyle changes: Daily monitored caloric intake between kcal/d Daily steps averaged per day (up from 3000 steps per day at start) Joined a gym and plans on attending 2 times per week

39 ADA Recommendations for Managing Diabetes Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for T2DM (A rating) Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed T2DM and markedly symptomatic and/or elevated blood glucose levels or A1c (E rating) If non-insulin monotherapy at maximum-tolerated dose does not achieve or maintain the A1c target over 3 months, then add a second oral agent, a GLP-1 RA, or basal insulin (A rating) A patient-centered approach should be used to guide the choice of pharmacological agents; considerations include efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and patient preferences (E rating) For patients with T2DM who are not achieving glycemic goals, insulin therapy should not be delayed (B rating) Recommendations are assigned ratings of A, B, or C, depending on the quality of evidence. The E rating for expert opinion is a separate category for recommendations in which there is no evidence from clinical trials, clinical trials may be impractical, or evidence is conflicting. Recommendations with an A rating are based on large, well-designed clinical trials or high-quality meta-analyses. Recommendations with lower levels of evidence may be equally important but are not as well-supported. Chamberlain JJ, et al. Ann Intern Med. 2016;164(8):

40 Relative Function (%) Glucose (mg/dl) Natural History of T2DM Postprandial Glucose Fasting Glucose Insulin Resistance Insulin Level At Risk for T2DM β-cell Failure Time (y) Obesity IFG* Diabetes Uncontrolled hyperglycemia IFG = impaired fasting glucose Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Kendall DM, Bergenstal RM International Diabetes Center at Park Nicollet, Minneapolis, MN. All rights reserved. Used with Permission.

41 Considerations and Controversies in the Selection of Monotherapy, Dual, and Triple Therapies for the Treatment of T2DM Target A1c Duration of diabetes Preservation of beta cell function Comorbidities and patient-centered approach Selection of initial, dual, and triple therapies Early combination therapy vs the traditional stepwise approach Responder vs nonresponder Emerging clinical trial outcomes on newer treatment options Cefalu WT, et al. Diabetes Care 2014;37:

42 Comparison of ADA and AACE Guidelines ADA A1c goal <7% (6-6.5% if healthy, 7.5%- 8% if not) AACE <6.5% in new onset; >7% if multiple comorbidities, labile glycemia Use of A1c in choice of agents If >9%, consider dual therapy If >7.5%, >9%, >8%, or <8%, in initial insulin dose selection SMBG targets Classes listed Choice of agents Insulin intensification Bloomgarden ZT, Handelsman Y. J Diabetes. 2016;8(1):4-6. Preprandial <130 mg/dl Peak PPG <180 mg/dl MET, SU, DPP-4 inhibitor, GLP-1 RA, SGLT-2 inhibitor (other classes are mentioned but are not recommended) Consider efficacy, then safety, weight, hypoglycemia, cost, renal disease After basal, 1 bolus or mixed, may consider GLP-1 RA FPG <110 mg/dl 2-h PPG <140 mg/dl Use all approved classes (emphasize avoiding SU); MET, GLP-1 RA, DPP-4 inhibitor, SLGT-2 inhibitor, TZD, AGI, BAS, BCR-QR, pramlintide Consider safety, then efficacy, weight, hypoglycemia, side effects After basal, either GLP-1 RA, SGLT-2, DPP-4, or add bolus; mixed insulin discouraged

43 Targeting the Preservation or Rejuvenation of Beta Cell Function Progressive deterioration in cell function and mass occurs with duration of diabetes - Approximately 50% loss of normal at the time of diagnosis - Reduction in beta cell mass of about 60% at necropsy Reduction of beta cell mass is thought to be attributable to accelerated apoptosis Major clinical factors affecting progressive loss of beta cell function and mass: - Glucotoxicity - Lipotoxicity - Adipocyte-secreted cytokines and hormones Pro-inflammatory cytokines (TNF-, IL-6, and IL-1 receptor antagonists) are produced and secreted by fat tissue, increased in obesity, and have been causally linked to insulin resistance Leptin - Islet cell amyloid deposition Wajchenberg BL. Endocr Rev. 2007;28(2):

44 Targeting the Preservation or Rejuvenation of Beta Cell Function (cont d) Impaired cell function and possibly cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased beta cell mass has probably not been passed Interventions found to preserve or rejuvenate beta cell function: - GLP-1 RA - DPP-4 inhibitors - Thiazolidinediones (TZDs) - Insulin Wajchenberg BL. Endocr Rev. 2007;28(2):

45 Summary of Effects of GLP-1 RA and DPP-4 Inhibitors GLP-1 RA DPP-4 Inhibitors Administration injection oral GLP-1 concentrations pharmacological physiological Mechanism of actions GLP-1 GLP-1, GIP Activation of the portal glucose sensor Insulin secretion no yes Glucagon secretion Fasting glucose Weight reduction yes no Gastric emptying +/- Nausea and vomiting yes (approx 45%) no Expansion of β cell mass yes yes Potential immunogenicity yes no Druker DJ, Nauck MA. Lancet. 2006;368(9548):

46 Factors to Consider When Choosing Medications for T2DM Clinician factors Patient factors Adherence factors Efficacy Patient preference Complexity Cost Cost Multiple doses Tolerability Health beliefs Polypharmacy Impact on body weight Health literacy Side effects Comorbidities Adherence Potential adverse effects Risk of hypoglycemia Patient preference Duration of diabetes Fear System factors: Inadequate follow-up or support Cefalu WT, et al. Diabetes Care. 2014;37:

47 Clinical Case Considerations for a personalized approach to treatment: - Newly diagnosed (58-year-old) - Comorbidities: Class 2 obesity (BMI = 37 kg/m 2 ) Hypertension not at treatment goal on 2 antihypertensives Atherogenic dyslipidemia (elevated TG, low HDL, Pattern B) - Personal preferences: Nearly 5% total body weight loss in the past 3 months Highly motivated to continue with weight loss efforts Concerned about weight gain with diabetes medications

48 Considerations When Prescribing Medications for T2DM Met SU TZD DPP-4 inhibitor GLP-1 RA SGLT-2 inhibitor Basal insulin Efficacy (A1c lowering) high (1-2) high (1-1.5) moderate (0.5-1) moderate (0.5-1) high (1-1.5) high (1-1.5) highest ( ) Hypoglycemic risk none high low rare/low low low high Effect on body weight loss or neutral gain gain neutral loss loss gain Tolerability GI effects hypoglycemia edema, HF, fractures rare GI effects GU infections, dehydration hypoglycemia Cost low/free low low high high high variable - high Uccellatore A, et al. Diabetes Ther. 2015;6: Hawes EM, et al. Journal of Family Practice. 2016;65(2):85-89.

49 Adverse Effects and Patient Education Adverse Effect Nausea, vomiting, diarrhea Injection site reactions and nodules Increased risk for hospitalization for heart failure (?) Increased risk for acute pancreatitis (?) Increased risk for medullary thyroid carcinoma (?) Patient Education Often transient nature Possibility that drug needs to be withdrawn in a minority of patients Potential pharmacotherapy for side effects Information about nature of this side effect (immunological responses potentially related to antibody formation) Possibility that repeated episodes may suggest the need to discontinue this treatment Information on recognition of symptoms Clinical significance of study findings are undetermined Caution for those at high risk Discussion of this as an unresolved issue Early signs and symptoms of pancreatitis, behavioral advice in such a case (seek medical advice, discontinue treatment) Advice for alternative treatment in the case of past episodes of pancreatitis Information about the low likelihood in the face of the rarity of this disease Advice for alternative treatment in the case of a personal or family history or with a given genetic background (multiple endocrine neoplasia syndrome type 2) Cefalu WT, et al. Diabetes Care. 2014;37:

50 Clinical Case Started on liraglutide 0.6 mg per day with a titration schedule to 1.2 mg in 1 week Educated on common adverse effects Encouraged to continue with her lifestyle program Follow-up scheduled for 2 to 3 weeks

51 Common Barriers to Adherence Patient-based Barriers Cost/insurance coverage Education/ knowledge Adverse effects Complexity of treatment Health Care System based Barriers Clinician s attitudes toward treating diabetes Time constraints Management of multiple comorbidities Patient s insurance/finances

52 Conclusion The incretin effect is severely reduced in patients with T2DM - Incretin-based agents act to stimulate insulin secretion, suppress glucagon secretion, slow gastric emptying, and stimulate beta cell proliferation Benefits of incretin-based therapies include: - Reduced A1c, FPG, PPG - Improvement in markers of pancreatic beta cell function - Cardiovascular benefits Weight loss or weight-neutral effects Reduced blood pressure Improved lipid parameters GLP-1 RAs and DPP-4 inhibitors provide safe and effective glycemic control targeting the underlying pathophysiologic defects and the comorbidities associated with T2DM, which may modify the natural course of the disease and long-term outcomes

53 Conclusion (cont d) Treatment considerations: - When prescribing medications for the management of T2DM, decision making should include a personalized approach taking into account the patient s clinical circumstances, comorbidities, preferences, and costs - Regardless of the specific therapy selected, the goal should be to safely achieve glycemic control at the earliest possible stage with the least risk for adverse effects to improve outcomes and reduce complications

54 Please Complete the Post-Activity Survey and Activity Evaluation

55 Q&A