Reducing T2DM Complications. ADA/EASD Position Statement Setting Glycemic Goals in T2DM. ADA Recommendations Managing Hyperglycemia in T2DM

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2 Scientific Insights Into Incretin Signaling and T2DM Key Points Incretin effect: more insulin is secreted in response to orally delivered glucose compared with intravenously administered glucose 1 The gastrointestinal hormones GLP-1 and GIP stimulate insulin release in response to food intake 2 GLP-1 also reduces glucagon release following food intake, slows gastric emptying, and increases satiety 2 Reduced incretin effect is an early sign of T2DM development 3 GLP-1 and GIP are rapidly degraded by DPP-4 2 Clinical research has focused on degradation-resistant GLP-1 RAs and inhibitors of DPP-4 DPP-4, dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagon-like peptide-1 receptor agonist; T2DM, type 2 diabetes mellitus. 1. Elrick H, et al. J Clin Endocrinol Metab. 1964;24: ; 2. Grunberger G. J Diabetes. 2013;5(3): ; 3. Holst JJ, et al. Diabetes Care. 2011;34 (suppl 2):S251-S257. Reducing T2DM Complications BP <140/90 mm Hg (<130/80 mm Hg for some people) Multidimensional Treatment Goals Comprehensive Diabetes Management A1c ADA <7.0% AACE 6.5% Lipids a LDL-C: <100 mg/dl (<70 mg/dl with CVD) HDL-C: >40 mg/dl in men >50 mg/dl in women TG: <150 mg/dl Lifestyle Modifications Healthy Diet; Exercise; Smoking Cessation BMI <25 kg/m 2 a 2015 ADA/AHA guidelines: Treat patients years old with T2DM and LDL-C levels between 70 and 189 mg/dl with moderate-intensity statin therapy (lower LDL-C by 30%-50%); use high-intensity therapy (lower LDL-C by 50%) if 10-year ASCVD risk is 7.5%). A1c, glycated hemoglobin; AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglycerides. ADA. Diabetes Care. 2016;39(suppl 1):S1-S112; Garber AJ, et al. Endocr Pract. 2016;22(1):84-113; Fox CS, et al. Diabetes Care. 2015;38(9): ADA/EASD Position Statement Setting Glycemic Goals in T2DM More Stringent Factors Less Stringent ly motivated, adherent, excellent selfcare capacities Low Patient attitude and expected treatment efforts Risks potentially associated with hypoglycemia, other adverse events EASD, European Association for the Study of Diabetes. Inzucchi SE, et al. Diabetes Care. 2012;35: ; Inzucchi SE, et al. Diabetes Care. 2015;38(1): ; Ismail-Beigi F, et al. Ann Intern Med. 2011(6);154: Less motivated, nonadherent, poor self-care capacities Newly diagnosed Disease duration Long-standing Long Life expectancy Short Absent Important comorbidities Severe Absent Established vascular complications Severe Readily available Resources, support system Limited Monotherapy Efficacy ( A1c) Hypoglycemia Weight Side Effects Costs Dual Therapy a Efficacy ( A1c) Hypoglycemia Weight Major Side Effect(s) Costs ADA Recommendations Managing Hyperglycemia in T2DM + SU Moderate risk Gain Hypoglycemia Low Healthy Eating, Weight Control, Increased Physical Activity Metformin Neutral/Loss GI/Lactic acidosis Low If individualized A1c target not reached after ~3 months, proceed to 2-drug combination + TZD Gain Edema, HF, Fx + DPP-4 Inhibitor Intermediate Neutral Rare Metformin + SGLT-2 Inhibitor Intermediate Loss GU, Dehydration + GLP-1 RA Loss GI a Consider starting at this stage when A1c 9%. DPP-4, dipeptidyl peptidase-4; Fx, bone fracture; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; GU, genitourinary; HF, heart failure; SGLT-2, sodium glucose cotransporter-2; SU, sulfonylurea; TZD, thiazolidinedione. ADA. Diabetes Care. 2015;38(suppl 1):S1-S94. + Insulin (Basal) est risk Gain Hypoglycemia Variable AACE/ACE Algorithm Glycemic Control and Early Dual Therapy Lifestyle Modification Entry A1c <7.5% Entry A1c 7.5% Entry A1c >9.0% Monotherapy a Metformin GLP-1 RA SGLT-2 inhibitor DPP-4 inhibitor TZD AG inhibitor SU/GLN If not at goal in 3 months, proceed to dual therapy METFORMIN or other first-line agent Dual Therapy a GLP-1 RA SGLT-2 inhibitor DPP-4 inhibitor TZD Basal Insulin Colesevelam Bromocriptine QR AG inhibitor SU/GLN If not at goal in 3 months, proceed to triple therapy a Order of medications listed are a suggested hierarchy of usage. ACE, American College of Endocrinology; AG, α-glucosidase; GLN, glinide; QR, quick release. Garber AJ, et al. Endocr Pract. 2016;22(1): NO Dual Therapy OR Triple Therapy Symptoms YES Insulin ± Other Agents Add or Intensify Insulin Possible benefits or few adverse events Use with caution Patients With 1 Hypoglycemic Event(s), % ADVANCE Severe Hypoglycemia vs Adverse Endpoints HR (95% CI): 3.53 (2.41, 5.17) a HR (95% CI): 2.19 (1.40, 3.45) a b HR (95% CI): 3.27 (2.29, 4.65) a a Adjusted for multiple baseline covariates; b Primary endpoints. Major macrovascular event=cv death, nonfatal myocardial infarction, or nonfatal stroke. Major microvascular event=new or worsening nephropathy or retinopathy. CI, confidence interval. Zoungas S, et al. N Engl J Med. 2010;363(15): b HR (95% CI): HR (95% CI): 3.79 (2.36, 6.08) a 2.80 (1.64, 4.79) a

3 Glucose Control and DPP-4 Inhibitors Monotherapy and Metformin Combinations Therapy vs Comparator Monotherapy vs ΔA1c for Saxagliptin vs Comparator, % 1-3 ΔA1c for Sitagliptin vs Comparator, % 4-6 ΔA1c for Linagliptin vs Comparator, % 7-9 ΔA1c for Alogliptin vs Comparator, % vs 0.19 a vs 0.12 b vs 0.25 a vs b Initial Combination with Metformin vs Metformin vs -2.0 a vs b -1.7 vs -1.2 a -1.1 vs -1.6 c Add on to Metformin vs Metformin vs 0.13 a vs b vs 0.15 a -0.6 vs -0.1 b a P< vs comparator; b P<0.001 vs comparator; c P<0.05 vs comparator. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25: ; 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: ; 3. DeFronzo RA, et al. Diabetes Care. 2009;32: ; 4. Raz I, et al. Diabetologia. 2006;49: ; 5. Goldstein BJ, et al. Diabetes Care. 2007;30: ; 6. Scott R, et al. Diabetes Obes Metab. 2008;10: ; 7. Del Prato S, et al. Diabetes Obes Metab. 2011;13: ; 8. Haak T, et al. Diabetes Obes Metab. 2012;14: ; 9. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74; 10. DeFronzo RA, et al. Diabetes Care. 2008;31: ; 11. Drugs@FDA ( 12. Nauck MA, et al. Int J Clin Pract. 2009;63: DPP-4 Inhibitors Additional Safety Considerations Generally well tolerated Most common adverse effects Nasopharyngitis Headache Nausea Hypersensitivity Skin reactions Dose reductions are required for alogliptin, saxagliptin, and sitagliptin in patients with moderate or severe renal impairment, or ESRD (CrCl 50 ml/min) CrCl, creatinine clearance; ESRD, end-stage renal disease. Grunberger G. J Diabetes. 2013;5(3): DPP-4 Inhibitors Recent FDA Warnings Joint pain DPP-4 inhibitor class carries a warning about joint pain that can be severe and disabling In rare identified cases, symptoms abate <1 month after drug is stopped May relate to cytokines, chemokines, and matrix metalloproteinases Heart failure For saxagliptin and alogliptin, consider benefits vs risks in patients at risk for heart failure, and to consider discontinuing if heart failure develops SAVOR: more patients hospitalized for heart failure in the saxagliptin group than in the placebo group (HR, 1.27; 95% CI: 1.07, 1.51) Post hoc analysis showed that patients at highest risk of heart failure related hospitalization had previous heart failure or chronic kidney disease 4 EXAMINE: more patients hospitalized for heart failure in the alogliptin group (3.9%) than in the placebo group (3.3%) Drugs@FDA ( Mascolo A, et al. Drug Saf. 2016;39(5): ; Scirica BM, et al. Circulation. 2014;130(18): ; White WB, et al. N Engl J Med. 2013;369(14): Exenatide Twice Daily Label includes data with basal insulin Lixisenatide a GLP-1 RAs Pharmacokinetic Properties Short Acting GLP-1 RAs Liraglutide Label includes data with basal insulin Dulaglutide Label includes data with prandial insulin Long Acting Semaglutide a Exenatide Once Weekly Not recommended for use with insulin Albiglutide Label includes data with basal insulin Insulin degludec/liraglutide and insulin glargine/lixisenatide fixed combinations recently received recommendations for approval from an FDA advisory panel a Not approved by the US Food and Drug Administration. Anderson SL, Trujillo JM. Ther Adv Chronic Dis. 2016;7(1):4-17; Nauck MA, et al. Diabetes Care. 2016;39(2): ; See Drugs@FDA: FDA Approved Drug Products; Accessed June 5, Short Acting Long Acting Medication Exenatide BID 1 Liraglutide 2 FDA-Approved GLP-1 RAs Daily Formulations Dosage Forms 5 μg/dose in 1.2-mL prefilled pen 10 μg/dose in 2.4-mL prefilled pen Prefilled, multidose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg Adverse Events a Nausea, vomiting, dyspepsia Nausea, diarrhea, vomiting, constipation, headache Dosing 1.Start at 5 μg BID (1 hour before morning and evening meals) 2.Increase to 10 μg twice daily after 1 month 1.Initiate at 0.6 mg once daily, regardless of meals 2.After 1 week, increase dose to 1.2 mg 3.If glycemic control is not acceptable, dose can be increased to 1.8 mg a Treatment-emergent adverse reactions with 5% incidence in clinical trials with drug as monotherapy (excluding hypoglycemia). BID, twice daily. 1. See Drugs@FDA ( 2. See Drugs@FDA ( Long Acting FDA-Approved GLP-1 RAs Weekly Formulations Medication Dosage Forms Adverse Events a Dosing Exenatide QW 1 Albiglutide 2 Dulaglutide 3 Single-dose tray with 2-mg vial Single-dose 2-mg prefilled pen 30-mg or 50-mg lyophilized powder in single-dose pen for reconstitution Single-dose pen in or 1.5-mg doses Prefilled, single-dose syringe in 0.75-mg or 1.5-mg doses Nausea, diarrhea, injection-site nodule, constipation, headache, dyspepsia URTI, diarrhea, nausea, injection-site reaction, cough, back pain, arthralgia, sinusitis, influenza Nausea, diarrhea, vomiting, abdominal pain, and decreased appetite 1. Administer at 2.0 mg once every 7 days (weekly), independent of meals 1. Administer at 30 mg once every 7 days (weekly), regardless of meals 2. If glycemic control not acceptable, dose can increase to 50 mg 1. Initiate at 0.75 mg weekly, regardless of meals or time of day; dose can be increased to 1.5 mg 2. If dose is missed, missed dose must be taken within 3 days QW, once weekly; URTI, upper respiratory tract infection. a Treatment-emergent adverse reactions with 5% incidence (excluding hypoglycemia) in clinical trials with drug as monotherapy. 1. See Drugs@FDA ( 2. Albiglutide prescribing information. US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF; 3. Dulaglutide prescribing information. Accessed September 23rd, 2014.

4 Safety With Incretin-Based Agents Precautions Cases have been reported Consider treatments other than GLP-1 RAs in patients with history of pancreatitis Unknown if pancreatitis history increases risk with DPP-4 inhibitors Acute Pancreatitis Recommendations Ask about pancreatitis history Educate patients about signs and symptoms of pancreatitis Discontinue if pancreatitis symptoms occur Report cases of pancreatitis to Safety of Incretin Therapy 2014 FDA and EMA Analysis FDA and EMA conducted parallel, independent safety assessments of incretin-based drugs following postmarketing reports of pancreatitis or pancreatic cancer in treated individuals Assertions of a causal association are not consistent with current data Product information and labeling reflect current understanding of risk Both agencies continue to investigate safety signals and data from ongoing trials Drugs@FDA: EMA, European Medicines Association. Egan AG, et al. N Engl J Med. 2014;370(9): Nausea/Vomiting & GLP-1 RAs Results From -Controlled Trials Medication Nausea Incidence, % Vomiting Incidence, % Albiglutide 1 11% 4% Dulaglutide 2 12%-21% 6%-13% Exenatide BID 3 8%-44% 4%-18% Exenatide QW 4 11%-27% 11% Liraglutide 5 8%-35% 6%-17% Potential approaches to reduce risks for nausea and vomiting 3,6 Educate on meal size, eating pace, and dose timing relative to meals Use incremental dose titration, particularly with shorter-acting agents Prescribe short-term antiemetic therapy for select patients 1. Albiglutide prescribing information. Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF; 2. Dulaglutide prescribing information Drugs@FDA ( 4. Drugs@FDA ( 5. Drugs@FDA ( 6. Ellero C, et al. Diabet Med. 2010;27(10): GLP-1 RAs Additional Safety Considerations Use with caution in patients with renal impairment or renal transplantation, especially when initiating or escalating doses 1-6 Hypovolemia due to nausea/vomiting may worsen renal function Do not use exenatide formulations in patients with severe renal impairment (CrCl <30 ml/min) or ESRD All long-acting GLP-1 RAs should not be used in patients with MEN2 or personal/family history of MTC 2-5 Counsel regarding MTC risk and symptoms of thyroid tumors Report MTC to state cancer registry, regardless of treatment MEN2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma. 1. See Drugs@FDA ( 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. Albiglutide prescribing information. COMBINED.PDF; 5. Dulaglutide prescribing information Idorn T, et al. Diabetes Care. 2016;39(2): Incretin-Based Therapies CV Effects Direct effects of GLP-1 in humans Improved endothelial function 1,2 Reduced fasting and postprandial plasma free fatty acid levels 3,4 Reduced postprandial levels of TG and apob 3,5 Reduced levels of CV risk biomarkers (eg, PAI-1, BNP) 6,7 DPP-4 targets multiple peptide substrates that positively affect CV function 8 Effects have not translated to positive results in large CV trials Indirect effects of incretins on CV function 8 Insulin-induced increases in glucose utilization and decreases in fatty acid metabolism in myocardial tissue Reduced visceral body fat and body weight apob, apolipoprotein B; BNP, B-type natriuretic peptide; PAI-1, plasminogen activator inhibitor Basu A, et al. Am J Physiol Endocrinol Metab. 2007;293:E1289-E1295; 2. Nystrom et al. Am J Phsyiol Endocrinol Metab. 2004;287:E1209-E1215; 3. Meier JJ, et al. Diabetologia. 2006;49: ; 4. Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86: ; 5. Schwartz EA, et al. Atherosclerosis. 2010;212: ; 6. Courrèges JP, et al. Diabetes Med. 2008;25(9): Vilsbøll T, et al. Diabetes Care. 2007;30: ; 8. Ussher JR, Drucker DJ. Endocr Rev. 2012;33: GLP-1 RAs and Blood Pressure Parameter Meta-Analysis of Data From Obese and Overweight Individuals a Change vs Control 95% CI Systolic blood pressure 3.57 mm Hg 5.49 to 1.66 Diastolic blood pressure 1.38 mm Hg 2.02 to 0.73 a Includes 11 or 12 trials examining overweight and obese individuals with or without T2DM; treatments included exenatide BID, exenatide QW, or liraglutide. Vilsbøll T, et al. BMJ. 2012;344:d7771.

5 Cumulative Incidence of Primary Endpoint Events a, % EXAMINE Alogliptin After ACS in T2DM HR, 0.96 (upper boundary of 1-sided repeated CI, 1.16) P<0.001 for noninferiority P=0.32 for superiority Alogliptin Months No significant between-group differences in death from any cause, CV death, or the secondary endpoint b a Composite: death from CV cause, nonfatal myocardial infarction, or nonfatal stroke. b Composite: death from CV cause, nonfatal myocardial infarction, nonfatal stroke, or revascularization due to UA in 24 h after hospitalization. N=5380 patients with T2DM and either an acute myocardial infarction, or UA requiring hospitalization within the previous 15 to 90 days. ACS, acute coronary syndrome. White WB, et al. N Engl J Med. 2013;369(14): Patients With Event, % LEADER Liraglutide in T2DM With CV Risk Primary Outcome a HR, 0.87 (95% CI: 0.78, 0.97) P<0.001 for noninferiority P=0.01 for superiority CV-Related Death Liraglutide Liraglutide Liraglutide Months Since Randomization a Composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. N=9340 patients with T2DM and high CV risk. Marso SP, et al. N Engl J Med June 13 [Epub ahead of print] HR, 0.78 (95% CI: 0.66, 0.93) 10 P=0.007 Death From Any Cause HR, 0.85 (95% CI: 0.74, 0.97) P=0.02 Combining GLP-1 RAs and Basal Insulin Analogs Basal Insulin Analogs Simple to initiate Control nocturnal hyperglycemia and FPG Less hypoglycemia risk vs NPH Can cause weight gain Achieve A1c target in ~50% a Complementary Actions Additive Effects GLP-1 RAs Simple to initiate Can control FPG and PPG Do not impair α-cell response to hypoglycemia (reduce severe hypoglycemia) Reduces weight Achieve A1c target in ~60% a Potential for better overall A1c control Study Name (Drug) DUAL II 1 (IDegLira) DUAL III 2 (IDegLira) DUAL IV 3 (IDegLira) DUAL V 4 (IDegLira) Additional Published IDegLira Studies Study Population Inadequate control with MET + basal insulin ± SU Inadequate control with GLP-1 RAs + OADs Inadequate control with SU ± MET Inadequate control with MET + insulin glargine U Background Therapy MET Pretrial OADs SU ± MET MET Comparator Degludec (max dose, 50 U) Continued GLP-1 RA Up-titration of glargine ΔA1c IDegLira, -1.9% Degludec, -0.9% P< IDegLira, -1.3%, -0.3% P<0.001 IDegLira, -1.5%, -0.5% P<0.001 IDegLira, -1.81% Glargine, -1.13% P<0.001 a Percentage achieving <7% across baseline A1c quartiles for liraglutide and exenatide QW vs insulin glargine. NPH, neutral protamine Hagedorn; PPG, postprandial glucose. Buse JB, et al. Diabetes Obes Metab. 2015;17(2): ; Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15(1):3-14; Vora J, et al. Diabetes Metab. 2013;39(1):6-15. OADs, oral antidiabetes drugs (MET±PIO±SU). 1. Buse JB, et al. Diabetes Care. 2014;37(11): ; 2. Linjawi S, et al. Diabetes. 2015;64(Suppl 1):A255.abstract 1002-P; 3. Rodbard HW, et al. Diabetes. 2015;64(Suppl 1):A255-A256. abstract 1003-P; 4. Lingvay I, et al. JAMA. 2016;315(9): # Injections 2 ADA/EASD Position Statement When Basal Insulin ± Oral Agents Do Not Achieve Target Glycemia If not controlled after FBG target is reached (or if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin. (Consider initial GLP-1 RA trial) Add 1 rapid insulin injection before largest meal Initiate, Adjust, and Monitor for Hypoglycemia Change to premixed insulin twice daily Initiate, Adjust, and Monitor for Hypoglycemia Complexity Moderate Improving Prandial Hyperglycemia Glycemic Control Not at Goal AACE Recommendations Add GLP-1 RA Or SGLT-2 inhibitor Or DPP-4 inhibitor Intensify (prandial control) Add Prandial Insulin TDD, U/kg 50% Basal Analog 50% Prandial Analog Less desirable: NPH and regular insulin or premixed insulin 3+ If not controlled, consider basal-bolus Flexibility More Flexible Less Flexible Inzucchi SE, et al. Diabetes Care. 2015;38(1): Add 2 rapid insulin injections before meals ( basal-bolus ) Initiate, Adjust, and Monitor for Hypoglycemia If not controlled, consider basal-bolus Insulin Titration Every 2-3 days to reach glycemic goal Increase prandial dose by 10% for any meal if the 2-h postprandial or next premeal glucose is >180 mg/dl Premixed: Increase TDD by 10% if fasting/premeal blood glucose >180 mg/dl If fasting AM hypoglycemia, reduce basal insulin If nighttime hypoglycemia, reduce basal and/or presupper or pre-evening snack short/rapidacting insulin If between-meal daytime hypoglycemia, reduce previous premeal short/rapid-acting insulin TDD, total daily dose. Garber AJ, et al. Endocr Pract. 2015;21(4):

6 Mean A1c, % Albiglutide Once Weekly vs Thrice-Daily Insulin Lispro Week With Basal Insulin for T2DM Mean FPG, mmol/l Week Compared with lispro, albiglutide caused more nausea (11.2% vs 1.4%) and vomiting (6.7% vs 1.4%), but less hypoglycemia (15.8% vs 29.9%) N=563 patients with T2DM treated with insulin glargine with metformin and/or pioglitazone. Rosenstock J, et al. Diabetes Care. 2014;37(10): ΔWeight From Baseline, kg Lispro (n=281) Albiglutide (n=282) -1.5 (95% CI: -2.1, -1.0) Week Simplify the Regimen Core Principles Action Adjust timing, frequency, amount, and dosage Prescribe once-daily medications Match regimen to patient s activities of daily living Dose to regular activities (eg, meals) Consider combination formulations Recommend all medications be Assess for drug-drug interactions and food taken together absorption issues Avoid medications with special requirements Avoid unnecessary side effects Avoid medications that should not be taken with meals Evaluate all potential side effects May need to choose among side effects Change the situation rather than change the patient! American College of Preventative Medicine. Available at: adherenceclinicalreference.pdf. 66-year-old owner of a local bakery Lives with husband of 30 years Visits you for the first time in 3 years Has felt rundown over last 6 months Recently wakes often to urinate at night SARAH Background Has trouble eating healthy States that she needs to sample her offerings at the bakery each day 2-3 glasses of wine with dinner each night Smokes ½ pack/day Does not exercise other than walking b/w commuter train and work 6 days/week Medical history SARAH Patient History Hyperlipidemia diagnosis 6 years ago Atorvastatin 20 mg once daily Stage 3 CKD, first diagnosed 2 years ago egfr, 45 ml/min/1.73 m2 UACR, 28 mg/g Family history Father died of major stroke at 74 years old Mother was obese Died following MI at 65 years old SARAH Physical Exam and Lab Testing SARAH Initial Treatment Height, 5 4 Weight, 175 lb BMI, 30.0 kg/m2 Abdominal obesity Afebrile BP, 131/78 mm Hg FPG, 181 mg/dl 2nd test, 179 mg/dl A1c, 8.8% Normal sensory and fundoscopic exams Lipids TC, 186 mg/dl LDL-C, 105 mg/dl HDL-C, 45 mg/dl TG, 155 mg/dl Framingham risk, 5.5% Target A1c, <7.0% (provided hypoglycemia is not a problem) PCP begins initial discussions about lifestyle modifications Suggests a certified diabetes educator Patient education Detailed dietary and exercise recommendations Receives a diagnosis of T2DM

7 After educating SARAH on her diagnosis of T2DM, what would you recommended pharmacologically to help her manage her diabetes? 60-yr-old Caucasian man Advertising executive Lives with wife of 25 years and 2 daughters Family history Parents had long history of HTN and died from CVD Social history Does not smoke or use illicit drugs Rarely drinks alcohol Does not follow dietary recommendations JOSEPH Background Medical history T2DM diagnosis 7 years ago Metformin 1000 mg twice daily Insulin glargine, 48 U each morning Hypertension diagnosis 10 years ago Lisinopril 40 mg daily Atenolol 50 mg daily JOSEPH Recent Lab Testing JOSEPH Current Presentation Height, 5 7 Weight, 260 lb BMI, 40.7 kg/m2 BP, 124/78 mm Hg (on therapy) Recent FPG, 87 mg/dl A1c, 7.8% A1c Goal, <7.0% Lipids TC, 187 mg/dl LDL-C, 105 mg/dl HDL-C, 50 mg/dl TG, 160 mg/dl egfr, 90 ml/min/1.73 m2 UACR, 5.5 mg/g Numerous episodes of shakiness and sweating over the last few months Often occur when he is late and skips breakfast Occasionally awakes feeling unwell and offkilter Sporadic BGM shows morning hypoglycemia episodes Blood glucose readings mg/dl Case Question What would be your next step in managing Joseph? 1. Counseling to address poor diet 2. Discontinue basal insulin and start another antihyperglycemic agent 3. Reduce basal insulin dose and add another antihyperglycemic agent 4. Obtain detailed information about his glycemic profile (eg, postprandial glucose readings) JOSEPH Follow-Up Visit At a follow-up appointment 1 week later, Joseph presents more detailed blood glucose testing Day AM Fasting 2-h PPG Bedtime 5/ / / / / /

8 JOHNNY Background What recommendations would you make to JOSEPH to improve the management of his T2DM? 62-year-old African American man Retired construction worker Lives alone Divorced wife of 30 years 5 years ago Presents for a check-up Last visit 6 months ago Nonsmoker Relatively unhealthy lifestyle Some physical activity Regularly consumes fast food Rarely eats fruits or vegetables Drinks 4-5 beers each night JOHNNY Patient History JOHNNY Physical Exam and Lab Testing Medical history Hypertension diagnosis 5 years ago Lisinopril 40 mg daily and atenolol 50 mg daily NSTE myocardial infarction 2 years ago PCI, 12 months of ticagrelor, daily low-dose aspirin T2DM diagnosis at admission for the MI Metformin 1000 mg twice daily Glyburide 10 mg once daily Hyperlipidemia diagnosis 1 year ago Atorvastatin 40 mg daily Family history Mother died of MI at 62 years old Father is alive at 80 years old but has T2DM NSTE, non ST-segment elevation; PCI, percutaneous coronary intervention. Height, 5 10 Weight, 235 lb BMI, 33.7 kg/m2 Abdominal obesity Afebrile BP, 130/78 mm Hg FPG, 165 mg/dl A1c, 8.4% Previous value 7.6% 6 months ago Goal, <7.0% Lipids (on therapy) TC, 166 mg/dl LDL-C, 90 mg/dl HDL-C, 46 mg/dl TG, 150 mg/dl egfr, 73 ml/min/1.73 m2 UACR, 25.2 mg/g JOHNNY Clinical interview Forgets to take various pills 2-3 times/week Has been taking walks but is having a difficult time sticking to dietary recommendations Wife used to do the cooking Now that he lives alone he often eats fast food even though he know that he shouldn t Has been skipping breakfast occasionally in an effort to lose weight Ends up snacking more later in the day Describes 3 occasions over the last 6 months where he felt shaky and sweaty What steps would you take to help JOHNNY better manage his T2DM?

9 Conclusions Monitor multiple parameters for good T2DM management and reduced CV risk A1c, lipids, BP Hypoglycemic episodes are associated with serious adverse outcomes Consider appropriate roles for DPP-4 inhibitors Modest reductions in A1c Weight neutral and low risks of hypoglycemia Well tolerated with few major side effects Consider appropriate roles for GLP-1 RAs Robust reductions in A1c Relatively low risks of hypoglycemia Most common side effects are gastrointestinal Potential for weight loss and CV benefits