Progressive Loss of β-cell Function in T2DM

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2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of November The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

3 Usage Rights This slide deck is provided for educational purposes and slides may be used for personal, non-commercial presentations only as long as content and references remain the same. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts.

4 Learning Objectives Appraise the use of traditional insulin therapies as an adjunct to basal insulin for patients unable to achieve A1C goals with basal insulin alone. Despite adequate control of fasting plasma glucose, briefly examine the significant impact of postprandial hyperglycemia on glycemic-related outcomes. Explore the use of GLP-1 receptor agonists (RAs) in combination with basal insulin to help patients achieve glycemic goals in terms of pharmacokinetics, adverse effects, administration, and place in therapy. Using case-based scenarios, design treatment and educational strategies for patients at increased risk for hypoglycemia, or those who have fears of hypoglycemia.

5 -cell function (% ) Progressive Loss of β-cell Function in T2DM data Early type 2 Causes of β-cell Failure Reduction of β-cell mass Apoptosis Decreased proliferation Amyloid deposition Glucotoxicity Lipotoxicity Decreased incretin effect data Late type 2, type At diagnosis, a patient with T2DM has ONLY 20 50% of the -cells as a person without T2DM Time (years) DeFronzo RA. Diabetes Rev. 1997; DeFronzo RA, et al. ADA 2008.

6 ADA Standards of Medical Care in Diabetes (2015) Metformin American Diabetes Association. Diabetes Care

7 Current Basal and Prandial Insulin Products Insulin* Onset Peak Effective Duration Rapid-Acting Aspart, glulisine, lispro (U100, U200) Inhaled Insulin 5-15 minutes Comparable to insulin lispro minutes 50 minutes <5 hours 2-3 hours Short-Acting Regular minutes 2-3 hours Regular: 5-8 hours Long-Acting (Basal) Glargine, detemir U100 Glargine U hours** 6 hours No peak Relatively peakless hours >24 hours *Assumes units/kg/injection. Onset and duration may vary significantly by injection site. ** Time to steady state DeWitt DE, et al. JAMA. 2003; Hirsch IB, et al. Clin Diabetes. 2005; FDA Prescribing Information.

8 When to Initiate Insulin Therapy in Type 2 Diabetes ADA/EASD Writing Group: As initial therapy in patients with significant symptoms associated with hyperglycemia Patient with dramatically elevated glucose concentrations (> mg/dl) or A1C ( 10.0%) Failure of non-insulin therapies Unintentional weight loss AACE/ACE Writing Group: As dual therapy in patients an A1C value of >7.5% (use with caution) or in asymptomatic patients with an A1C value of >9.0% As triple therapy in asymptomatic patients with an A1C value of >9.0% or when patient does not achieve A1C goal on dual therapy with two non-insulin agents after three months As initial therapy in symptomatic patients with an A1C value of >9.0% Other considerations: At start of pregnancy In hospitalized patients with diabetes Inzucchi SE, et al. Diabetes Care. 2015; Handelsman Y, et al. Endocr Pract. 2015; Garber AJ, et al. Endocr Pract

9 Initiation and Titration of Basal Insulin Bedtime intermediate-acting insulin or bedtime/morning long-acting insulin (10 units or 0.2 units/kg) Check fasting glucose daily and increase dose 2 units Q3 days until fasting consistently mg/dl; can increase by 4 units Q3 days if fasting >180 mg/dl If hypoglycemia or fasting <70 mg/dl reduce bedtime dose by 4 units or 10% (whichever is greater) Recheck A1C after 2-3 months Nathan DB, et al. Diabetes Care

10 A1C (%) Patients Can Safely and Effectively Self-Titrate Basal Insulin Incidence of Hypoglycemia (%) AT.LANTUS Frequent contacts with patients (12 in 24 weeks) Mixed specialty and general medicine clinics Audit to ensure investigator compliance of protocol algorithms Insulin was titrated by the provider at every visit (algorithm 1); vs. patient titrating every 3 days (algorithm 2) Patient Adjusted A1C Change Baseline weeks 7.9 Physician Adjusted Severe Hypoglycemia Patient adjusted Physician adjusted 3.2 Symptomatic Nocturnal Davies M, et al. Diabetes Care

11 Treat-to-Target Trial: Timing and Frequency of Hypoglycemia # Hypoglycemia Episodes (PG 72 mg/dl) Hypoglycemia by Time of Day Basal insulin * * Insulin glargine NPH insulin * * * * * B L D 20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 * P<.05 (between treatment) PG=Plasma-Referenced Glucose Time Riddle MC, et al. Diabetes Care

12 ADA 2015 Standards of Care Sequential Insulin Strategies in Patients With T2DM # Injections 1 Basal Insulin (usually with metformin +/- other noninsulin agent) Start: 10 U/day or U/kg/day Adjust: 1-15% or 2-4 U once-twice weekly to reach FBG target For hypo: Determine and address cause: dose by 4 U or 10-20% Complexity low 2 3+ Add 1 rapid insulin injection before largest meal Start: 4 U, 0.1 U/kg, or 10% basal dose. If A1C <8%, consider basal by same amount Adjust: dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached For hypo: Determine and address cause: corresponding dose by 2-4 U or 10-20% If not controlled, consider basal-bolus 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 2 rapid insulin injections before meals ( basal-bolus ) Change to premixed insulin twice daily mod. Start: Divide current basal dose into 2/3 AM, 1/3 PM or ½ AM, ½ PM Adjust: dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached For hypo: Determine and address cause: corresponding dose by 2-4 U or 10-20% Start: 4 U, 0.1 U/kg, or 10% basal dose/meal. If A1C <8%, consider basal by same amount Adjust: dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached For hypo: Determine and address cause; corresponding dose by 2-4 U or 10-20% If not controlled, consider basal-bolus high Flexibility More flexible Less flexible Inzucchi S, et al. Diabetes Care

13 Basal-Bolus Insulin Treatment With Insulin Analogues U/mL B Lispro / Aspart / Glulisine L D Insulin glargine Insulin detemir Time of day B=breakfast; L=lunch; D=dinner

14 Basal/Bolus Prandial Insulin Basal insulin The intent of basal insulin: Suppress hepatic glucose production and improve fasting hyperglycemia-both overnight (fasting) and between meals. Bolus insulin (prandial or mealtime) The intent of bolus insulin: Cover the carbohydrate load of meals to control postprandial hyperglycemia.

15 Algorithm for Adding/Intensifying Insulin START BASAL (long-acting insulin) INTENSIFY (prandial control) A1C <8% TDD U/kg A1C >8% TDD U/kg Insulin titration every 2-3 days to reach glycemic goal Fixed regimen: increased TDD by 2 U Adjustable regimen: FBG >180mg/dL: add 20% of TDD FBG mg/dL: add 10% TDD FBG mg/dL: add 1 unit If hypoglycemic, reduce TDD by: BG<70mg/dL: 10%-20% BG<40mg/dL: 20%-40% Glycemic control not at goal** Add GLP-1 RA or SGLT-2i or DPP-4i Add Prandial Insulin TDD U/kg 50% Basal Analog 50% Prandial Analog Less desirable: NPH and regular insulin or premix insulin Insulin titration every 2-3 days to reach glycemic goal Increased prandial dose by 10% for any meal if the 2hr postprandial or next premeal glucose is >180mg/dL Premixed: increase TDD by 10% if fasting/premeal BG>180mg/dL If fasting AM hypoglycemia, reduce basal insulin If nighttime hypoglycemia, reduce basal and/or presupper or pre-evening snack short/rapid-acting insulin If between-meal daytime hypoglycemia, reduce previous premeal short/rapid-acting insulin Glycemic Goal**: <7%: most patients with type two diabetes; fasting and premeal BG<110mg/dL A1C and FBG targets may be adjusted based on patient s age, duration of diabetes, presence of comorbidities, diabetic complications, and hypoglycemia risk Garber AJ, et al. Endocr Pract

16 Contribution (%) Fasting vs. Postprandial Glucose Contribution to A1C Fasting plasma glucose (FPG) Postprandial plasma glucose (PPG) % 50% 55% 60% 70% % 50% 45% 40% 30% 0 < >10.2 A1C Range (%) Monnier L, et al. Diabetes Care

17 Adjusted HR for Mortality Both FPG and 2-h PPG Predict Mortality in Persons Not Known to Have Diabetes 2.5 All Subjects (N 25,000) 2.5 Subjects With FPG <110mg/dL < > < >200 FPG (mg/dl) 2-h PPG (mg/dl) FPG=fasting plasma glucose; PPG=postprandial glucose; HR=hazard ratio DECODE Study Group. Lancet

18 Incidence in 3.5 Years (%) A1C as a Predictor of CHD in Type 2 Diabetes Low (<6.0%) Middle (6.0%-7.9%) High (>7.9%) 15 * CHD Mortality All CHD Events *P<.01 vs lowest tertile; P<.05 vs lowest tertile CHD=coronary heart disease Kuusisto J, et al. Diabetes

19 Mixed meal GLP-1 Secretion and Inactivation Intestinal GLP-1 release DPP-4 Inhibitors Alogliptin Linagliptin Sitagliptin Saxagliptin GLP-1 active GLP-1 Receptor Agonists Albiglutide Dulaglutide Exenatide Liraglutide DPP-4 GLP-1 inactive Rothenberg P, et al. Diabetes. 2000; Drucker DJ, et al. Expert Opin Invest Drugs. 2003; Ahrén B. Curr Diab Rep

20 The Incretin Effect of GLP-1 and GIP CNS: promotes satiety and reduction of appetite Liver: glucagon reduces hepatic glucose output Alpha cell: glucagon secretion post-meal Stomach: regulates gastric emptying Beta cell: enhances glucosedependent insulin secretion and beta cell functional mass * * Improvements in beta cell mass have only been shown in animals; GIP=Gastric Inhibitory Polypeptide Flint A, et al. J Clin Invest. 1998; Larsson H, et al. Acta Physiol Scand. 1997; Nauck MA, et al. Diabetologia. 1996; Drucker DJ. Diabetes

21 Postprandial Hyperglycemia: The Result of Increased Glucagon and Poor Insulin Secretion Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) Carbohydrate Meal Healthy Subjects (N=14) Type 2 Diabetes (N=12) Time (min) Müller WA, et al. N Engl J Med

22 Glucose-Dependent Actions of GLP-1 in T2DM Patients Placebo GLP-1 Insulin (pmol/l) Glucagon (pmol/l) Glucose (mmol/l) GLP-1/PBO infusion * * * * * * * * GLP-1/PBO infusion * * * * GLP-1/PBO infusion * * * * * * * Time (min) Time (min) Time (min) Data are mean ± SE *P<.05 Nauck MA, et al. Diabetologia

23 AACE 2015 and ADA 2015 Goals for Glycemic Control Target Treatment Goals AACE ADA A1C 6.5% <7.0% Fasting glucose Postprandial glucose Fasting and premeal plasma glucose: <110 mg/dl 2-hour postprandial glucose: <140 mg/dl AACE=American Association of Clinical Endocrinologists ADA=American Diabetes Association Preprandial capillary plasma glucose: mg/dl Peak postprandial capillary plasma glucose: <180 mg/dl For most healthy patients with T2DM without concurrent illness and at low risk for hypoglycemia 1 Garber A, et al. Endocr Pract. 2015; 2 American Diabetes Association. Diabetes Care

24 GLP-1 RAs vs. Insulin Glargine Dose A1C (%) FPG (mg/dl) PPG (mg/dl) Weight (kg) Exenatide 10 mcg twice daily Exenatide 2 mg/week Liraglutide 1.8 mg/day Albiglutide 30 mg/week N/A Insulin Glargine Titrated to FPG <100mg/dL Glycemic control: Similar A1C reductions FPG reduction greater with insulin glargine PPG reduction greater with GLP-1 RAs Weight: GLP-1 RAs more effective to to to to +1.8 Heine RJ, et al. Ann Intern Med. 2005; Diamant M, et al. Lancet. 2010; Russell-Jones D, et al. Diabetologia. 2009; Weissman PN, et al. Diabetologia

25 Exenatide Twice Daily: Head to Head 4 studies: exenatide twice daily (N=2,444) Dose A1C (%) FPG (mg/dl) PPG (mg/dl) Weight (kg) Exenatide 10 mcg twice weekly -0.8 to to to -3.6 Exenatide 2 mg/week -1.6 to to -41 N/A -2.3 to -3.7 Liraglutide 1.8 mg/week N/A Dulaglutide mg/week to to to to Glycemic control: Less effective with exenatide BID than with exenatide weekly, liraglutide, dulaglutide Weight loss: Less effective with exenatide BID than with liraglutide but similar with dulaglutide 1.5 mg dose and exenatide weekly Buse JB, et al. Lancet. 2009; Drucker DJ, et al. Lancet. 2008; Blevins T, et al. J Clin Endocrinol Metab. 2011; Buse J, et al. Lancet. 2013; Wysham C, et al. Diabetes Care

26 Liraglutide: Head to Head 4 studies: liraglutide (N=2,786) Dose A1C (%) FPG (mg/dl) PPG (mg/dl) Weight (kg) Liraglutide 1.8 mg/day -.98 to to to to Exenatide 10 mcg twice weekly Exenatide 2 mg/week N/A Dulaglutide 1.5 mg/week Albiglutide mg/week N/A Liraglutide s glycemic control: Was more effective than exenatide twice daily and weekly, and albiglutide Stated as noninferior to dulaglutide Weight: More effective than: exenatide weekly, dulaglutide, albiglutide Buse JB, et al. Lancet. 2009; Buse J, et al. Lancet. 2013; Dungan KM, et al. Lancet. 2014; Pratley RA, et al. Lancet Diabetes Endocrinol

27 Initiation and Titration Initial Dose Treatment Dose Maximum Dose Dose Adjustments Comments Exenatide twice weekly Exenatide once weekly 5 mcg for 1 month 10 mcg 10 mcg 2 mg CrCl <30 ml/min: Not recommended Within 60 minutes prior to a meal Liraglutide daily 0.6 mg for 1st week 1.2 to 1.8 mg 1.8 mg* None; Limited experience with renal impairment Albiglutide once weekly 30 mg 30 or 50 mg 50 mg None Missed dose, administer as soon as possible within 3 days Dulaglutide once weekly 0.75 mg 0.75 mg or 1.5 mg 1.5 mg None recommended *May need to decrease dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia FDA Prescribing Information.

28 Summary: Overall Efficacy Glycemic control: Monotherapy, combination with oral antidiabetic agents and basal insulin 0.67% - 1.9% reduction in baseline A1C 60 mg/dl decrease PPG Weight: Potential weight loss 3.6 kg weight loss

29 Side Effects and Safety Side effects Nausea and gastrointestinal symptoms most common (up to 30%) Headache (up to 13%) Hypoglycemia (more common in combination therapy) Injection site reactions (more common with exenatide once weekly and albiglutide) Safety Acute pancreatitis Medullary thyroid carcinoma FDA Prescribing Information.

30 Primary Benefits of GLP-1 Receptor Agonists Monotherapy or add on therapy for type 2 diabetes A1C by 1-1.7% Avoidance of hypoglycemia insulin secretion in a glucosedependent manner glucagon secretion similarly May need to dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia Can be used with elevated PPG and FPG Avoidance of weight gain/ promotion of weight loss Promote a 1-4 kg weight loss in most Promotion of satiety appetite and food intake Pts appear to maintain weight loss while on therapy Nauck MA. Diabetes Care. 2013; Handelsman Y, et al. Endocr Pract

31 Mitigation of Common Adverse Effects Nausea Usually mild moderate Peaks within 4-10 weeks Resolves in all but ~10% of cases in a similar time frame Within 28 weeks with exenatide twice daily Hypoglycemia Depends on background therapy Mostly in combination with insulin and insulin secretagogues May need to decrease the dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia Nauck MA. Diabetes Care

32 Pharmacological Therapy Selection Considerations Efficacy (A1C-lowering capacity) Effect on fasting blood glucose (FBG) and postprandial plasma glucose (PPG) Mechanism of action Route of administration Ease of use Patient preference Cost Adverse effects/tolerability Hypoglycemia risk Effect on weight Effect on nonglycemic factors (eg, serum lipids, blood pressure) Likely adherence Contraindications in comorbidities (hepatic or renal failure, coronary disease) American Diabetes Association. Diabetes Care

33 Clinical Point of Interest Although there is good evidence for a GLP-1 receptor agonist being the 1 st injectable, often clinicians add basal insulin instead. Furthermore, after a patient is on basal insulin with other OAD s many providers don t consider or add a GLP-1 RA.

34 GLP-1 RA + Insulin Options Diet, exercise, weight loss, oral agents + GLP-1 RA** + Basal Insulin Diet, exercise, weight loss, oral agents + Basal Insulin + GLP-1 RA** **GLP-1RAs approved with Basal insulin: Exenatide twice daily Exenatide LAR QW Liraglutide once daily

35 And how about adding a GLP-1 receptor agonist to basal insulin?

36 HARMONY 6: Albiglutide vs. TID Prandial Insulin Lispro HARMONY 6: albiglutide vs. insulin lispro Randomized, open-label trial (N=563) Insulin glargine + oral diabetes agents Metformin, pioglitazone, and/or AGIs Sulfonylureas, glinides, and DPP-4 inhibitors d/c 1 week prior to start Dose A1C (%) FPG (mg/dl) PPG (mg/dl) Weight (kg) Abiglutide 30 mg/week N/A -0.7 Insulin Lispro TID Prandial N/A +0.8 Glycemic control noninferior to lispro Weight change significant vs. lispro Rosenstock J, et al. Diabetes Care

37 Exenatide BID Added to Insulin Glargine P< Glargine + Placebo Glargine + Exenatide A1C Change (%) Outcome PBO EXN BID P Value Δ FPG (mg/dl) * Δ Insulin dose (U/d) Δ Weight (kg) <.001 Hypoglycemia (events/patient-y) Discontinuation due to AEs (% of patients) <0.01 * Baseline FPG: 149 and 142 mg/dl for PBO and EXN BID groups, respectively. Baseline insulin: 47.4 and 49.5 U/d for PBO and EXN BID groups, respectively. 1 reported event of major hypoglycemia (PBO group). Buse JB, et al. Ann Intern Med

38 GLP-1 RAs vs. Prandial Insulin Added to Basal Insulin Basal Insulin* + LIS (N=321) 4B-Study (30 week trial) 1 Mathieu C, et al. (26 week trial) Noninferior Basal Insulin* EXN BID (N=316) A1C (%) Basal Insulin** + ASP (N=89) Basal Insulin** + LIRA (N=88) P= A1C (%) Outcome EXN BID LIS Weight (kg) a Minor hypo (events/y) Major hypo (events/y) Noct. hypo (events/y) Outcome LIRA ASP Weight (kg) b Confirmed hypo (EPY) b Noct. hypo (EPY) c ASP=Insulin Aspart; EPY=Events Patient-Year; LIS=Insulin Lispro a P<.002, b P<.0001, c P=.0002; *Insulin glargine; **Insulin degludec is not approved by the US FDA 1 Diamant M, et al. ADA 73 rd Scientific Sessions. 2013; 2 Mathieu C, et al. ADA 73 rd Scientific Sessions

39 Patient: Max 47 male with a 7 year h/o T2DM Social Operates a residential landscape company very busy days spending long hours on heavy equipment. He states, I cannot afford to have low blood sugars, I need to avoid them at all costs. ETOH 4 beers on weekend twice monthly Exercise uses elliptical machine 3-4 days/week for 35 minutes Diet 3 meals daily, avoids white foods no sweet beverages, occasional popcorn snack in evenings

40 Patient: Max Ht=73 Wt=244 lbs. BMI=32 kg/m 2 Labs: GFR=94 Remainder of full Chemistry panel normal. A1C: 6.5% 7.1% for the past 2 years Today A1C 7.8% MEDS: Metformin ER 500 mg, 2 each evening Pioglitazone 30 mg, one each morning Glargine U100, 27 units each evening Note he was unable to tolerate 2,000 mg metformin ER/day

41 Max: Blood Glucose Log DAY BB AB BL AL BD AD SUN MON TUE WED THU FRI SAT SUN MON TUE WED THU

42 ? Patient: Max What Would You Suggest Now? Increase Glargine Add GLP-1 RA Add DPP-4 inhibitor Add SGLT-2 inhibitor Add Sulfonylurea Add Prandial insulin with meals Nothing

43 Max - Revisited From a Different Prospective A1C: 6.5% 7.1% for the past 2 years Today A1C 8.0% MEDS Metformin ER 500 mg, 2 each evening Pioglitazone 30 mg, one each morning Max dose of GLP-1 RA: (exenatide 2x/day or liraglutide or albiglutide) Note he was unable to tolerate 2,000 mg metformin ER/day

44 ? Patient: Max What Would You Suggest Now? Add SGLT-2 inhibitor Add Sulfonylurea Add basal insulin once daily Add Prandial insulin with meals Need to see actual blood sugars

45 Max: Blood Glucose Log DAY BB AB BL AL BD AD SUN MON TUE WED THU FRI SAT SUN MON TUE WED THU

46 ? Patient: Max What Would You Suggest Now? Add SGLT-2 inhibitor Add Sulfonylurea Add basal insulin once daily Add Prandial insulin with meals

47 Summary Type 2 diabetes patients need therapeutic intervention to control glycemic levels. Lifestyle interventions remain the cornerstone of therapy. Most patients will require combination pharmacotherapy in addition to lifestyle changes. Incretin-related agents have good glycemic lowering efficacy, a low risk for hypoglycemia, and weight neutrality or weight loss. Incretin optimization of endogenous insulin secretion before adding exogenous insulin may reduce insulin requirements, hypoglycemia and weight gain. When insulin is needed, basal and prandial analog insulins have a number of advantages compared to human insulin.

48 Team Approach to Care Treatment adherence optimized when patients are taught the skills and behaviors required for diabetes self-management and provided with the support needed for implementing those skills and behaviors ADA recommends an interdisciplinary approach to care from a team Physicians, nurse practitioners, physician assistants, nurses, dietitians, pharmacists, and mental health professionals with expertise and a special interest in diabetes Collaborative approach should be designed to empower patients to assume an active role in their care and encourage appropriate self-management of their disease American Diabetes Association. Diabetes Care

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