Principles on Insulin Treatments. Insulin & Type 2 Diabetes. Natural History of Type 2 Diabetes. Why Consider Insulin Early?

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1 Principles on Treatments & Type 2 Diabetes Jessica Castle, MD Assistant Professor, OHSU Harold Schnitzer Diabetes Health Center Natural History of Type 2 Diabetes Severity of Diabetes UKPDS: Over Time, Need for Exogenous Increases Prediabetes Frank Diabetes Resistance Hepatic Glucose Production Endogenous Postprandial Blood Glucose Fasting Blood Glucose Patients Requiring (%) Oral agents Chlorpropamide Glyburide By 6 years, more than 5% of UKPDS patients required insulin therapy Time Microvascular Complications Macrovascular Complications Years to Decades Typical Diagnosis of Diabetes Years From Randomization Ramlo-Halsted BA, Edelman SV. Clin Diabetes. 2;18(2):8-85. Wright A, et al. UKPDS. Diabetes Care. 22;25: When to Consider in Type 2 Diabetes Basal insulin may be second agent after metformin When combination oral/injectable agents become inadequate High FPG or high PPG Unacceptable side effects of other agents Patient with advanced hepatic or renal disease Special circumstances (e.g., steroids, infection, pregnancy) Patient with hyperglycemia in the hospital Severely uncontrolled diabetes (A1C >1%) Why Consider Early? The most predictable glucose reduction Most effective Effective targeting of fasting glucose Also enhances post-prandial insulin response as well Potential for preservation of beta cell function Evidence of diabetes prevention in Origin Trial Evidence of improved insulin secretion when added to oral agents Evidence of beta cell preservation/ prolonged remission when used early in T2DM Good safety record other than hypoglycemia No evidence of increased cancer or heart disease with glargine in Origin Trial ADA. Diabetes Care. 215;38 (suppl 1):S41-S48; Weng J, et al. Lancet. 28;371:1753-6; Pennartz C, et al. Diabetes Care. 211; 34: ORIGIN Trial Investigators, Gerstein HC, et al. N Engl J Med. 212;367(4):

2 Impediments to the Potential Benefit of Therapy in Type 2 Diabetes Provider inertia Delay in progression of therapy to reach target Worse with insulin than other agents Behavioral barriers to initiating insulin Patients Providers Objective limitations once initiated Non-adherence Hypoglycemia Weight Gain Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Derr RL, et al. Diabetes Spectrum. 27; 2(3): Karter AJ, et al. Diabetes Care. 21;33(4): Clinical Inertia Leads to Delayed Initiation Patients (%) % SOLVE: Baseline A1C Distribution at Initiation A1C (%) Data from Khunti K, et al. SOLVE Study Group. Diabetes. 211;6(Suppl 1):A36. Patient Barriers to Initiation Patient Barriers to Initiation Barriers Addressing the Barriers Barriers Addressing the Barriers Sense of failure is a physiologic, inevitable step Discuss the eventual use of insulin with patients early Do not use insulin as threat, but as solution Fear of injections needles are very small Less painful than finger sticks for BG testing Have patient give a saline injection in office causes complications Loss of independence ineffectiveness Acknowledge the patient s fear Provide information about the provider s experiences of the effectiveness and safety of insulin Empower patient to take control of BG Provide self-management education Use insulin pens and insulin regimens that offer maximum flexibility Give limited trial with appropriate insulin doses Monitor for symptom improvement Patient to monitor for improved glucose at time of primary insulin effect (e.g. AM for basal insulin) Fear of hypoglycemia Weight gain Cost pen is usually less intimidating Educate: with basal insulin the incidence is low, especially with analog insulin Teach patient to recognize and treat (Rule of 15) Initially increase glucose monitoring to reassure Meet with dietitian before initiation of insulin Mention options of combinations with metformin and GLP-1 receptor agonists Basal is usually less expensive than adding multiple other non-generic medications Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Risk of Hypoglycemia Increases as Therapy Intensified in UKPDS Percentage of Patients Reporting 1 Hypoglycemic Event per Year For all therapies, the significance of differences between levels is p<.1.8% Diet Alone 1.7% 7.9% SU = sulfonylurea. Wright AD, et al. J Diabetes Complicat. 26;2: (UKPDS 73). 21.2% Metformin SU Basal Only 32.6% Basal + Bolus Overcoming the Barrier of Hypoglycemia with Less hypoglycemia with basal only approach Analog insulins reduce hypoglycemia Appropriate dosing reduces hypoglycemia Choose the right target for each individual e.g. Higher targets for elderly or those with renal insufficiency Proper patient education is crucial Learning to have consistent meals, adjust for exercise, monitor glucose, etc. Morales J and Schneider D. Am J Med. 214;127:S American Diabetes Association. Diabetes Care. 215;38 (suppl 1):S41-S48.

3 Options In Type 2 Diabetes Basal only Added to oral agents Basal plus Adding one rapid acting analog sequentially starting with largest meal Basal bolus Rapid acting analog before each meal Pre-mixed The Evolution of Products First Regular 1922 Protamine Zinc (PZI) NPH Lente s First Human s Rapid Acting Analogs Basal Analogs Inhaled Human s 2s 215 Toujeo Degludec Tibaldi JM. Am J Med. 214;127:S25-S38. Current Available Human and Analog s Type Onset Peak, h Duration of Action, h Rapid-acting Analogs lispro, aspart, glulisine 15 min Short-acting Regular human (U-1) Regular human (U-5) 3-6 min 3-6 min Intermediate-acting Human NPH insulin 1-3 h Long-acting (basal) glargine U-1 glargine U-3 detemir degludec 2-4 h 2-4 h 1-3 h 1 h No pronounced peak No pronounced peak 6-8 No pronounced peak >42 McMahon GT, Dluhy RG NEJM Walia M and Molitch M. JAMA. 214;311: Premixed s Inhaled (Afrezza) Type Onset Peak, h 7% NPH/ 3% Regular.5-1 h 75% NPL / 25% Lispro 15 min 5% NPL / 5% Lispro 15 min 7% NPA / 3% Aspart 15 min Walia M and Molitch M. JAMA. 214;311: h (dual) 1-4 (dual) 1-4 (dual) 1-4 (dual) Duration of Action, h % Degludec / 3% Aspart 15 min 1-peakless >42 Indications Pre-meal time insulin for Type 1 and 2 diabetes Pharmacokinetics Absorption: T max =12-15 min; Duration: min Place in therapy An inhaled alternative to injection for meal-time insulins Contraindications Patients with chronic lung disease (i.e., asthma, COPD) Common side effects Cough, throat pain/irritation, headache, and hypoglycemia Monitoring Pulmonary function prior to initiation, at 6 months of therapy and annually thereafter

4 Comparative Trials in T2DM Summary of Key Findings ADA Recommendations For Advancing Any insulin will lower glucose and A1C All insulins are associated with some weight gain and some risk of hypoglycemia Long-acting insulin analogs reduce the incidence of nocturnal hypos Premixed insulin preparations are effective in reducing HbA1c but are associated with more hypoglycemia and weight gain than using individual short and long-acting insulin Inzucchi SE, et al. Diabetologia. 212;55: ADA. Diabetes Care. 215; 38 (suppl 1): S41 S48. Benefits Start with Basal Added to Oral Agents Effective in reaching A1c goals for most Convenient once daily and easy titration Dosing Start 1 units per day or.1-.2 units per kg per day Adjust by 1-15% every 2-3 days to reach target For hypoglycemia Assess cause and correct or dose 4 U or 1-2% Tips for titration of basal insulin Patient engagement Avoid early hypoglycemia Achievable goals Simple and understandable Early follow up ORIGIN Investigators. N Engl J Med. 212; 367: American Diabetes Association. Diabetes Care. 215; 38(suppl 1)S41-S48. Dr. Richard Bergstrom, PDEC WORKSHEET TITRATION OF BASAL INSULIN NAME: DATE: TYPE OF BASAL INSULIN: WHEN IS THE BASAL INSULIN INJECTED: INITIAL DOSE OF BASAL INSULIN: FASTING BLOOD SUGAR TARGET: INCREASE ON EVEN DAYS (SUCH AS 2, 4, 16, 28, 3, ETC.) AND NO INCREASE ON ODD DAYS (SUCH AS 1, 5, 17, 29, 31, ETC.) YES = Yes increase on Even days NO = No increase on Odd days IF TODAY'S (EVEN) AND YESTERDAY'S (ODD ) BLOOD SUGARS ARE BOTH ABOVE THE FASTING BLOOD SUGAR TARGET THEN INCREASE THE BASAL INSULIN. INCREASE BASAL INSULIN BY AN INCREMENT OF: Dr. Richard Bergstrom, PDEC WORKSHEET TITRATION OF BASAL INSULIN NAME: DATE: TYPE OF BASAL INSULIN: Glargine WHEN IS THE BASAL INSULIN INJECTED: Bedtime INITIAL DOSE OF BASAL INSULIN: 1 Units FASTING BLOOD SUGAR TARGET: 15 INCREASE ON EVEN DAYS (SUCH AS 2, 4, 16, 28, 3, ETC.) AND NO INCREASE ON ODD DAYS (SUCH AS 1, 5, 17, 29, 31, ETC.) YES = Yes increase on Even days NO = No increase on Odd days IF TODAY'S (EVEN) AND YESTERDAY'S (ODD ) BLOOD SUGARS ARE BOTH ABOVE THE FASTING BLOOD SUGAR TARGET THEN INCREASE THE BASAL INSULIN. INCREASE BASAL INSULIN BY AN INCREMENT OF: 1 Unit MAXIMIUM DOSE OF BASAL INSULIN 4 Units MAXIMIUM DOSE OF BASAL INSULIN DECREASE BASAL INSULIN FOR HYPOGLYCEMIA 4 Units DECREASE BASAL INSULIN FOR HYPOGLYCEMIA Author: R Bergstrom Date Fasting blood sugar Basal insulin dose Date Fasting blood sugar Basal insulin dose Author: R Bergstrom Date 7/24 7/25 7/26 7/27 7/28 7/29 7/3 Fasting blood sugar Basal insulin dose Date 7/31 8/1 8/2 8/3 8/4 8/5 8/6 Fasting blood sugar Basal insulin dose

5 When Basal Alone Is Not Enough Regimens Basal Plus When A1C values are still not at target AND Basal insulin dose titrated to.4-.6 units/kg/day Fasting BG levels at or approaching target Post-prandial BG values remain above target Options: Advance insulin therapy with additional prandial insulin Add GLP-1 agonist therapy if tolerated, not contraindicated and is affordable for the patient Advantages Basal plus Two injections only, bolus typically targeted to largest meal of day Adherence is greater for twice daily than more frequent dosing Eliminates the barrier of lunch dosing Nearly as effective in lowering A1c as full basal bolus therapy in many Disadvantages Basal plus May not cover all prandial needs May not reach goal in some patients BG = blood glucose. American Diabetes Association. Diabetes Care. 215;38(suppl 1):S41-S48. Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: How to Intensify Using the Basal Plus Approach Choose a target meal to initiate prandial insulin Breakfast or the largest meal of the day Start rapid acting insulin analog 4 U,.1 U/kg or 1% of basal dose 1-15 minutes before meal If A1c is <8.% consider decreasing basal by 1% Adjust Increase dose 1-2 units or 1-15% once or twice weekly until SMBG following that meal is at target 2-h PPG -> target < 18 mg/dl Next pre-prandial or HS BG -> target < 13 mg/dl For Hypoglycemia Determine cause and correct; corresponding dose by 2-4 units or 1-2% Once titrated to goal, if A1C remains above target add 2nd prandial dose American Diabetes Association. Diabetes Care. 215;38(suppl 1):S41-S48. Regimens Basal Bolus Advantages Basal bolus Flexible regimen, basal plus bolus whenever eating meal, allows for correction insulin use Appropriate for patients willing to do multiple injections daily with frequent BG monitoring and capable of managing the complexity Disadvantages Basal bolus Many injections, adds complexity to daily insulin regimen May impact adherence Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: Guides for adjustments of insulin dosing Regimens Pre-Mixed Advantages Disadvantages Basal HS Prandial breakfast Prandial lunch Prandial dinner CBG Fasting Prior to lunch Prior to dinner Prior to bedtime Pre-mixed Can minimize daily injection number Appropriate for patients that cannot use basal bolus, wanting only 2 injections, and who have regular lifestyles, eat similar amounts at similar times each day (similar total calories and similar content for carbohydrate/fat/protein) Pre-mixed Fixed ratio, does not allow flexibility in dosing, increased risk of hypoglycemia Compliments of R Bergstrom Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85:

6 Strategies for Selection Convenience (once daily vs. twice or three times daily) Proven safety Analogs ORIGIN study showed low hypoglycemic risk, no adverse CV effects, and no cancer risk 1 NPH a little more hypoglycemic risk than analogs 2 Adverse Effects (Hypoglycemia, weight gain) Cost NPH $ Analogs $$-$$$ Insurance coverage Analogs coverage varies and may require prior authorization Recently approved insulins 1. ORIGIN Trial Investigators. N Engl J Med. 212;367(4): Riddle M, et al. Diabetes Care. 23; 26: High Concentration Glargine (U3) U-3 Glargine U3 insulin glargine offers a smaller depot surface area leading to a reduce rate of absorption Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency Half-life is ~23 hours Steady state in 4 days Duration of action 36 hours FDA approved February 215 Only available in pens 3 U/mL, 1.5 ml Max dose per shot is 8 units with 1 unit increments using current pen New pen in development will allow a max dose of 24 units U-3 glargine pen is white and green with the concentration highlighted in orange to distinguish it from U-1 glargine purple and gray Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Steinstraesser A, et al. Diabetes Obes Metab. 214 Feb 26. [Epub ahead of print]. Accessed March 11, Accessed January Accessed March 26, Accessed March 26, 215. Pharmacokinetic and Pharmacodynamics of U3 Glargine vs U1 Glargine INS [μu/ml -1 ] GIR [mg/kg -1 /min -1 ] LLOQ Time (h) Gla-1.4 U/kg -1 Gla-3.4 U/kg -1 U3 glargine displays a more even and prolonged PK/PD profile compared with U1 glargine, offering blood glucose control beyond 24 hours LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD = pharmacodynamic. Becker RH, et al. Diabetes Care. 214;pii:DC_146. N=3 36 Reduction in Documented Hypoglycemia with U3 Glargine vs U1 Glargine Added to Oral Agents Cumulative Number of Confirmed or Severe Hypoglycemic Events per Participant (nocturnal) (any time) Nocturnal RR.71 ( ) Any Time of Day RR.9 ( ) Time (weeks) Yki-Yarvinen H, et al. Diabetes Care. 214;37: Participants with 1Confirmed ( 3.9 mmol/l) or Severe Hypoglycemic Event (%) Differences by Time of Day Gla-1 Clock Time (hours) Gla-3

7 U3 Glargine vs U1 Glargine in T2DM: Meta-Analysis of Phase III Trials EDITION 1, 2, & 3 Baseline to Month 6 Glar U3 (N=1247) Glar U1 (N=1249) RR (95% CI) A1C (%), LS mean NS Weight (kg), LS mean P=.58 Any hypo in 24 hr* ( ) Any nocturnal hypo* ( ) Confirmed BG <54 mg/dl or severe hypo* (.72-.9) Confirmed nocturnal BG <54 mg/dl or severe hypo* ( ) *% people 1 event. LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval. Ritzel RA, et al. Presentation 963, 5th EASD Annual Meeting, September 15-19, 214, Vienna, Austria. Flexible vs Fixed Dosing U3 Glargine: Sub-Studies of Phase III Trials Percentage of Injections (%) Month Treatment Period (main study) U3 once daily every 24 h Edition 1 Sub-Study N=19 <1 h 6 Months (randomization, sub-study) 1-3 h >3 h Edition 2 Sub-Study N=89 Flexible Dosing Fixed Dosing <1 h 6 Month Extension Period (main study) U3 once daily every 3h sub-study U3 once daily every 24 h 1-3 h 9 Months (end of sub-study) >3 h No difference in A1C between flexible- vs fixed-dosing No difference in severe or nocturnal hypoglycemia within each sub-study Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 214, San Francisco, CA. Accessed August 15, 214. Degludec Pharmacodynamics of Degludec desb3 insulin acylated (16 carbon fatty acid chain) at LysB29 Duration of action >42 hours Half-life ~25 hours Detectable for at least 5 days Steady state in 2-3 days FDA approval in 215 Glucose Lowering Effect on Day 6 (mg/kg/min) Degludec.8 U/kg 6 Degludec.6 U/kg Degludec.4 U/kg Time since Injection (hours) Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Josse RG and Woo V. Diabetes Obes Metab. 213;15(12): Degludec vs U1 Glargine In Type 2 DM Equal Efficacy, Less Nocturnal Hypoglycemia and Less Overall Documented Hypoglycemia with Degludec Nocturnal Confirmed 1.6 Hypoglycemia p = Time (weeks) Garber AJ, et al. Lancet. 212;379(9285): A1C (%) Cumulative Events per Participant Cumulative Events per Participant A1C (mmol/mol) Degludec once-daily (N=744) Glargine once-daily (N=248) Cumulative Hypoglycemia per Participant per 24 hours p = Time (weeks) Basal s in Development PEGylated Lispro* Polyethylene glycol polymer covalently attached to lispro Half-life 2-3 days Steady state in 7-1 days Duration of action >36 hours Phase II-III clinical trials *Not FDA approved. Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Accessed March 11, 214. Sinha VP, et al. Diabetes Obesity Metab. 214;16(4):

8 PEGylated Lispro (LY265541) vs Glargine U1 in T1DM A1C (%) Weight (kg) Treatment Period 1 4 p <.1 8 Week Treatment Period 2 (Crossover) p < LY Treatment at 8 wks Significantly lowered A1C vs glargine Significantly reduced weight (1.2 kg) Increased overall hypos (p =.4) but less nocturnal hypos (p =.1) Lowered prandial insulin dose Significantly increased liver enzymes Glargine LY & Type 1 Diabetes Rosenstock J, et al. Diabetes Care. 213;36(3): The Natural Progression Of Type 1 Diabetes Case Beta cell function 1 % 2% Slower progression possible in adults Disease onset Honeymoon 23 yo female who presents for management of newly diagnosed diabetes Presented to outside provider with 3 week history of polyuria & polydipsia with 15 lb weight loss Time Case cont. Case cont. At time of presentation: Weight 124 lbs, BMI 22 CMP showed: glucose 395, bicarb 18, anion gap 18, A1c 12.6

9 Case cont. Presents to diabetes center with average CBG of 314 Her mother has type 1 diabetes Patient diagnosed with type 1 diabetes and started on insulin Basal-Bolus Regimen Glargine + Lispro/Aspart/Glulisine Basal Breakfast Lunch Dinner 8 AM 8 AM Aspart, Lispro or Glulisine How would you dose insulin for this patient? Type 1 insulin treatment will usually start in the range of.3-.5 u/ kg/ day (TDD) For this patient kg x.4 u/kg = 2 units per day 5% basal = 1 units - 1 units glargine q AM (or PM) or - 5 units detemir twice daily 5% pre-prandial = 1 units divided between 3 meals - aspart, lispro, or glulisine Glucose Monitoring Recommend at least ac & hs monitoring Look for mean glucose and trends Look for variability (e.g. SD) Identify hypoglycemia frequency/ timing Then adjust 3 units breakfast, 3 units lunch 4 units dinner Look for patterns that guide management Patterns at a given time of the day, indicating the insulin therapy controlling that time is faulty Carbohydrate (CHO) Counting CHO have the largest effect on blood glucose Establish a ratio from total daily insulin dose This is the amount of carbohydrate covered by 1 unit of fast-acting insulin (typical = 1:15 gm starting) Concept -- calculate intake of 6 Gm carb / 15 = 4 units Carbohydrate Ratio Can use rule of 17 to estimate starting CHO ratio 17/TDD/3 = number of grams of CHO covered by 1 unit of short-acting insulin TDD = total daily dose of insulin (basal + bolus) or can use an estimate of TDD based on weight (.4 units per kg) Example: Person with TDD of 55 units per day 17/55/3 1 Use starting carb ratio of 1 unit for every 1 grams of CHO

10 Correction Factor Back to the rule of 17 17/ TDD of insulin = correction How much we might expect 1 unit of rapid-acting insulin to drop the glucose at steady state Example a patient is taking 55 units daily Correction factor is 17/55 = 3 points If the pre-meal BG = 25 and your goal is 1 Pumps 216 Accu-Chek Spirit Animas Vibe Insulet Omnipod No tubing Medtronic 53G Low glucose suspend T:slim with G = 15 / 3 = 5 units for correction Pump info at Pump Settings Bolusing with Pump Infusion Sets Basal: Injections versus Pump Glargine or Detemir Pump 2: 7: 12: 16: 2: 24: 7: Time

11 Smart Pumps Are Standard Alerts for BG reminders, bolus reminders, set change, etc Can receive glucose level directly from meters and sensors Can be customized with different setting per day for: Blood glucose targets Carbohydrate ratios -sensitivity (correction) factors Who should consider a pump? Inadequate glucose control History of significant hypoglycemia or hypoglycemia unawareness Need for flexibility in lifestyle Pregnancy or planned pregnancy Relatively low insulin requirements A person who: Will monitor regularly Feels comfortable with technology Has reasonable expectations Summary T2DM is marked by progressive beta cell dysfunction requiring progressive pharmacological therapy to maintain glucose control Available guidelines promote stepwise advancement of therapy that includes basal insulin as an option after metformin regimens should be tailored to the patient s preferences and needs taking into consideration the pros and cons of each regimen The real and the perceived threat of hypoglycemia are major barriers among the multiple barriers to appropriately advancing therapy New basal insulins in development appear to offer further advantages in more consistent 24 hour coverage, reduced hypoglycemia and possibly weight advantage