Drug List. Drug List (cont d) Objectives. Case and Initial CME Questions. Presenter Disclosure Information

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1 :3 :5 PM How to Select and Initiate Insulin Therapy in the Type Diabetes Patient SPEAKERS Intekhab Ahmed, MD, FACE, FACP Felice Caldarella, MD, FACE, FACP, CDE Presenter Disclosure Information The following relationships exist related to this presentation: Intekhab Ahmed, MD, FACE, FACP: No financial relationships to disclose. Felice Caldarella, MD, FACE, FACP, CDE: Speaker's Bureaus for Novo Nordisk Inc. and Takeda Pharmaceuticals U.S.A, Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Drug List Drug List (cont d) Generic Drug Name US Trade Name Generic Drug Name US Trade Name Glyburide/glibenclamide DiaBeta, Glynase Insulin human isophane (NPH) Humulin N, Novolin N Glimepiride Insulin aspart Insulin detemir Insulin degludec Insulin glargine U3 Insulin glargine Insulin glulisine Amaryl Novolog Levemir Tresiba Lantus Toujeo Apidra Insulin lispro Lisinopril Metformin Nateglinide Pioglitazone Repaglinide Humalog, Lispro-PFC Zestril, Prinivil Glucophage Starlix Actos Prandin Insulin human regular Humulin R, Novolin R Sitagliptin Januvia Objectives Implement strategies for the timely intensification of antihyperglycemic therapy, including the initiation of insulin therapy in patients with type diabetes Describe the pharmacologic and clinical differences between currently available basal insulins Assess the role of new ultralong-acting basal insulins and formulate insulin regimens that are specific to patient needs while minimizing risk Educate patients about self-management and strategies for prevention and management of Case and Initial CME Questions

2 Case # Steve 66-year-old male with type diabetes for 9 years. He is seeing you for the first time since moving here for work. PMH: Hypertension for 5 years PE: BP 3/8, Weight 5 lb (93 kg), Height 5 9 Upon diagnosis Steve was referred for diabetes education Steve s physician informed him about his diabetes and the various treatment options, including diet and exercise, which he elected to try first before initiating medications Case # Steve cont d After approximately 3 months on diet control and exercise, Steve s AC decreased to 8.3% Based on the improvement seen in his AC with diet and exercise, a decision was made to continue with it; another 3 months later, his AC increased to 8.5% Steve then started metformin and titrated to mg twice daily Case # Steve cont d Over the next 8 months, Steve s AC was at its lowest of 7.3% 3 months after starting metformin and at its highest of 8.% at 8 months following the initiation of metformin Glimepiride at mg daily was added to his metformin After adding glimepiride, Steve s AC ranged from a best of 7.% to a worst of 8.7% during the next 7 years After moving here, he is in to see you for a checkup Case # Steve cont d Current meds: Lisinopril mg daily Metformin mg twice daily Glimepiride 8 mg daily Labs: AC 8.7% Steve states that he has been exercising roughly 3 times per week and is taking his medications regularly He also states that he has experienced a episode since starting glimepiride when he missed lunch Clinical Inertia Common in Real-World Treatment of Type Diabetes Retrospective cohort study of 8,573 type diabetes patients in the United Kingdom Clinical Practice Research Datalink between January and December 6, with follow-up until April # of OADs AC Median Time to Intensification 7.%.9 years 7.% >7. years # of OADs AC at Insulin Initiation OADs = oral antidiabetic drugs. Khunti K, et al. Diabetes Care. 3;36():3-37. Median Time to Intensification with Insulin 8.7% 7. years 9.% 6. years Reasons for Clinical Inertia Provider Time constraints Lack of knowledge Potential risks of Variations in guideline recommendations Patient Nonadherence Concerns about and weight gain Healthcare System Cost of newer medications Khunti K, et al. Br J Diabetes Vasc Dis. 5;5:65-69.

3 Provider Clinical Inertia Primary reasons providers fail to intensify treatment Overestimation of care provided i.e., providers overestimate their adherence to guidelines and the care they provide Citing soft reasons to avoid intensification of treatment i.e., perception that the overall care of their patient is improving, nonadherence among patients, and concerns about results from recent large CV trials Lack of training Khunti K, et al. Br J Diabetes Vasc Dis. 5;5: Cost of Clinical Inertia Retrospective cohort study using UK Clinical Practice Research Datalink 5,77 newly diagnosed type diabetes from 99 with follow-up data available until Mean AC 8.% at diagnosis, % had history of cardiovascular disease, and 7.% experienced at least one CV event during 5.3 years of median follow-up One year delay in receiving intensified therapy (goal AC < 7.%) was associated with significantly increased risk of MI by 67%, stroke by 5%, HF by 6%, and composite CVE by 6% MI = myocardial infarction; CV = cardiovascular Paul SK, et al. Cardiovasc Diabetol. 5;:. Reduction in AC with OADs and Insulin Reduction in AC with OADs and Insulin -.3*. -.* -.5* +.* Pretreatment Posttreatment. -.* -.5* +.* Pretreatment Posttreatment Mean AC (%) 8. Mean AC (%) Two OADs Three OADs Four OADs 6. Two OADs Three OADs Four OADs Insulin *p <. OADs = oral antidiabetic drugs Calvert MJ, et al. Br J Gen Pract. 7;57:55-6. *p <. OADs = oral antidiabetic drugs Calvert MJ, et al. Br J Gen Pract. 7;57:55-6. Patients (%) Insulin Initiation Delayed Distribution of AC at time of insulin initiation 8 8.9% 6 (%) 9.% (%).% Baseline AC (%) When to Start Basal Insulin Consensus Statement of the ADA and EASD- AC is not at goal AC > 8.5% with two-drug therapy should receive insulin vs adding a third agent Not prepared or able to take multiple daily injections Fasting glucose is consistently above goal Patient is willing to monitor fasting glucose Possibly the beginning step to progress to basal-bolus therapy SOLVE, study of once daily Levemir. N = 7,37. Khunti K, et al. Diabetologia. ;5(suppl ):S6 and Poster 377-P. Inzucchi SE, et al. Diabetes Care. ;35(6):

4 The Benefits of Insulin The most predictable glucose reduction Most effective Effective targeting of fasting glucose Also enhances postprandial 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 type diabetes Good safety record other than No evidence of increased cancer or heart disease with glargine in ORIGIN Trial ORIGIN = Outcome Reduction With Initial Glargine Intervention ADA. Diabetes Care. 5;38 (suppl ):S-S8; Weng J, et al. Lancet. 8;37:753-76; Pennartz C, et al. Diabetes Care. ; 3:8-53. ORIGIN Trial Investigators, et al. N Engl J Med. ;367(): Responding to Patient Fears and Misconceptions about Insulin. Less than % of insulin naïve patients feel insulin is beneficial In the past, insulin was started too late when complications already occurred Clinical trials show the benefit of blood-glucose control in decreasing the risk of microvascular complications. 5% see insulin as a punishment and self blame Explain that a decrease in insulin production is a natural progression of diabetes 3. 5% fear injection Start with injection a day and have patient self inject in the office Prescribe an insulin pen. Fear of weight gain Chance of weight gain will decrease with healthy eating and daily activity 5. Fear of Encourage home glucose monitoring Use the newer insulins Encourage patients to maintain follow-up appointments Hypoglycemia teaching: causes, signs and symptoms, and treatment Funnell MM, Kruger DF, Spencer M. Diabetes Educ. ;3():7-8. Polonsky WH, Jackson RA. Clin Diabetes. ;(3):7-5 Additional Barriers: Severe Hypoglycemia with Therapy Intensification Annualized Rate of Severe Hypoglycemia (%) 3 p<. vs Conventional.8..7 Conv Gly Insulin AC 7.9%7.% 7.% UKPDS p<..7. p<. 3.. p= Std Int Std Int Std Int 7.3% 6.5% 7.5% 6.% 8.% 6.9% ADVANCE ACCORD 3 VADT Lots of Guidance AACE Algorithm IDF Algorithm Intensive glycemic control was defined differently in these trials; defined as any hypo. requiring any assistance in glucose-lowering trials. Conv = conventional therapy; Gly = glibenclamide; Int = intensive therapy; Std = standard therapy; UKPDS = United Kingdom Prospective Diabetes Study; VADT = Veterans Affairs Diabetes Trial.. UKPDS Group. Lancet. 998;35: ADVANCE Collaborative Group. N Engl J Med. 8;358: Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 8;358: Duckworth W, et al. N Engl J Med. 9;36:9-39. Inzucchi S, et al. Diabetes Care. 5;38:-9. Garber AJ, et al. Endocr Pract. 5;():38-7. IDF Guideline for Type Diabetes. Strategy for the Timely Intensification of Treatment Set appropriate glycemic targets AC < 7.% for most patients AC of 7 8% is reasonable in patients with known CVD or multiple comorbidities Tailor treatment decisions to individual patient preferences, prognoses, and comorbidities Diet and exercise is integral to the treatment of type diabetes, and some patients may achieve glycemic control with it alone, but many will require medications Assess glycemic control regularly (~3 months) and intensify treatment if AC target is not achieved Inzucchi S, et al. Diabetes Care. 5;38:-9. American Diabetes Association. Clin Diabetes. 6;3():3-. When to Start a Basal Insulin Consensus Statement of the ADA and EASD- AC is not at goal AC > 8.5% with two-drug therapy should receive insulin vs adding a third agent Not prepared or able to take multiple daily injections Fasting glucose is consistently above goal Patient is willing to monitor fasting glucose Possibly the beginning step to progress to basal-bolus therapy Inzucchi SE, et al. Diabetes Care. ;35(6):

5 Current Available Insulins Insulin Type Onset Peak, h Rapid-acting analogs Insulin lispro, aspart, glulisine Insulin human inhaled Short-acting Regular human (U-) Intermediate-acting Human NPH insulin Regular human (U-5) Long-acting (basal) Insulin glargine Insulin detemir Follow-on insulin glargine* Ultralong-acting (basal) Insulin glargine U-3 Insulin degludec (U-/U-) 5 min -5 min.5-.5 ~. Duration of Action, h min h 3-6 min - h -3 h - h Develops over 6 h 3-9 min *FDA approved but not yet available. Walia M and Molitch M. JAMA. ;3: Nasrallah SN, et al. Clin Med Insights Endocrinol Diabetes. :5:3-37. PDR.net. Accessed April 5, 5. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist s Letter/Prescriber s Letter. March No pronounced peak No pronounced peak No pronounced peak Nearly peakless Nearly peakless > Plasma Insulin Levels PK Profile of Currently Available Insulins Inhaled insulin Aspart, lispro, glulisine Regular Intermediate (NPH insulin) Long (insulin detemir) Long (insulin glargine) Time (h) Ultralong (U3 glargine) Ultralong insulin degludec PK = pharmacokinetic; NPH = neutral protamine Hagedorn. Adapted from Hirsch IB. NEJM. 5;35:7-83. Flood TM. J Fam Pract. 7;56(suppl ):S-S. Becker RH, et al. Diabetes Care. 5;38: Accessed April 5, 5. Hompesch M, et al. Clin Ther. ;36(): Comparative Insulin Trials in TDM Summary of key findings Any insulin will lower glucose and AC All insulins are associated with some weight gain and some risk of The larger the doses and the more aggressive the titration, the lower the AC but often with a greater possibility of adverse effects Long-acting insulin analogs reduce the incidence of overnight Rapid-acting insulin analogs reduce postprandial glucose excursions (compared with corresponding human insulins [NPH, regular]), but they generally do not result in clinically significantly lower AC Premixed (Biphasic) Insulin Analogs Premixed insulins Humalog 75/5, 5/5: Intermediate + rapid-acting Novolog 7/3: Intermediate + rapid-acting Humulin 7/3: Intermediate + short-acting Novolin 7/3: Intermediate + short-acting Degludec Novolog 7/3: Long acting + rapid acting NPH = neutral protamine hagedorn Riddle M, et al. Diabetes, Obesity, and Metabolism. ;6:396-; Orozco-Beltran D, et al. Diabetes. 3; 6(suppl ): A{Abstract 397-P}. Little S, et al. Diabetes Technol Ther. :3(suppl ) S63-S6. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist s Letter/Prescriber s Letter. March 5. Premixed vs Basal Insulin Analogs in TDM Premixed 9.7 Basal Glargine 9.8 AC (%) 9..8* Premixed Basal P-value 5 AC < 7% 66% % p <. Hypoglycemia (events/yr) Baseline Wk 8 3. Baseline.7 Wk 8 p <.5 BID Bisphasic QD Insulin Weight (kg) Insulin Aspart 7/3 Glargine p <. Insulin dose (units/day) N=7 79 ± N=6 5 ± 7 p <.5 Felice Caldarella, MD, FACE, FACP, CDE *P <. vs glargine Data from Raskin P, et al. Diabetes Care. 5;8:6-65.

6 ADA Recommendations for Advancing Insulin Basal Insulin (usually with metformin ±other noninsulin agent) # Injections Complexity Start: U/day or.-. U/kg/day Low Adjust: -5% or - U once-twice weekly to reach FBG target. For hypo: Determine & address cause; dose by units or -%. Flexibility: If not controlled after FBG target is reached (or if dose >.5 U/kg/day),, treat PPG excursions with mealtime insulin (Consider initial GLP--RA trial) Mod Add rapid insulin injection Change to before largest meal (basal-plus) premixed insulin twice daily If not controlled, Add rapid insulin If not controlled, 3+ consider Injections before meals consider High basal-bolus ( basal-bolus ) basal-bolus More Flexible ADA. Diabetes Care. 5;38(suppl ):S-S8. Less Flexible Strategies for Insulin 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 NPH a little more hypoglycemic risk than analogs New ultralong-acting basal insulin formulations have a lower risk of particularly nocturnal compared to analogs 3, Cost NPH $ Analogs $$-$$$ Insurance coverage Analogs coverage varies and may require prior authorization. ORIGIN Trial Investigators. N Engl J Med. ;367(): Riddle M, et al. Diabetes Care. 3; 6: Ritzel R, et al. Diabetes Obes Metab. 5;7(9): Garber AJ, et al. Lancet. ;379(985): Insulin Regimens Insulin Regimens cont d Advantages Disadvantages Advantages Disadvantages Basal only Basal only Basal bolus Basal bolus Convenient, shot only, low risk of, especially with analog insulin Appropriate for most patients starting insulin Basal plus Two injections only, bolus typically targeted to largest meal of day Does not address PPG, may not provide sufficient insulin for patients with advanced disease Basal plus May not cover all prandial needs 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 Many injections, adds complexity to daily insulin regimen Appropriate for patients not achieving goal AC on basal insulin and wanting only two shots daily Plank J, et al. Arch Intern Med. 5;65: Horvath K, et al. Cochrane Database Syst Rev. 7; ():CD563. Davies M, et al. Diabetes Care. 5;8:8-8. Yki-Järvinen H, et al. Diabetes Care. 7; 3: Crasto W, et al. Postgrad Med J. 9;85: Plank J, et al. Arch Intern Med. 5;65: Horvath K, et al. Cochrane Database Syst Rev. 7; ():CD563. Davies M, et al. Diabetes Care. 5;8:8-8. Yki-Järvinen H, et al. Diabetes Care. 7; 3: Crasto W, et al. Postgrad Med J. 9;85: Insulin Regimens cont d Starting and Titrating Basal Insulin Advantages Premixed Can minimize daily injection number Appropriate for patients who cannot use basal-bolus, wanting only injections, and who have regular lifestyles, eat similar amounts at similar times each day (similar total calories and similar content for carbohydrate/fat/protein) Disadvantages Premixed Fixed ratio, does not allow flexibility in dosing, increased risk of Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: U or.-. U/kg Check FPG daily Adjust dose -5% or - U once-twice weekly to reach FPG target 8-3 mg/dl Initiate insulin with a single injection of a basal insulin In the event of or FPG level <8 mg/dl, reduce insulin dose by U or -% Continue regimen and check HbAC every 3 months Plank J, et al. Arch Intern Med. 5;65: Horvath K, et al. Cochrane Database Syst Rev. 7; ():CD563. Davies M, et al. Diabetes Care. 5;8:8-8. Yki-Järvinen H, et al. Diabetes Care. 7; 3: Crasto W, et al. Postgrad Med J. 9;85: Inzucchi S, et al. Diabetes Care. 5;38:-9.

7 How to Intensify Using the Basal Plus Approach Choose a target meal to initiate prandial coverage Breakfast or the largest meal of the day Start 6 units of a rapid-acting insulin analog 5 minutes before the meal Adjust prandial insulin dose based on -h PPG target <8 mg/dl Next preprandial or HS BG target <3 mg/dl If AC remains above target, add second prandial dose Usually need about 8 units of prandial insulin to cover meal(s) Basal-bolus dosing ~5% bolus insulin and ~5% basal insulin Limitations of First-Generation Basal Insulins Variability Glargine and detemir are not truly peakless Predictability Inconsistent glucose-lowering activity between doses Duration of action hours: leads to a lack of flexibility in dosing regimens Fear of Do not have a completely flat pharmacodynamic profile HS = at bedtime; PPG = postprandial glucose Lankisch MR, et al. Diabetes, Obesity and Metabolism. 8:; Meneghini L, et al. Endocrine Practice. ;7; New Options to Address Challenges in Care Longer-acting insulin Glargine U3 Degludec U and U Concentrated insulin Glargine U3 Degludec U Lilly U5 Lispro U Glargine 3 U/mL Clinical Evidence Summary What s the Difference Between Glargine U3 and Glargine U? Glar U3 contains 3-times the amount of insulin glargine per ml as Glar U The same unit amount in /3 the volume Release rate and duration of action depend on precipitate size and compactness Surface Area, cm 3 Surface to Volume Ratio Glar U Glar U Volume, ml dp glar /dt Steinstraesser A, et al. Diabetes Obes Metab. ;6: Release Rate P glar Glar U Glar U3 PK/PD Profile with Glar U3 vs Glar U Insulin Concentration (µu/ml) Glucose Infusion Rate (mg/kg/min) LLOQ 3 U3 glargine has a more even and prolonged PK/PD profile Time (h) LLOQ = lower limit of quantification Becker RH, et al. Diabetes Care. 5:; Glar U3. U/kg, N=6 Glar U. U/kg, N=7

8 U3 Glargine vs U Glargine in TDM: Meta-Analysis of Phase III Trials: Edition,, & 3 Baseline to Month 6 Glar U3 (N=7) Glar U (N=9) RRR P Value AC (%), LS mean ~ NS Weight (kg), LS mean %.39 Any hypo in hr* % <.5 BG 7 mg/dl or severe hypo* %.6 Nocturnal BG 7 mg/dl or severe hypo* %. Number needed to treat with Glar U3 to prevent BG 7 mg/dl or severe hypoglycemic event is 6 *Events per participant-year, people event. LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval. Ritzel R, et al. Diabetes Obes Metab. 5;7(9): Flexible vs Fixed Dosing of Glargine U3 Percentage of Injections (%) Sub-Studies of Phase III Trials Type diabetes receiving U3 insulin glargine were allowed to administered their insulin ± 3 hours from their schedule dose 8 6 Edition Sub-Study N=9 ± < h ± -3 h ± >3 h Edition Sub-Study N=89 ± < h ± -3 h Dailey G, Lavernia F. Diabetes Obes Metab. 5;7():7-. ± >3 h Flexible Dosing Fixed Dosing No difference in AC between flexible- vs fixed-dosing No difference in severe or nocturnal within each sub-study U3 Insulin Glargine Only available in pens 3 U/mL,.5 ml Maximum dose per shot is 8 units with -unit increments using current pen New pen in development will allow a maximum dose of units U3 glargine pen is white and green with the concentration highlighted in orange to distinguish it from U glargine, which is purple and gray PDR.net. Accessed March 6, 5. PDR.net. Accessed March 6, 5. U3 Insulin Glargine Dosing Insulin-Naïve Patients Type Diabetes: Start with one-third to one-half of the total daily insulin dose calculated by using.. U/kg/day; give the remainder of the total daily insulin dose as a short-acting insulin and divide between each daily meal Type Diabetes: Start with. U/kg/day Type or Type Diabetes Changing from once-daily long-acting or intermediate-acting insulin (i.e. NPH once daily) Initial dose can be the same as the once-daily long-acting dose; for patients controlled on U insulin glargine, expect that a higher daily dose of U3 glargine will be needed to maintain the same level of glycemic control Changing from twice-daily NPH insulin Initial dose is 8% of the total daily NPH dosage PDR.net. Accessed March 8, 5. Glargine U3: Summary A flatter and more even PK/PD profile allows for less glycemic variability With a duration of action 36 hours, it provides stable bloodglucose control beyond hours Similar AC reduction compared to standard analog insulins Significantly less overall and nocturnal Flexibility to adapt the timing of injections to either AM or PM dosing and with a ± 3-hour window Higher dose by 7% Similar overall safety and tolerability Insulin Degludec Clinical Evidence Summary

9 BEGIN Flex: Degludec Flexible Dosing Day of the Week Dosing Time Interval between Doses (h) Mon Tue Wed Thu Fri Sat Sun Mon AM* PM AM PM AM PM PM AM Dosing schedule for IDeg OD Flex treatment group *Defined as the period from waking up until first meal of the day Defined as the period from start of evening meal until bedtime; a -h interval was introduced between Saturday and Sunday evening doses to ensure an equal number of short (8 h) and long (36 h) intervals during the week. Begin Flex = Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type diabetes: a 6-week randomized, treat-to-target trial with a 6-week extension Matheiu C, et al. J Clin Endocrinol Metab. 3;98:5-6. Begin Flex: Efficacy After 6 treatment weeks, mean AC was reduced with IDeg Forced-Flex (.%), IDeg (.%), and IGlar (.58%), which met noninferiority for IDeg Forced-Flex AC (%) Treatment difference between IDeg Forced-Flex and IGlar: non-inferior Main Extension Time since Randomization (weeks) IDeg Forced-Flex IDeg Iglar U IDeg Free-Flex IDeg = insulin degludec; IGlar = insulin glargine U. Matheiu C, et al. J Clin Endocrinol Metab. 98:5-6, 3. Both treatment arms switch to NPH for week then resume IDeg or IGlar AC (%) Confirmed Hypoglycemia (cumulative events per patient) Nocturnal Confirmed Hypoglycemia (cumulative events per patient) BEGIN Flex: Safety 7 7 Both treatment arms switch 6 6 to NPH for week then 5 resume IDeg or IGlar Main Extension % lower risk with IDeg Forced-Flex than with IGlar, p <. 37% lower risk with IDeg Forced-Flex than with IDeg, p <. Main Time since Randomization (weeks) IDeg Forced-Flex IDeg IGlar IDeg Free-Flex Matheiu C, et al. J Clin Endocrinol Metab. 3;98:5-6. Both treatment arms switch to NPH for week then resume IDeg or IGlar 5% lower risk with IDeg Free-Flex than with IGlar, p <.5 Extension Confirmed Hypoglycemia (cumulative events per patient) Nocturnal Confirmed Hypoglycemia (cumulative events per patient) Only available in pens Insulin Degludec U/mL (3. ml), max dose per injection 8 units U/mL (3. ml), max dose per injection 6 units Degludec U- pen is yellow and blue while the U- is green and blue with the concentration highlighted in blue Dosing Insulin-naïve patients, start with U daily When converting, start with the same unit dose as the total daily long- or intermediate-acting insulin unit dose Recommended days between dose increases is 3 to days FDA. History#labelinfo. Accessed October 6, 5. Insulin Degludec: Summary A flat and more even PK/PD profile allows for less glycemic variability with glucose-lowering With a duration of action 36 hours, it provides stable bloodglucose control beyond hours Significantly greater reductions in FPG in insulin-naïve patients with TD, compared with insulin glargine U Significantly lower rates of both overall and nocturnal confirmed in TD Similar glycemic control compared to insulin glargine U Allows for flexibility in the timing of insulin administration when needed, without compromising glycemic control or Case Steve cont d Steve initially was reluctant to start insulin but after meeting with the clinic pharmacist to review insulin use and realizing that giving himself a shot was no big deal, he agreed He remains concerned about and wants to avoid experiencing it again, if possible Based on the lower risk of, he was started on insulin glargine U3 with 8 units (. U/kg) at bedtime Steve was taught to titrate his insulin dose units once or twice weekly based on SMBG for a target FPG of 8 3 mg/dl

10 Insulin Pens Prefilled pen device allows for easy delivery of insulin Needles available in different gauges (9G, 3G, and 3G) and lengths (.7 mm, 6 mm, and mm) Good option for people with limited vision (can count clicks) or poor dexterity (neuropathy) Basal Insulin + Oral Meds Continue metformin Less weight gain when used together Decreases insulin requirements No good data for continuing sulfonylureas Reasonable to continue as it may provide some prandial benefit Guidelines for Preventing Hypoglycemia Practical Tips for Treating Hypoglycemia AACE Address during each patient contact If problematic, adjust regimen by: Reviewing/applying diabetes self-management Frequent SMBG Flexible, appropriate insulin regimens Individualized glycemic goals Ongoing professional guidance and support Consider each of the known risk factors for ADA Re-evaluate SMBG skills periodically Avoid aggressive targets in advanced disease Limit alcohol intake drink/day in adult women drinks/day in adult men Add carbohydrate before exercising if BG is < mg/dl Strict avoidance of for several weeks partly resolves repeated severe and unawareness Patient, family, and friends should be aware of signs and symptoms Have a plan to manage (e.g., Rule of 5) Note timing of physical activity (exercise), e.g., before meal If experiencing, rest quietly Test BG, if possible Treat with 5 g of sugar ( 5 glucose tablets) or carbohydrates if needed (e.g., ½ cup juice) Wait 5 min and test BG again Take additional 5 g ( glucose tabs), if necessary Follow treatment of with ingestion of protein Resume activity when feeling better and BG is > mg/dl SMBG = self-monitoring of blood glucose. Cryer PE, et al. J Clin Endocrinol Metab. 9;9: American Diabetes Association. Diabetes Care.;37(suppl ):S-S8. BG = blood glucose ADA. Hypoglycemia (low blood glucose). Accessed March,. Case Steve Follow-up Over the next months, Steve titrated his basal to units at bedtime At a 3-month follow-up, his AC was at 6.8% Steve is very happy with this blood-sugar control and tells you that in the 9 years since he has been diagnosed, this was the first time his AC is 7.% Summary Type diabetes progresses and requires ongoing review to match therapies with individual needs Be aware of clinical inertia, as it is common in clinical practice and is a major barrier to achieving glycemic control in patients with type diabetes The ideal initial insulin therapy would provide effective and stable glycemic control for a full h with minimal and weight gain

11 Summary New ultralong-acting basal insulins (U3 glargine and degludec) have advantages over currently available analogs basals including: Longer durations of action ( 36 hours) Significantly less overall and less nocturnal Have less variability with a flatter and more even PK/PD profile When using combination medications with insulin, consider newer insulin options that lower the risk of and weight gain and minimize other side effects Questions?