Achieving Glycemic Control: When Optimized Basal Insulin Isn t Adequate

Transcription

1 Achieving Glycemic Control: When Optimized Basal Insulin Isn t Adequate AAFP State Chapter Meeting Faculty Louis Kuritzky MD Clinical Assistant Profess Emeritus Department of Community Health and Family Medicine College of Medicine University of Flida, Gainesville

2 Statements of Sponsship and Suppt This CME symposium is sponsed by: This CME symposium is suppted by an educational grant from Sanofi US Diabetes

3 Register at:

4 Learning Objectives After completing this program, the primary care provider should be able to: Identify patients who have reached the likely maximum benefits of their optimized basal insulin Compare medications available f use in combination with basal insulin to lower postprandial glucose Compare the outcomes of patients treated with the addition of prandial insulin vs a GLP-1RA to basal insulin

5 CME Infmation This Live activity, Achieving Glycemic Control: When Optimized Basal Insulin Isn t Adequate, from 04/15/ /15/2016, has been reviewed and is acceptable f up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

6 Faculty Disclosure Louis Kuritzky, MD discloses that he is on the advisy board f Amgen, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Lilly, Novo Ndisk, Sanofi, and Takeda Pharmaceuticals. He is on the speakers bureau f Amgen, Lilly, and Novo Ndisk.

7 Case Study- Alison 48 yo female diagnosed with T2DM 8½y ago 10 months ago HbA 1c 8.6%, FPG mg/dl despite metfmin SU Basal insulin added, SU discontinued Basal insulin titrated; now 58 units (0.56 units/kg) at dinner HbA 1c 7.6% Glucose: fasting mg/dl; bedtime mg/dl 2 episodes of symptomatic hypoglycemia during past 3 mos; last episode causing a fall At diagnosis Insulin ini.ated Now Body weight (kg) BMI (kg/m 2 )

8 Patients with Diabetes Have Basal and Prandial Hyperglycemia Plasma Glucose (mg/dl) Basal hyperglycemia Type 2 Diabetes Mealtime/Prandial hyperglycemia Healthy 0 6 AM 12PM 6 PM 12 AM 6 AM Time of Day Adapted from: Riddle M. Pract Cardiol. 1986;12:65-79.

9 Desirable Clinical Effects of Basal Insulin Basal analog insulin 1 Long-acting (24 hours) Peakless (doses <0.5 units/kg) Reduces hepatic glucose production (gluconeogenesis, glycogenolysis) and lipogenesis Primarily targets fasting plasma glucose Approximately 60% of patients with T2DM can achieve HbA 1c 7.0% with basal insulin ( al agents) if taken CONSISTENTLY 2 1. Unger, J. Diabetes Therapy. 2011;2 (1): Holman RR, et al. N Engl J Med. 2009;361:

10 What is Meant by Optimized Basal Insulin? Efficacy HbA 1c at goal 7% f this pavent FPG mg/dl Safety/Tolerability Minimize hypoglycemia Severe Nocturnal Minimize weight gain PaVent Facts Needs, interests, capabilives Schedule/Lifestyle OccupaVon SMBG American Diabetes AssociaVon. Diabetes Care. 2015;38(Suppl 1):S1- S93. Philis- Tsimikas A. Am J Med 2013;126:S21- S27.

11 When Basal Insulin May Not Be Enough to Achieve Glycemic Control! HbA 1c >7.0%, despite FPG mg/dl! And! Total basal insulin dose exceeds unit/kg/day 1! Severe, nocturnal, frequent symptomatic hypoglycemia! Difference between bedtime and AM (BeAM) blood glucose >55 mg/dl 2! Less likely to achieve HbA 1c 7.0%! Increased risk of nocturnal hypoglycemia! Weight gain 1. Inzucchi S, et al. Diabetes Care. 2012;35: Zisman A, et al. ADA Scientific Sessions 2011; Abstract 1121-P.

12 Is Me Basal Insulin Better? Total Daily Insulin Dose (U) Increasing doses of basal insulin may lead to diminishing returns End of 4- week run- in period 198 mg/ dl 10 units Mean Glargine Dose 25 units 149 mg/ dl Insulin Dose FP 47 units (0.48 units/kg) 117 mg/dl Week of Treatment 4 N=367 In combinavon with 1 2 al agents Mean FPG (mg/dl) Meover, ReducVon in the HbA 1C plateaus Incidence of hypoglycemia (blood glucose 56 mg/dl) rises over Vme Riddle MC, et al. Diabetes Care. 2003;26(11):

13 Avoiding Overbasalization If the basal insulin dose is crect, the bedtime BG should be about the same as the next mning s FPG (assuming no prandial insulin at nighttime) If the BG decreases significantly overnight (ie, BeAM>55 mg/dl), the basal dose is too high If the BG increases significantly overnight, the basal dose is too low Caution to avoid Dawn Phenomenon BeAM, bedvme to pre- breakfast

14 Glycemic Effects of Glucose-Lowering Medications Glycemic Effects Fas.ng Plasma Glucose Lowering Neutral Mild Moderate Moderate/ Marked Postprandial Glucose Lowering Neutral Mild Moderate Moderate/ Marked Bromocrip.ne AGi Rapid- / Sht- ac.ng Insulin Colesevelam DPP- 4i Megli.nide Pramlin.de GLP- 1R Agonist a MeQmin SGLT- 2i TZD SU Basal Insulin a FPG lowering: mild- albigluvde, exenavde BID; moderate- dulagluvde, exenavde QW, liragluvde Handelsman Y, et al. Endocr Pract. 2015;21(Suppl 1):1-87. Inzucchi SE, et al. Diabetes Care 2015;38(1): Garber AJ et al. Endocr Pract. 2013;19(Suppl 2):1-48.

15 As a patient s HbA 1c approaches 7%, controlling the postprandial glucose the fasting plasma glucose.? 1. Becomes me imptant than 2. Becomes less imptant than 3. Remains as imptant as

16 Fasting vs Postprandial Glucose Contribution to HbA 1c ContribuVon 100% 80% 60% 40% 20% 0% [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] [VALUE] < >10.2 HbA 1c Range (%) Postprandial Plasma Glucose FasVng Plasma Glucose American Diabetes AssociaVon Diabetes Care, American Diabetes AssociaVon, Copyright and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. Monnier L, et al. Diabetes Care. 2003;26:

17 Imptance of Postprandial Glucose Increasing 2- hour PPG is associated with an increasing risk of all- cause mtality, parvcularly f PPG 200 mg/dl RelaVve Risk of All- Cause Mtality Upper Limit of Nmal f PPG Two- Hour Plasma Glucose (mg/dl) < Skin JD, et al. Diabetes Care 2005;28:

18 Imptance of Postprandial Glucose (cont) Hyperglycemic spikes following every meal induce oxidavve stress, endothelial dysfuncvon, and inflammaty reacvons. Node K, et al. Cardiovasc Diabetol. 2009;8:23.

19 Case Study- Alison 48 yo female diagnosed with T2DM 8½y ago Current Treatment Metfmin basal insulin 58 units at dinner Glucose levels HbA 1c 7.6% Fasting mg/dl Bedtime mg/dl 2 episodes of symptomatic hypoglycemia during past 3 mos; last episode causing a fall How should her treatment be modified?

20 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy! Triple therapy Efficacy * Hypo risk Weight Side effects Costs Combination injectable therapy! Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD DPP-4-i SGLT2-i GLP-1-RA Insulin Metfmin Thiazolidinedione high low risk gain edema, HF, fxs low Metfmin Thiazolidinedione SU DPP-4-i SGLT2-i GLP-1-RA Insulin Metfmin DPP-4 inhibit Basal Insulin intermediate low risk neutral rare high Metfmin DPP-4 Inhibit SU TZD Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist high low risk loss GI high If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): SGLT2-i DPP-4-i Insulin basal Insulin insulin TZD Insulin Metfmin Insulin (basal) DPP-4-i SGLT2-i GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Metfmin Metfmin This is SGLT2 inhibit Alison s intermediate low risk loss current GU, dehydration treatment high These are the op.ons f TZD intensifying MeQmin Metfmin Metfmin GLP-1 recept Insulin (basal) agonist Insulin (basal) SU TZD American Diabetes AssociaVon Diabetes Care, American Diabetes Mealtime AssociaVon, Insulin Copyright GLP-1-RA and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. Inzucchi SE, et al. Diabetes Care 2015;38(1): Diabetes Care 2015;38: ; Diabetologia 2015; /s Insulin (basal) highest highest high risk high risk gain hypoglycemia gain variable MeQmin hypoglycemia variable TZD DPP- 4i SGLT2- I GLP- 1 RA

21 Glycemic Effects of Glucose-Lowering Medications Glycemic Effects Fas.ng Plasma Glucose Lowering Neutral Mild Moderate Moderate/ Marked Postprandial Glucose Lowering Neutral Mild Moderate Moderate/ Marked Bromocrip.ne AGi Rapid- / Sht- ac.ng Insulin Colesevelam DPP- 4i Megli.nide Pramlin.de GLP- 1R Agonist a MeQmin SGLT- 2i TZD SU Basal Insulin a FPG lowering: mild- albigluvde, exenavde BID; moderate- dulagluvde, exenavde QW, liragluvde Handelsman Y, et al. Endocr Pract. 2015;21(Suppl 1):1-87. Inzucchi SE, et al. Diabetes Care 2015;38(1): Garber AJ et al. Endocr Pract. 2013;19(Suppl 2):1-48.

22 Other Considerations in Selecting Therapy to Lower Postprandial Glucose Medication Facts Magnitude/Durability of response Mechanism of action Requirement f functioning β-cell Adverse events Warnings/Contraindications Cost/Insurance Patient Facts Body weight Regularity/Quality of meals Variations in physical activity/wk schedule Hypoglycemia awareness/tolerance Adherence

23 Pathophysiologic Mechanisms in Hyperglycemia of T2DM CNS: Delayed sa.ety Kidney: Glucose reabsp.on Gut: Diminished incre.n effect Altered intes.nal glucose absp.on BLOOD GLUCOSE Muscle and adipose.ssue: Glucose uptake Liver: Hepa.c glucose secre.on Pancreas: Insulin secre.on Glucagon secre.on

24 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy! Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Metfmin Thiazolidinedione high low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare high Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration high American Diabetes AssociaVon Diabetes Care, American Diabetes AssociaVon, Copyright and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. Inzucchi SE, et al. Diabetes Care 2015;38(1): Metfmin GLP-1 recept agonist high low risk loss GI high Metfmin Insulin (basal) highest high risk gain hypoglycemia variable Triple therapy Metfmin Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): TZD Metfmin Thiazolidinedione SU Metfmin DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA Insulin GLP-1-RA Insulin Insulin Insulin GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Combination injectable Basal Insulin Mealtime GLP-1-RA therapy Basal Insulin MealVme Insulin GLP- 1 RA! MeQmin Metfmin Diabetes Care 2015;38: ; Diabetologia 2015; /s

25 Case Study- Alison Mermin Basal Insulin HbA 1c 7.6% FPG mg/dl BedVme mg/dl SymptomaVc hypoglycemia Weight gain Which should be added? Rapid- /Sht- acvng Insulin GLP- 1 Recept Agonist DPP- 4 Inhibit SGLT- 2 Inhibit

26 Case Study- Alison (cont) Alison Rapid- /Sht- ac.ng Insulin GLP- 1 Recept Agonist DPP- 4 Inhibit SGLT- 2 Inhibit is concerned about: Further hypoglycemia Further weight gain PotenVal f mulvple daily injecvons AddiVonal injecvon Transient N/V?Acute pancreavvs C- cell hyperplasia/ medul- lary thyroid tums in animals Immune- mediated dermatologic effects?acute pancreavvs?heart failure hospitalizavons Genital yeast infecvons Polyuria Volume deplevon/ hypo- tension/ dizziness LDL- C CreaVnine (transient) likes: PotenVal f weight loss Low risk of hypoglycemia PotenVal f reducing basal insulin dose PotenVal f no further weight gain Low risk of hypoglycemia Oral PotenVal f weight loss Low risk of hypoglycemia Oral Inzucchi S, et al. Diabetes Care. 2015;38:

27 Bolus Insulin vs GLP-1RA in Combination with Optimized Basal Insulin Metfmin Glargine optimization over 12 wks to achieve FPG 100 mg/ dl Those who didn t achieve HbA 1c 7.0%... R A N D O M I Z E 315 1:1 312 ExenaVde mcg BID ( Basal Insulin 10%) 30 weeks Lispro TID ( Basal Insulin 33-50%) Diamant M, et al. Diabetes Care. 2014;37;

28 Bolus Insulin vs GLP-1RA in Combination with Optimized Basal Insulin Metfmin (cont.) 0 ExenaVde BID Lispro TID HbA 1c (%) Weeks Following Randomiza.on American Diabetes AssociaVon Diabetes Care, American Diabetes AssociaVon, Copyright and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. Diamant M, et al. Diabetes Care. 2014;37;

29 Bolus Insulin vs GLP-1RA in Combination with Optimized Basal Insulin Metfmin (cont.) Fas.ng Glucose* (mg/dl) Blood Glucose (mg/dl) ExenaVde BID Lispro TID *P=0.002 f all Vme points except # Weeks Following Randomiza.on American Diabetes AssociaVon Diabetes Care, American Diabetes AssociaVon, Copyright and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. Diamant M, et al. Diabetes Care. 2014;37; # # P<.001 Dowed line: At randomizavon Solid line: Study end

30 Bolus Insulin vs GLP-1RA in Combination with Optimized Basal Insulin Metfmin (cont.) 3 Change in Key Endpoints* ExenaVde BID Lispro TID 50 Safety *P<.001 f all key endpoints Percent of Pa.ents Diamant M, et al. Diabetes Care. 2014;37;

31 Bolus Insulin vs GLP-1RA in Combination with Optimized Basal Insulin Metfmin (cont.) Study Results: Summary HbA 1c reducvon ExenaVde = Lispro FPG reducvon ExenaVde > Lispro PPG reducvon ExenaVde Lispro Min hypoglycemia ExenaVde < Lispro Nocturnal hypoglycemia ExenaVde < Lispro Weight change ExenaVde Lispro Glargine dose ExenaVde > Lispro Treatment savsfacvon ExenaVde > Lispro Diamant M, et al. Diabetes Care. 2014;37;

32 Basal insulin in combination with a GLP-1R agonist does not lead to a:? 1. Higher incidence of maj hypoglycemia (<54 mg/dl) compared with basal insulin alone kg average weight loss compared with basal insulin alone % average HbA 1c reduction compared with either alone

33 Exenatide BID vs. Placebo Add-on Therapy to Insulin Glargine Oral Agents R A N D O M I Z E 137 1:1 122 ExenaVde 10 mcg BID 30 weeks Placebo Buse JB, et al. Ann Intern Med. 2011;154:

34 Exenatide BID vs. Placebo as Add-on Therapy to Insulin Glargine Oral Agents (cont.) % Achieving HbA 1c <7.0% Body Weight (kg) 0.25 Insulin Dose (U/kg) * ExenaVde BID Placebo - 2 * *P< Buse JB, et al. Ann Intern Med. 2011;154:

35 Exenatide BID vs. Placebo as Add-on Therapy to Insulin Glargine Oral Agents (cont.) 220 Glucose Level (mg/dl) * * * * * ** FasVng Mning 2h PP Pre- Lunch Lunch 2h PP Pre- Dinner Dinner 2h PP 0300 Hours Glargine ExenaVde; baseline Glargine ExenaVde; 30 wks Glargine Placebo; baseline Glargine Placebo; 30 wks *P<.001 f between- group difference; **P<.01 f between- group difference Buse JB, et al. Ann Intern Med. 2011;154: With permission Copyright 2011, The American College of Physicians

36 Exenatide BID vs. Placebo as Add-on Therapy to Insulin Glargine Oral Agents (cont.) There were no episodes of maj hypoglycemia (blood glucose < 54 mg/dl resulvng in loss of consciousness seizure responding to glucose/glucagon, requiring assistance) Hypoglycemic Events (events/pavent- year) ExenaVde BID Placebo Buse JB, et al. Ann Intern Med. 2011;154:

37 Insulin Detemir as Add-on Therapy to Metfmin Liraglutide: Study Design Patients with T2DM treated with metfmin (HbA 1C 7-10%) metfmin SU (HbA 1C 7-8.5%) 12-wk run-in: SU DC d; liraglutide initiated, titrated to 1.8 mg/d After run-in: If HbA 1C 7.0%: Continued metfmin liraglutide OR Added insulin detemir 10 units evening/bedtime and titrated to FPG mg/dl If HbA 1C <7.0%: Continued metfmin liraglutide (observational group) DeVries JH, et al. Diabetes Care. 2012;35(7):

38 Insulin Detemir as Add-on Therapy to Metfmin Liraglutide 1 (cont.) Change in HbA 1c (%) RandomizaVon SMBG (mg/dl) * ** # Time (weeks) 100 *P=.0003 **P=.0244 # P= Weeks 0-26 LiragluVde Detemir LiragluVde BedVme LiragluVde (obs) American Diabetes AssociaVon Diabetes Care, American Diabetes AssociaVon, Copyright and all rights reserved. Material from this publicavon has been used with the permission of the American Diabetes AssociaVon. DeVries JH, et al. Diabetes Care. 2012;35(7):

39 Insulin Detemir as Add-on Therapy to Metfmin Liraglutide 1 (cont.) Change in Body Weight (kg) 0 Rate of Min Hypoglycemia (events/participant-year) * 0.2 No maj hypoglycemia occurred during weeks ** LiragluVde Detemir LiragluVde 1 Weeks 0-26; *P=.03; **P=.004 DeVries JH, et al. Diabetes Care. 2012;35(7):

40 Efficacy Results from Observational Studies of Basal Insulin in Combination with a GLP-1RA HbA 1c (%) Body Weight (kg) Insulin Dose (units/d) Conclusion: CombinaVon therapy improved glycemic control without weight gain an increased risk of hypoglycemia. From: Balena R, et al. Diabetes Obes Metab. 2013;15: Copyright 2013 John Wiley & Sons, Inc. All rights reserved

41 GLP-1 Recept Agonists in Combination with Insulin Approved f Use in CombinaVon with Basal Insulin Prandial Insulin AlbigluVde QW! DulagluVde QW ExenaVde BID! ExenaVde QW LiragluVde QD! 1. Tanzeum [package insert]. Research Triangle Park, NC: GlaxoSmithKline LLC; June Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; January Byewa [package insert]. San Diego, CA: Amylin PharmaceuVcals, Inc.; August Bydureon [package insert]. San Diego, CA: Amylin PharmaceuVcals, Inc.; February Victoza [package insert]. Princeton, NJ: Novo Ndisk; April 2013.

42 Summary Residual postprandial hyperglycemia may prevent achieving HbA 1c target Postprandial hyperglycemia is associated with cardiovascular risk Basal insulin may not be enough to achieve glycemic control Rapid-/Sht-acting insulin has been the standard to lower postprandial glucose; however, compared with thrice-daily rapid-acting insulin, a GLP-1RA provides Similar better glycemic control Less nocturnal hypoglycemia Weight loss (vs gain) Greater treatment satisfaction

43 Achieving Glycemic Control: When Optimized Basal Insulin Isn t Adequate AAFP State Chapter Meeting Louis Kuritzky MD Clinical Assistant Profess Emeritus Department of Community Health and Family Medicine College of Medicine University of Flida, Gainesville