Conflicts of interest

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1 9/7/3 Star,ng and intensifying with insulin analogues: how and when? Dr. Chih Hao Chen Ku, FACE Endocrinology Department, San Juan de Dios Hospital Department of Pharmacology and Clinical Toxicology, University of Costa Rica Conflicts of interest I have received payment as speaker, member of advisory board and/or inves,gator in clinical trials from: Astra Zeneca Novar,s Pharma Logis,cs Inc Novar,s Oncology Novo Nordisk Merck Sharp & Dohme Roche Glaxo SmithKline Sanofi Aven,s Boehringer Organon Abbo[ Nutri,on Agenda When should we start insulin? Which are the different available strategies? Is there any difference between basal insulins? Which is the best strategy when we need to intensify insulin treatment?

2 9/7/3 Clinical case 55 years old female pa,ent with T2D diagnosed en 25, hypertension. No coronary disease and no end organ damage Current treatment meaormin 85 mg bid and glimepiride 4 mg per day PE: weight 9 kg, height 64 cm. BMI kg/m2 Hbac 8.%. FPG 6 (8.9 mmol) mg/dl Clinical case What should be her Hbac target? Approach to management of hyperglycemia: more stringent less stringent Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities less motivated, non-adherent, poor self-care capacities Risks potentially associated with hypoglycemia, other adverse events low high Disease duration newly diagnosed long-standing Life expectancy long short Important comorbidities absent few / mild severe Established vascular complications absent few / mild severe Resources, support system readily available limited Figure Diabetes Care, Diabetologia. 9 April 22 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2;54:554) 2

3 9/7/3 Initial drug monotherapy Efficacy (! HbAc) Hypoglycemia Weight Side effects Costs Two drug combinations* Efficacy (! HbAc) Hypoglycemia Weight Major side effect(s) Costs Three drug combinations Metformin Sulfonylurea high moderate risk gain hypoglycemia low Metformin Sulfonylurea Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbAc target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): TZD Metformin Thiazolidinedione high low risk gain edema, HF, fx s high Metformin Thiazolidinedione SU Metformin DPP-4 Inhibitor intermediate low risk neutral rare high Metformin DPP-4 Inhibitor SU Metformin GLP- receptor agonist high low risk loss GI high If needed to reach individualized HbAc target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin GLP- receptor agonist SU Metformin Insulin (usually basal) highest high risk gain hypoglycemia variable Metformin Insulin (usually basal) TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP--RA or GLP--RA or Insulin or Insulin or GLP--RA or Insulin or Insulin If combination therapy that includes basal insulin has failed to achieve HbAc target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with -2 non-insulin agents: More complex Insulin insulin strategies # Diabetes Care, Diabetologia. (multiple daily doses) 9 April 22 [Epub ahead of print] Belfast Diet Study: biphasic decline in β function 6 5 Slow decline (~2%/año) Diagnosis Fast decline (8%/año) β function (HOMA%B) Years since diagnosis Diet failure: additional non-dietary intervention required. Fallo Dieta en años 8 Fallo Dieta en años 2 4 No fallo de dieta años Fallo Dieta en años 5 7 Bagust A & Beale S. QJM 23; 96: Clinical case 55 years old female pa,ent with T2D diagnosed en 25, hypertension. No coronary disease and no end organ damage Current treatment meaormin 85 mg bid and glimepiride 4 mg per day PE: weight 9 kg, height 64 cm. BMI kg/m2 Hbac 8.%. FPG 6 (8.9 mmol) mg/dl 3

4 9/7/3 Clinical case What should be her Hbac target? How should we start insulin treatment? Non-insulin regimens Number of Regimen injections complexity Basal insulin only (usually with oral agents) low Basal insulin (meal-time) rapid-acting insulin injection Premixed insulin twice daily mod. Basal insulin!2 (meal-time) rapid-acting insulin injections less flexible Flexibility Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 9 April 22 [Epub ahead of prin Basal and postprandial contribu,ons to hyperglycemia by Ac range Pooled baseline data from 6 Treat-to-Target design studies 699 T2DM patients on diet ± OAD Mean Ac 8.69%, FPG.8 mmol/l (94 mg/dl) 7-point ambulatory SMBG profiles (ac, 2hr-pc, and hs) Calculations assume hyperglycemia is >5.6 mmol/l ( mg/dl) Basal hyperglycemia < Baseline Ac ranges On oral therapy, fas,ng hyperglycemia dominates over a wide range of Ac Riddle et al, Diabetes Care 34: , 2 Postprandial hyperglycemia 4

5 9/7/3 Pre- insulin Glicemias Post- insulin Basal insulin Desayuno Almuerzo Cena Chen- Ku CH. AMPMD. 22. DIFFERENCES BETWEEN BASAL INSULINS Mechanism of action: glargine ph 4. Subcutaneous tissue, ph 7.4 Precipitation Dissolution 3 M dimers monomers 5 M -8 M Capillary membrane Sangre capilar 5

6 9/7/3 Insulin detemir LysB29(N- tetradecanoyl)des(b3) C4 Fatty acid! (miristic acid)! A Gly! Ile! Val! Glu! Gln! Thr! Lys! Cys! Cys! Crystalline solu,on Neutral ph IU= 24 nmol Lys! Thr! Pro! B29 Ser! B Thr! Ile! Phe! Tyr! A2 Cys! Val! Phe! Asn! Phe! Ser! Cys! Leu! Asn! Gln! Gly! Tyr! Tyr! Arg! Asn! Glu! Leu! Gln! His! Glu! Leu! Cys! Gly! Cys! Ser! Gly! Val! Leu! Tyr! Leu! Ala! Glu! Val! Leu! His! DIFFERENCES BETWEEN BASAL INSULINS: VARIABILITY, WEIGHT AND HYPOGLICEMIAS Glucose infusion (mg/kg/min) Less intraindividual variability: insulin analogues vs NPH Heise T et al. Diabetes 24;53: NPH Glargina insulin 3 Detemir insulin Time (hours) 6

7 9/7/3 Glycemic variability: DM- Study NPH Detemir P Bartley 2 <. Home 2 <. Rusell- Jones 2 <. Pieber 2 <. Vague 2. De Leeuw Standl Kolendorf 2 <. Hermansen 2 <. Frier BM. Diab Obes Metab. 23: online april 3. Glycemic variability: DM- 2 Study NPH Detemir P Raslova 2 <. Hermansen 2.8 Haak 2.2 Fajardo Montaña 28 2 <. Philis- Tsimikas NS Frier BM. Diab Obes Metab. 23: online april 3. Cochrane: variability in plasma glucose profiles Swinnen et al. Cochrane Database Syst Rev 2: CD6383 7

8 9/7/3 NPH vs detemir in DM- 2: hypoglicemias Frier BM. Diab Obes Metab. 23: online april 3. Cochrane: Hypoglycemia rate Swinnen et al. Cochrane Database Syst Rev 2: CD6383 Differences in weight Szypowska A. Por Arch Med Wewn. 2;2:737 8

9 9/7/3 Cochrane: weight gain Swinnen SG. Cocharen Database of Systematic Reviews. 22 Cochrane: changes in Hbac Swinnen SG. Cocharen Database of Systematic Reviews. Swinnen 22 et al. Cochrane Database Syst Rev 2: CD6383 STARTING AND DOSE TITRATION 9

10 9/7/3 Dose adjustment by the pa,ents: improvement in Hbac. TITRATE Study. HbA c (%) mg/dl 8- mg/dl Inicial Sem 2 Sem 2 Time/weeks 7.* * -.94% HbA C -.22% HbA C * Change in both groups p =.9 at 2 weeks Blonde L et al., Diabetes Obesity & Metabolism. 29; : Blonde L. Diabetes Obes Metab. 29;:623 Basal insulin: Dose,tra,on FPG >9 mg/dl (>5 mmo/l) Increase 3 units FPG > mg/dl (>6 mmo/l) Fasting glucose 7-9mg/dl (3.8-5 mmol/l) Maintain dose Fasting glucose 8- mg/dl (4.4-6 mmol/l) 244 patients with T2DM with OAD failure initiated with detemir insulin FPG <7 mg/dl (<3.8 mmol/l) Decrease 3 units FPG <8 mg/dl (<4.4mmo/L) Every 3 days FPG (according average) Diabetes Obes Metab. Jun 29;(6): Glycaemic Goals ACE ADA HbAc <6.5% <7.% Fasting plasmatic glucose (FPG) < mg/dl (6mmol/L) 7-3 mg/dl (4-7 mmol/l) PPG <4 mg/dl (<8mmo/L) <8 mg/dl (<mmol/l) Adapted from Diabetes Care 23;36(suppl):pp S-S66

11 9/7/3 Treatment goals Goal FasGng glucose Postprandial glucose <6.5% 7 (4 mmol)- (6 mmol) mg/dl <7% 8 (4.4 mmol)- 4 (7.7 mmol) mg/dl <4 (8 mmol) mg/dl <8 ( mmol) mg/ dl SUSTAINABLE EFFECT WITH BASAL INSULIN AC (%) 7, 6,5 6, 5,5 ORIGIN: Median AC Levels -.5 kg IQR ,5 6,5 6,5 6,4 6,4 6,4 6,3 6,4 6,2 6,3 6,2 6,2 6, 6 6 Glargine 5,9.5 kg Standard IQR Year Origin Trial Investiators. N Engl J Med. 22

12 9/7/3 st Co- primary: MI, Stroke, or CV Death Time to Adjudicated Primary Outcome - CV Death MI Stroke Proportion with events # at Risk G SC Adj. HR.2 (.94,.) Log Rank P =.63 Glargine Standard Care Years of Follow-up Origin Trial Investiators. N Engl J Med. 22 Basal Insulin: Percent of patients with HbAc < 7% 29 trials, with 7,588 patients HbAc < 7% was achieved in 4.4% (95% CI, %). Predictors of response: - first insulin treatment, - lower insulin dose - use of 2 oral drugs Hypoglycemic events: to 4.7 events/patient/3 days Weight gain ~.75 kg (.2-2.) Final Insulin dose:.48 (.4-.57) Giugliano et al. Diabetes Research & Clinical Prac,ce 92 (2) Basal Insulins Basal analogues have a lower hypoglicemia risk and variability compared to NPH Detemir and glargine have similar efficacy in reduc,on of Hbac and hypoglycemia rates Less weight gain with insulin detemir Self,tra,on by pa,ents 2

13 9/7/3 Clinical case 55 years old female pa,ent with T2D diagnosed en 25, hypertension. No coronary disease and no end organ damage Current treatment meaormin 85 mg bid and glimepiride 4 mg per day PE: weight 9 kg, height 64 cm. BMI kg/m2 Hbac 8.%. FPG 6 (8.9 mmol) mg/dl Clinical case What should be her Hbac target? How should we start insulin treatment? Pa,ent was started with u daily of insulin detemir and up,trated to 32 u daily Fas,ng plasma glucose 6 (5.9 mmol) mg/dl Hbac 6.4% year later, her Hbac increased to 7.5%. FPG 3 mg/dl (6.3 mmol) What should be the next step? Op,mizing and intensifying Adjust basal insulin dose Single prandial dose Sequential prandial doses Full prandial coverage Premixed insulin therapy Fixed vs flexible prandial doses OPAL study STEPwise study Sequential vs full basal bolus 4T study Fix vs Flex study PREFER study Lankisch et al. Diab Obes Metab 28;:78 85 Holman et al. NEJM 29;36:736 Meneghini et al. Diabetes 47; Milek et al. Diabetologia 28; Liebl et al. Diab Obes Metab 2;59(Suppl. ):A99 5(Suppl. ):S42 29;:

14 9/7/3 Non-insulin regimens Number of Regimen injections complexity Basal insulin only (usually with oral agents) low Basal insulin (meal-time) rapid-acting insulin injection Premixed insulin twice daily mod. Basal insulin!2 (meal-time) rapid-acting insulin injections less flexible Flexibility Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 9 April 22 [Epub ahead of prin STEPwise : study design Randomisa,on ExtraSTEP IAsp IAsp 2 IAsp 3 Largest measured PPG increment Target postprandial: 4 8 mmol/l Insulin detemir ini,ated Run- in period detemir OADs IAsp SimpleSTEP IAsp 2 IAsp 3 Largest perceived meal Target preprandial: 4 6 mmol/l Weeks Period Period 2 Period 3 Inclusion criteria: T2DM >6 months HbA c 7.5-.% Basal insulin 3 months 3 OADs T2DM, type 2 diabetes; OAD, oral an,diabe,c drug; IAsp, insulin aspart Meneghini et al. Diabetes 2;59(Suppl. ):A99 STEPwise : change in HbA c. Change to week Change to week 23 Change to week HbA c (%) ExtraSTEP SimpleSTEP Change was adjusted for baseline HbA c Meneghini et al. Diabetes 2;59(Suppl. ):A99 4

15 9/7/3 STEPwise : addi,on of first bolus injec,on 7 Percentage of patients (%) ExtraSTEP SimpleSTEP Breakfast Lunch Dinner ExtraSTEP group added insulin based on PPG measurement SimpleSTEP group added insulin based on pa,ent assessment Meneghini et al. Diabetes 2;59(Suppl. ):A99 and data on file WHAT ABOUT PREMIX INSULINS? PREFER: study design Inclusion criteria: - One or two OADs without insulin One or two OADs with od NPH/glargine 7% HbA c 2% Randomisa,on 3: IAsp,d IDet od or bid (n=537) Screening BIAsp 3 bid (n=78) 6- week,tra,on phase 2- week treatment phase OADs were discon,nued in both arms OAD, oral an,diabe,c drug; od, once daily; NPH, neutral protamine Hagedorn; glargine, insulin glargine; HbA c, glycated haemoglobin A c;;,d, three,mes daily Liebl et al. Diabetes Obes Metab 29;:

16 9/7/3 PREFER: HbA c reduc,on BIAsp 3 8.4% IDet/IAsp 8.52% Reduc,on in HbA c (%) %.234% p=.52 Baseline- corrected treatment difference 6.96% Liebl et al. Diabetes Obes Metab 29;:45 52 Change in HbA c (%) Premixed vs basal- bolus analogue (PREFER Study) Premixed 2 iny/day 8.5% 7.7% p =.6* Basal Bolus 4 inj/day 8.6% 6.92% Premixed 2 iny/day 8.7% 7.47% p =.29* Basal Bolus 4 inj/day 8.28% 7.5% *Basal- bolus Patients without previous use of insulin Liebl et al. Diabetes 26;55(Suppl. ):A23 Previous users of insulin PREFER: percentage of pa,ents achieving HbA c <7.% Pa,ents reaching HbA c target (%) % BIAsp 3 6% IDet/IAsp Liebl et al. Diabetes Obes Metab 29;:

17 9/7/3 PREFER: rate of hypoglycaemia Hypoglycaemia BIAsp 3 IDet/IAsp Major (n) 5 Minor* (% pa,ents) 28% 3% Nocturnal minor (% pa,ents) 7.3% 7.4% Incidence # of minor (events/subject/year) Incidence of nocturnal minor (events/subject/year) Between- treatment differences not significant *Confirmed by blood glucose<3. mmol/l # Calculated for the final 2 weeks of the study Liebl et al. Diabetes Obes Metab 29;:45 52 PREFER: change in body weight Change in body weight from baseline (kg) kg BIAsp kg IDet/IAsp Baseline*: 88.4 kg 89.4 kg *ITT popula,on (all subjects who received at least one treatment dose) Liebl et al. Diabetes Obes Metab 29;:45 52 WHICH IS THE BEST STRATEGY? 7

18 9/7/3 3 year study design to investigate insulin initiation and intensification Aspart TID Aspart TID Detemir OD 78 patients: Type 2 diabetes HbA c 7-% Max OAD dose Insulin naive BMI 4 kg/m 2 Detemir OD BiAsp 7/3 BID Detemir OD Aspart TID BiAsp BID midday aspart 2 3 Years SU therapy replaced by second insulin in the first year if: HbA c % or HbA c 8% on two consecutive occasions Or if: HbA c >6.5% at end of year one Adapted from Holman et al. NEJM 29; 36: The majority of patients were intensified with a second insulin 74.3% of patients had an intensified regimen * BiAsp 7/3 Aspart Detemir bid Detemir aspart *p=.2 for overall comparison Sustainable HbA c control in all three arms * Baseline HbA c *p<. vs. aspart and BiAsp groups BiAsp 7/3 Aspart Detemir bid Detemir aspart NB. Mean HbA c at year; median HbA c at 3 years Adapted from Holman et al. NEJM 27; 357:76-3 8

19 9/7/3 Low median rates of minor hypoglycaemia * ** # ## BiAsp 7/3 Aspart Detemir bid Detemir aspart *p=.2 and p<. vs. BiAsp 7/3 and Detemir respectively at year one **p<. vs. BiAsp 7/3 and Detemir at year three #p=. vs. Detemir at year one ##p<. vs. Detemir at year three Minor hypoglycaemia did occur in the first year with detemir, however the median rate was Holman et al. NEJM 27; 357:76-3 Low proportion of patients experiencing major hypoglycaemia over 3 years BiAsp 7/3 Aspart Detemir bid Detemir aspart No. of patients in the BiAsp 7/3 start group No. of patients in the aspart start group No. of patients in the detemir start group Holman et al. NEJM 27; 357:76-3 Detemir weight advantage was sustained throughout intensification ## ** # BiAsp 7/3 Aspart Detemir bid Detemir aspart p=.5 vs. aspart at year one *p<. vs. detemir at year one #p<. vs. detemir at year one **p=.5 vs. detemir at year three ## p<. vs. detemir at year three Holman et al. NEJM 27; 357:76-3 9

20 9/7/3 Non-insulin regimens Number of Regimen injections complexity Basal insulin only (usually with oral agents) low Basal insulin (meal-time) rapid-acting insulin injection Premixed insulin twice daily mod. Basal insulin!2 (meal-time) rapid-acting insulin injections less flexible Flexibility Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 9 April 22 [Epub ahead of prin What are the benefits of pre- mixed insulin analogues? Good for pa,ents moderately insulinopenic with: ) not enough control with basal insulin and 2) does not requires basal- bolus scheme Easier handling and less confusion for the pa,ent Can be used as first insuliniza,on instead of basal in type 2 diabetes Basal and Prandial coverage Mimics some insulin secre,on phases (st and 2nd) A second or third injec,on addi,on of biphasic aspart Mix 3 provides an addi,onal benefit in terms of reduc,on in: FPG, PPG and HbA c Garber et al. Diabetes Obes Metab 26;8:58 66 Basal-bolus: key advantage Advantage: Is more physiologic Is the best for pa,ents with type diabetes or pa,ents with type 2 with deep insulinopenia Considera,on: Requires mo,va,on and care (pa,ent) Is a more complex treatment 2

21 9/7/3 SWITCHING FROM HUMAN INSULINS TO INSULIN ANALOGUES HbA c results by type of insulin,, Aspart 9,6 9,5 Detemir Biphasic /Premix Basal Aspart HbA C (%) 9, 8,5 7, 7,5 7, 6,5 No previous insulin treatment, 9,5 9,5 9,59,4 9,4 9,2 9,3 9, 8,5 Insulin treated patients 8, 7,7 7,5 7,6 7,4 7,5 7,3 7,4 7, 7,3 7,3 6,5 6, 6, Start 24 weeks Start 24 weeks Results: global hypoglycemia rates by type of insulin Aspart 4, No previous insulin treatment 4,5 8,3 8, Insulin treated patients Detemir Biphasic /Premix Basal Aspart events/persons-year 3,5 3, 2,5 2,,7,6,5,,,,5 3,,3,,9 7, 6,5 6, 5,5 5, 4, 3, 2,, 4, 2,7,8,8,, Start 24 weeks Start 24 weeks 2

22 9/7/3 Results in body weight by type of insulin,8 No previous insulin treatment,8 Insulin treated patients Aspart Detemir Biphasic /Premix Basal Aspart Changes in body weight (kg),6,4,2, -,2 -,4,6,4 79,5 79,2,3 74,,2,2 76, 7, 68,3,, -,2 -,3 -,4 74,4 7,,2, -,3 -,6 -,8 -,6 -,7 -,8 Start 24 weeks Start 24 weeks Two NPH doses Efecto Insulínico 3 regular human insulin doses NPH dose Efecto Insulínico 22

23 9/7/3 WHAT OTHER BENEFITS CAN WE EXPECT FROM ULTRARAPID INSULIN ANALOGUES? AC and postprandial glucose control 9 AC 3 PPG 25 n=62 8 AC (%) 7 6 PPG (mg/dl) 2 5 * * * * n=63 * Insulin aspart 5 Regular human insulin Duration (years) Duration (years) Postprandial glucose levels 9 minutes a er breakfast. Values are given as mean ± SD. *p<.2 Nishimura et al. Diabetologia 28;5(Suppl. ):S543 (Poster 349) Long-term use of insulin aspart and effect on cardiovascular disease (CVD) Accumulation of CVD (%) % Duration (years) Regular human insulin (.%) Hazard ratio:.57 CI: p<.2 Insulin aspart (6.4%) Cumula,ve incidence of CVD primary composite endpoints analyzed by Cox s propor,onal hazard regression analysis Nishimura et al. Diabetologia 28;5(Suppl. ):S543 (Poster 349) 23

24 9/7/3 Rathman A. Diab Obes Metab. 23;5:358 Methods This is an analysis of a primary care database in Germany It included only pa,ents that received either insulin aspart or human regular insulin but it did not include combina,ons of pa,ents that had switched insulins Included only pa,ents who were prescribed insulin for the first,me Rathman A. Diab Obes Metab. 23;5:358 Rathman A. Diab Obes Metab. 23;5:358 24

25 9/7/3 Eventos cardiovasculares Rathman A. Diab Obes Metab. 23;5:358 Conclusions Natural history of type 2 diabetes will lead to insulinopenia so insulin treatment will be needed in most pa,ents Treatment goals differ in each pa,ent and this determines when is the right moment to start insulin Best strategy is to start with a basal insulin, then progress to a basal plus and the to a basal bolus QuesGons chenku249@gmail.com 25