When It s Time to Intensify What Are The Options?

Transcription

1 When It s Time to Intensify What Are The Options? with a focus on injectable options Prof. Bernard Charbonnel, University of Nantes - France

2 Disclosures Bernard Charbonnel has received fees for consultancy, speaking, travel or accommodation from: Sanofi, Takeda, GlaxoSmithKline, Merck Sharpe & Dohme, AstraZeneca, Boehringer Ingelheim, Novo-Nordisk, Novartis

3 In all guidelines, it is recommended to initiate insulin with a basal insulin regimen Start with basal insulin Basal-Plus or Basal-Bolus, Premix insulins are not for initiation, only for intensification (if needed) in a 2 nd step Diabetes Care 2015;38:

4 Basal insulin regimen : the concept Blood glucose (mg/dl) 400 ADO failure Very high post-prandial blood glucose Hours Cusi & Cunningham. Diabetes Care 1995;18:

5 Basal insulin regimen : the concept Blood glucose (mg/dl) 400 ADO failure Bedtime Insulin ± ADO Fix Fasting blood glucose First Basal insulin Hours Cusi & Cunningham. Diabetes Care 1995;18:

6 Basal insulin regimen : the concept Blood glucose (mg/dl) 400 ADO failure Bedtime Insulin ± ADO Post-prandial blood glucose levels are reduced in absolute value Basal insulin Hours Cusi & Cunningham. Diabetes Care 1995;18:

7 Basal insulin regimen : the concept Blood glucose (mg/dl) 400 ADO failure Bedtime Insulin ± ADO of post-prandial blood 300 glucose excursions (postprandial vs preprandial) remains unchanged Basal insulin does not adress the prandial blood glucose excursions Basal insulin Hours Cusi & Cunningham. Diabetes Care 1995;18:

8 Basal insulin regimen the concept of the treat-to-target strategy Blood glucose (mg/dl) 400 If fasting glucose is fixed at near-normal by a well 300 titrated dose of basal insulin Post-prandial glucose values are rarely normalized but reduced to absolute values which are acceptable Bedtime Insulin ± OADs HbA1c ~ 7% Good titration Hours Cusi & Cunningham. Diabetes Care 1995;18:

9 Basal insulin titration: Fix Fasting First Basal insulin generally + metformin Glargine is the gold standard in 2016 Other options: Degludec - Detemir - NPH Diabetes Care 2015;38: Start with 10 units (at dinner time) Check fasting glucose and increase dose by 1-2 units every 3 days to target : mg/dl (~5.5-7 mmoles/l) Down-titrate by 2-4 units if hypo Check HbA1c once FPG target is reached Titration Reduce or Stop sulfonylureas if hypos during the titration phase

10 Time to intensify: Failing basal insulin how to define it - scenario 1 Basal insulin 1st step for everybody Insulin titration on FPG Fix fasting first FPG remains above target (130 mg/dl or 7 mmoles/l) HbA 1c > 7.5 % INSULIN RESISTANCE despite high doses of insulin units/day is a reasonnable compromise for defining high doses in most patients

11 How to intensify: Failing basal insulin scenario 1: insulin resistance Basal insulin 1st step for everybody Insulin titration on FPG Fix fasting first FPG remains above target despite high doses of insulin Options which have been shown to be effective Adding: Pioglitazone++ (effective in many cases*) SGLT2-inhibitor (effective in some cases) GLP1r-agonist (effective in some cases) The insulino-resistance issue a difficult clinical situation *But some safety concerns, mainly fluid retention (risk of decompensation of heart failure)

12 Time to intensify: Failing basal insulin how to define it - scenario 2 Basal insulin 1st step for everybody Insulin titration on FPG FPG at target Fix fasting first despite a well titrated basal insulin HbA 1c > 7.5 to 8% Post-prandial glucose increments from pre-prandial are not addressed on basal insulin. A «PRANDIAL ISSUE» may explain why HbA1c remains high despite a good titration

13 Post-prandial glucose increments from pre-prandial are not addressed on basal insulin Glargine only Post-prandial excursion not adressed by Glargine FPG at target on Glargine Meal Test Arnolds et al. Diabetes Care 2010: 33;

14 How to intensify: Failing basal insulin scenario 2: prandial issue Basal insulin 1st step for everybody Insulin titration on FPG Fix fasting first HbA1c remains above target despite a good titration of basal insulin The prandial issue Intensification of insulin therapy usually consists of additional prandial injections: at each meal (basal-bolus) or at the main meal ( the basal + concept)

15 The Basal Plus regimen (one rapid-acting insulin at the main meal on the top of well-titrated Glargine) has proven to be effective The Basal Plus Concept: one injection of a rapid-acting insulin before the main meal, on the top of well-titrated Glargine, dramatically reduces the post-prandial glucose As a result, mean HbA1C is reduced to target The OPAL Study: Diabetes, Obesity and Metabolism, 10, 2008,

16 Mean HbA 1c (%) ± SE The Basal Plus regimen (one rapid-acting insulin at the main meal on the top of well-titrated Glargine) has proven to be almost as effective as the gold-standard Basal-Bolus GetGoal-Duo2 : Adding Lixisenatide to well titrated Glargine compared to Basal Plus or Basal-Bolus Change over time from baseline to Week 26 for mean HbA 1c 9.0 Insulin glargine ± metformin Insulin glargine (± metformin) + insulin Glulisine QD OR insulin glulisine TID % Insulin glulisine once a day + insulin glargine (n=298) % Insulin glulisine 3 times a day + insulin glargine (n=295) Basal Plus Screening 7.2% 7.0% Baseline Week 26 Time (weeks) Basal Bolus Insulin Glargine titration on FPG Guerci B, EASD 2015

17 Events by hour The Basal Plus regimen (one rapid-acting insulin at the main meal on the top of well-titrated Glargine) has proven to be almost as effective as the gold-standard Basal-Bolus, with fewer hypos GetGoal-Duo2 : Adding Lixisenatide to well titrated Glargine compared to Basal Plus or Basal-Bolus Lower rate of hypoglycaemia, mainly during the day, in the Basal Plus arm Insulin glulisine QD + insulin glargine Insulin glulisine TID + insulin glargine n=301 n= Basal Plus 80 Basal Bolus n= :00 <06:00 Nocturnal hypoglycaemia 06:00 <10:00 10:00 <14:00 14:00 <18:00 18:00 <23:00 Time period Guerci B, EASD 2015 Guerci B, EASD 2015

18 After basal insulin, how to intensify: the guidelines HbA1c > target Updated 2015 The ADA/EASD position statement endorsed the addition of 1 to 3 injections of a rapid-acting insulin analog before meals. As an alternative, the statement mentioned premixed insulins.

19 After basal insulin, how to intensify: the guidelines HbA1c > target Updated 2015 As an alternative, the statement mentioned premixed insulins But, in patients initiated on basal insulin, as recommended, switching to a different regimen is not logical, compared to adding rapid-acting to the basal... Basal-Plus and next Basal-Bolus are the good options for intensification with insulin

20 After basal insulin, how to intensify: the guidelines HbA1c > target Updated 2015 Basal Plus remains rather easy but multiple insulin injections regimens can be difficult to manage, requiring a complex adustment of insulin doses with a high risk of hypos

21 How to intensify, what options? Failing basal insulin scenario 2: the prandial issue Basal insulin 1st step for everybody Insulin titration on FPG Fix fasting first HbA1c remains above target despite a good titration of basal insulin The prandial issue Which other options to adress post-prandial glucose excursions on basal insulin, rather than adding short-acting insulins?

22 An alternative to multiple insulin injections: adding an oral agent with a predominant post-prandial effect: a DPP4-inhibitor A DPP4-inhibitor combined to glargine (+ metformin) + DPP4-inhibitor Glargine only FPG at target on Glargine Sitagliptin reduces post-prandial glucose excursion Meal Test Arnolds et al. Diabetes Care 2010: 33;

23 To combine an oral agent with basal insulin? A DPP-4 inhibitor (sitagliptin) 640 patients: ~75% of patients on basal insulins ~70% of patients on metformin - 0.6% Without change in insulin dose Slightly increased incidence of hypoglycaemia (sitagliptin, 16% vs placebo, 8%). No significant change in body weight

24 An alternative to multiple insulin injections: adding an oral agent with a predominant post-prandial effect: a SGLT2-inhibitor* Normal Subjects *Not yet available in many countries

25 An alternative to multiple insulin injections: adding an oral agent with a predominant post-prandial effect: a SGLT2-inhibitor* *Not yet available in many countries SGLT2-inhibitors act independently of insulin, why they may provide additional glycaemic control when used with insulin. Moreover, the caloric loss and osmotic diuresis secondary to increased urinary glucose excretion may counter insulin-related weight gain and fluid retention.

26 To combine an oral agent with basal insulin? A SGLT2-inhibitor* *Not yet available in many countries Patients inadequately controlled on basal insulin (glargine, detemir, NPH) were randomized to: empagliflozin 10 mg (n=169), empagliflozin 25 mg (n=155) or placebo (n=170) HbA1C Insulin dose constant Insulin dose could be adusted HbA1C

27 To combine an oral agent with basal insulin? A SGLT2-inhibitor* *Not yet available in many countries Similar percentages of patients had confirmed hypoglycaemia in all groups (35%) Genital infection was reported in 2% on placebo, 5% and 8% on empagliflozin. Weight Weight

28 NEJM, Sept 2015 SGLT2-inhibitors: the amazing results of The EMPA-REG Outcome Study In 7020 patients with established cardiovascular disease Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease HbA1c: only a small difference between the Empagliflozin and the placebo arms: ~0,4% since anti-diabetic treatments were more intensified in the placebo arm Study medication given in addition to standard of care 48% of patients on insulin at baseline

29 NEJM, Sept 2015 SGLT2-inhibitors: the amazing results of The EMPA-REG Outcome Study A significant 14% reduction in the composite MACE on Empagliflozin Driven by a very early and dramatic reduction in CV death

30 An alternative to multiple insulin injections: adding a non-insulin injectable agent, a GLP1r-agonist GLP1r-agonists: Pharmacokinetics Adapted from M.Riddle: Keystone 2011

31 An alternative to multiple insulin injections: adding a non-insulin injectable agent, a GLP1r-agonist GLP1r-agonists: Pharmacokinetics Prandial vs Basal Short-acting: prandial Adapted from M.Riddle: Keystone 2011

32 Exenatide (Byetta ): a short-acting GLP1r-agonist reduces mainly post-prandial glucose Exenatide combined to glargine (+ metformin) FPG at target on Glargine Glargine only + Exenatide Meal Test Arnolds et al. Diabetes Care 2010: 33; GLP1r-agonist short-acting dramatically reduces post-prandial glucose excursion

33 Exenatide (Byetta ): a short-acting GLP1r-agonist reduces mainly post-prandial glucose Exenatide has a half-life of 2.4 h and clinical effects lasting 6-8 h FPG is also reduced, but to a lesser extent. Exenatide dramatically reduces blood glucose excursion after breakfast and dinner, i.e. after each injection. This effect is due to slowing gastric emptying Heine et al, Ann Intern Med. 2005;143:

34 Lixisenatide is a potent prandial exendin-based GLP-1 receptor agonist Lixisenatide: Comparison of the Affinity of GLP-1RA Lixisenatide with Native GLP-1 Native GLP-1 ** IC nm 7 hours Lixisenatide nm High potency: Binding affinity ~4 times greater than native GLP-1 Lixisenatide s high affinity for the GLP-1 receptor accounts for its relatively long pharmacologic half-life which enables once-a-day dosing 1. Werner U, et al. Regul Pept. 2010;164(2-3): Barnett AH, et al. Core Evid. 2011;6: Christensen M, et al. IDrugs. 2009;12(8): Sanofi Internal Specific Non-clinical Pharmacology Report MVT Sanofi Internal Specific Non-clinical Pharmacology Report MVT0011.

35 Lixisenatide (Lyxumia ): a short-acting (once a day) GLP1r-agonist reduces mainly post-prandial glucose compared to the long-acting (once a day) Liraglutide Lixisenatide once a day Lixisenatide (once a day but short-acting) slows gastic emptying more than Liraglutide (long-acting once a day) and has a major post-prandial action. Kapitza et al, IDF 2011

36 GLP1r-agonists: Pharmacokinetics, prandial vs basal Short-acting: prandial Long-acting: basal Adapted from M.Riddle: Keystone 2011

37 Exenatide LAR : an action over the whole 24 hours, without any post-prandial specificity Head-to-Head study comparing Exenatide short and long-acting Exenatide LAR «once a week» lowers the whole 24 hours blood glucose profile, with little impact on post-meal glucose excursion Lancet 2008; 372:

38 Exenatide LAR : an action over the whole 24 hours, without any post-prandial specificity Head-to-Head study comparing Exenatide short and long-acting Exenatide LAR «once a week» lowers the whole 24 hours blood glucose profile, with little impact on post-meal glucose excursion At the différence of Exenatide «twice a day» which predominantly adresses post-prandial glucose excursion. Lancet 2008; 372:

39 Liraglutide (basal long-acting) decreases mainly Fasting Plasma Glucose and Post-Prandial Glucose, as absolute values but does not adresses post-prandial glucose excursions, Kapitza et al, Diabetes, Obesity and Metabolism 15: , 2013.

40 Liraglutide (basal long-acting) decreases mainly Fasting Plasma Glucose and Post-Prandial Glucose, but as absolute values but does not adress post-prandial glucose excursions, at the difference of Lixisenatide (prandial short-acting once a day) Small effect on FPG Strong action on PPG Kapitza et al, Diabetes, Obesity and Metabolism 15: , 2013.

41 GLP1r-agonists: clinical differences according to pharmacokinetics Summary The main difference is shown for gastric emptying Exenatide Lixisenatide Predominant Prandial Effect NO Slowing of gastic emptying is no longer shown on continuous administration of GLP1 (Tachyphylaxis) Predominantly Basal Liraglutide Exenatide once a week Dulaglutide Albiglutide Adapted from Meier, J. J. Nat. Rev. Endocrinol. 8, (2012)

42 GLP1r-agonists + basal insulin a good alternative option Oral Agents HbA 1c target Add basal insulin Titrated on FPG HbA 1c target obesity High Post-Prandial blood glucose Adding GLP1r-agonists Rather than intensifying with prandial insulins

43 HbA1c Better HbA1C

44 Hypos Fewer Hypos Weight Less weight gain

45 Insulin treatment intensification To add a GLP-1r agonist on the top of basal insulin The rationale seems to be stronger to combine a short-acting prandial GLP-1r agonist to basal insulin, than combining a long-acting GLP-1r agonist. Glargine: Acts mainly on fasting plasma glucose and glucose during the night. Short-acting GLP-1r agonists (Exenatide BID Lixisenatide...): Act mainly on post-prandial glucose Have little effect during the night: which should reduce the risk of nocturnal hypo and make Lantus titration easier than with a long-acting GLP-1r agonist.

46 Adding a prandial GLP1r-agonist on the top of Glargine, rather than rapid-acting insulins Short-acting «prandial» GLP1r-agonists, Exenatide - Lixisenatide, adress postprandial glucose excursion Exenatide twice a day The modern «Basal-Bolus»

47 Head-to-head comparison of 2 strategies of prandial intensification of insulin treatment The 4B Study Adding to well-titrated insulin Glargine a prandial GLP1r- agonist compared to switching to a basal-bolus regimen, with a short-acting insulin at each meal Diamant M et al. ADA 2013, 70OR

48 Head to head comparison of 2 strategies of prandial intensification of insulin therapy The 4B study Similar HbA1c reduction Diamant M et al. ADA 2013, 70OR With a major advantage for GLP1r-agonist for weight Diamant M et al. ADA 2013, 70OR

49 Head to head comparison of 2 strategies of prandial intensification of insulin therapy The 4B study Similar HbA1c reduction and fewer hypos on GLP1r-agonist Diamant M et al. ADA 2013, 70OR The modern «Basal-Bolus» Diamant M et al. ADA 2013, 70OR

50 Adding a prandial GLP1r-agonist on the top of Glargine, rather than rapid-acting insulins Lixisenatide once a day The modern «Basal-Plus»

51 The GetGoal program Lixisenatide as add-on to basal insulin Basal insulin OADs GetGoal-Duo1 Add-on to insulin glargine ± MET GetGoal-L Add-on to basal insulin ± MET GetGoal-L-Asia Add-on to basal insulin ± SU A meta-analysis was performed of results from the 3 trials in the GetGoal program concerning lixisenatide or placebo + basal insulin (with/without OADs)

52 HbA1c ITT population A consistent HbA1c reduction

53 FPG is adressed by basal insulin, not more by adding Lixisenatide

54 Adding Lixisenatide reduces PPG

55 A consistent weight loss

56 Adding the once a day Lixisenatide to well-titratred Glargine has proven to be as effective as adding one short-acting insulin (Basal Plus) and almost as effective as the gold-standard Basal-Bolus GetGoal-Duo2 : Adding Lixisenatide to well titrated Glargine compared to Basal Plus or Basal-Bolus Adding one injection of Lixisenatide to Glargine has a similar HbA1c reduction efficacy than adding one injection of short-acting insulin (Basal Plus) The difference with a classical Basal- Bolus (3 injections) is minor (0,2%) with the advantage of less weight gain and fewer hypos Insulin Glargine titration on FPG Guerci B, EASD 2015

57 A simple and convenient way to combine Lixisenatide and Glargine the fixed-combo LixiLan (the 2 agents in the same cartridge) 323 T2DM patients inadequately controlled on metformin alone Maximum dose for lixisenatide in the combo Rosenstock J, et al. EASD 2014

58 A simple and convenient way to combine Lixisenatide and Glargine the fixed-combo LixiLan (the 2 agents in the same cartridge) Final doses: 36 (which means 18 µg of Lixisenatide) and 39 units/day HbA1C reduced from 8 to 6.3%! with a difference in weight of 1.5 kgs Same rate in hypos Good GI tolerability (6% GI effects more than on Glargine, due to the slow increase in the Lixisenatide doses with insulin titration) Rosenstock J, et al. EASD 2014

59 A simple and convenient way to combine Lixisenatide and Glargine the fixed-combo LixiLan (the 2 agents in the same cartridge) Final doses: 36 (which means 18 µg of Lixisenatide) and 39 units/day HbA1C reduced from 8 to 6.3%! with a difference in weight of 1.5 kgs Same rate in hypos Good GI tolerability (6% GI effects more than on Glargine, due to the slow increase in the Lixisenatide doses with insulin titration) Rosenstock J, et al. EASD 2014

60 Which GLP1r-agonist to combine with insulin Prandial or Basal? To combine a short-acting GLP-1r agonist A predominant post-prandial effect good rationale and good clinical results To combine a long-acting GLP-1r agonist: Mainly basal : which means basal + basal The rationale is weaker, but results of clinical studies are also good

61 ADA 2014 With less insulin doses

62 ADA 2014 Slightly more hypos compared to placebo but for a better HbA1c and 3 Kgs

63 After basal insulin, how to intensify: the updated guidelines 2015 Diabetes Care 2015;38: Over the past 3 years, the effectiveness of combining GLP-1 receptor agonists (both short-acting and weekly formulations) with basal insulin has been demonstrated, with most studies showing equal or slightly superior efficacy to the addition of prandial insulin, and with weight loss and less hypoglycemia.

64 Patient with Type 2 DM failing basal insulin therapy Adding a GLP1r-agonist : Summary Basal insulin Insulin titration on fasting plasma glucose HbA 1c > target Add GLP1r-agonist as a step before switching to multi-injections of insulin GLP1-r agonist and basal insulin combination treatment can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia with no weight gain. Lancet 2014; 384:

65 When It s Time to Intensify: What Are The Options? Summary 1 1st step for everybody Fix fasting first Basal insulin + metformin* Insulin titration on fasting plasma glucose *If no renal impairment FFG and HbA 1c > target despite high doses of insulin insulin-resistance Add GLP1r-agonist (long-acting?) Not well studied in this indication Many positive case reports Add Pioglitazone The best option from an efficacy point of view No or slight increase in hypos Weight gain Fluid retention (CHF) Add SGLT2-inhibitor Rather good efficacy Genital infections Weight loss Some risk of DKA? No or slight increase in hypos CV benefit

66 When It s Time to Intensify: What Are The Options? Summary 2 1st step for everybody Basal insulin + metformin* *If no renal impairment Fix fasting first Insulin titration on fasting plasma glucose Add DPP-4 inhibitor HbA 1c >7.5 to 8% Add GLP1r-agonist FPG at target Prandial issue Add SGLT2-inhibitor These 3 options adress post-prandial glucose excursions HbA 1c >7 to 8% Add prandial injections of short-acting insulins, at each meal or at the main meal.