Optimal Use of Insulin In Type 2 Diabetes Martin J. Abrahamson, MD - - PowerPoint PPT Presentation

Optimal Use of Insulin In Type 2 Diabetes

Martin J. Abrahamson, MD FACP Associate Professor of Medicine, Harvard Medical School

Learning objectives

Discuss use of prandial insulin in diabetes Discuss use of insulin and GLP1 RA in type 2 diabetes Discuss initiation and intensification of basal insulin in type 2 diabetes (T2DM) Review the pharmacokinetics of the insulins used in clinical practice

Physiologic Insulin Secretion: 24-hour Profile

Insulin (µU/mL) 50 25 Basal insulin

Breakfast Lunch Dinner

150

Time of day

Glucose (mg/dL) 100 50

7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM PM

Basal glucose

Insulins Available for Clinical Use

• Prandial insulin
• Short acting - Regular
• Rapid acting analogues - Aspart, Lispro, Apidra
• Basal Insulin
• NPH
• Basal analogues
• U 100 Glargine, Detemir
• U 300 Glargine, Degludec
• Premixed insulins
• Provide both basal and meal time cover

Hours after injection Basal long (Detemir and U 100 Glargine) Rapid (Lispro, Aspart, Glulisine)

Hours

0 2 4 6 8 10 12 14 16 18 20 22 24 Short (Regular) Insulin level Basal ultralong (Degludec and U 300 Glargine)

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Pharmacodynamics of different insulins

NPH

Rapid-acting insulin Time (h) Insulin action (at mealtime)* From the normal pancreas Ultra-fast insulin Regular human insulin

Ultra-fast insulin should:

• Better approach physiological insulin

secretion in T1D

• Replace early insulin secretion in T2D
• Have a better profile for pump therapy

*Schematic representation T1D, type 1 diabetes; T2D, type 2 diabetes Adapted from Home. Diabetes Obes Metab 2015;17:1011–20

Ultra-fast insulin: Even closer to a physiological insulin profile

Niacinamide: absorption modifier Vitamin B3 L-Arginine: added for stability Naturally-occurring amino acid

• FDA. Inactive Ingredient Search for Approved Drug Products database. www.accessdata.fda.gov/scripts/cder/iig/index.cfm

Insulin aspart

Changing the formulation: Faster aspart is insulin aspart in a new formulation

Inhaled Technosphere Insulin

Santos Cavaiola T, Edelman S. Clin Ther. 2014;36:1275-1289 ; Afrezza Package insert RAA = Rapid-acting analog GIR = Glucose infusion rate

► “Ultra-rapid-acting” inhaled insulin: ► Onset 12-15 minutes

• Peak 60 minutes
• Duration 2.5-3 hours

The Ideal Basal Insulin

• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect – 24 hours
• Smooth, peakless profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycemia
• Once-daily administration

24 hour Plasma Glucose Curve: Rationale for Adding Basal Insulin

Time of Day

400 300 200 100 0600 0600 1000 1400 1800 2200 0200

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Glucose (mg/dL)

Diabetes Normal

400 300 200 100 0600 0600 1000 1400 1800 2200 0200

24 hour Plasma Glucose Curve: Rationale for Adding Basal Insulin

Normal Diabetes

Time of Day Glucose (mg/dL)

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Basal Insulin Added to Oral Agents Improves HbA1c

Philis-Tsimikas 2006 20 weeks

6.5 7.0 7.5 8.0 8.5 9.0 HbA1c (%) 9.5

1.8 1.9 1.5 1.7

Hermansen 2006 24 weeks Riddle 2003 24 weeks

1.6 1.6

NPH Detemir Glargine

p=ns for all

NO!

Are all basal insulin analogs the same?

Animal insulin preparations First generation basal insulin analogues Isolation of insulin (Banting & Best) Ultra-long-acting basal insulin analogues NPH insulin

High Half life (hours): Variability: Medium Low

λ

5–10 12.5 25 18–19

IGlar U300 IDet IDeg IGlar U100

IDet insulin detemir; NPH, neutral protamine Hagedorn

• Kalra. J Pak Med Assoc 2013;63:1442–4; Insulatard SmPC; Toujeo SmPC

The quest for the ideal basal insulin - From NPH to basal insulin analogues

Lower day-to-day glucose variability with first-generation basal insulin analogues versus NPH

GIR (mg/kg/min) GIR (mg/kg/min) GIR (mg/kg/min)

Time (hours) Time (hours) Time (hours) 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2 16 8 24 6 4 2

68 48 27

20 40 60 80 100 NPH IGlar U100 IDet

Intra-patient variability (CV%)

NPH 0.4 U/kg IGlar U100 0.4 U/kg IDet 0.4 U/kg

CV, coefficient of variation; GIR, glucose infusion rate; IDet, insulin detemir; IGlar U100, insulin glargine U100 Heise et al. Diabetes 2004;53:1614–20

1.0 0.6 0.4 0.8 * * * * * * * * * 0.2 *

Reduced risk of hypoglycemia with first-generation basal insulin analogues versus NPH

Relative risk of nocturnal hypoglycaemic events IGlar U100 IDet

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 * * * * * * Relative risk of confirmed hypoglycaemic events * *

Type 2 diabetes Type 1 diabetes

1.2

Approximate risk- reduction range T2D: 2 to 53% T1D: –20% to 46%

Hypoglycaemia definition varies across studies; direct comparisons cannot be made. Studies with two arrows compared different dosing times for IGlar U100 or IDet *Significant difference; †Not treat-to-target; T1D, type 1 diabetes; T2D, type 2 diabetes Devries et al. Diabetes Metab Res 2007;23:441–54; Fajardo Montanaña et al. Diabet Med 2008;25:916–23; Horvath et al. Cochrane Database Syst Rev 2007;18:CD005613; Robertson et al Diabet Med 2007;24:27–34; Bartley et al. Diabet Med 2008;25:442–9; Pieber et al. Diabet Med 2007;24:635–42

U300 Glargine (Toujeo) vs U100 Glargine: Equally effective but with higher dose of U300 Glargine

Yki Jarvinen H et al. Diabetes, Obesity and Metabolism 17: 1142–1149, 2015.

U300 Glargine is associated with less hypoglycemia than U100 glargine

Yki Jarvinen H et al. Diabetes, Obesity and Metabolism 17: 1142–1149, 2015.

N Engl J Med 377: 723–732

• Number of severe hypoglycemic episodes*
• Incidence of severe hypoglycemic episodes*

Time from randomization to first occurrence of a 3-point MACE: cardiovascular death*†, non-fatal myocardial infarction* or non-fatal stroke*

Primary and secondary confirmatory endpoints

*Confirmed by the Event Adjudication Committee. †Cardiovascular death includes undetermined cause of death.

Secondary confirmatory endpoints Primary endpoint

Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

Key inclusion criteria: cardiovascular profile

Type 2 diabetes Current treatment with ≥1 oral or injectable antidiabetic agent(s) HbA1c <7.0% and current basal insulin treatment ≥20 U/day High cardiovascular risk profile HbA1c ≥7.0% OR

• Cardiovascular or

chronic kidney disease and aged ≥50 OR

• Risk factors for

cardiovascular or chronic kidney disease and aged ≥60

Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

Similar mean HbA1c

Full analysis set. Bar graph shows observed mean change from baseline at month 24 (%). ET, end treatment visit; ETD, estimated treatment difference

Insulin degludec (N) 3774 3656 3608 3535 3525 2458 3344 IGlar U100 (N) 3776 3640 3562 3516 3500 2424 3277

• 0.86
• 0.84
• 1.0
• 0.5

0.0

Insulin degludec IGlar U100 Post hoc ETD: 0.01% [–0.05; 0.07]95% CI

6.5 7.0 7.5 8.0 8.5 9.0 3 6 9 12 15 18 21 24 27 30 HbA1c (%)

ET 75 69 64 59 53 HbA1c (mmol/mol)

Insulin degludec (N) 3774 3656 3608 3535 3525 2458 3344 IGlar U100 (N) 3776 3640 3562 3516 3500 2424 3277

Insulin degludec IGlar U100

Months since randomisation

2 4 6 8 10 12 3 6 9 12 15 18 21 24 27 30

Time to first 3-point MACE

Insulin degludec (N) 3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217 IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205

Time to first EAC-confirmed event (months) N=356 N=325 Event rate 4.29/100 patient-years

• f observation

Event rate 4.71/100 patient-years

• f observation

Patients with an event (%) HR: 0.91 [0.78; 1.06]95% CI Non-inferiority confirmed

Insulin degludec IGlar U100

Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

0.00 0.04 0.08 0.12 0.16 3 6 9 12 15 18 21 24 27 30 Mean number of episodes per patient

Rates of severe hypoglycemia

RR: 0.60 [0.48; 0.76]95% CI p<0.001

Time from randomisation (months) Insulin degludec IGlar U100

Insulin degludec (N=3818) IGlar U100 (N=3819) E R E R Confirmed episodes 280 3.70 472 6.25

Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

And 53% reduction in severe nocturnal hypoglycemia

Combining a GLP-1 RA and a basal insulin in one pen improves efficacy and safety

For illustrative purposes only, not drawn to scale GLP-1 RA, glucagon-like peptide-1 receptor agonist; FPG, fasting plasma glucose; PPG, postprandial glucose

• 1. Inzucchi et al. Diabetes Care 2015;38:140–9; 2. Garber et al. Endocr Pract 2016;22:84–113

HbA1c FPG PPG

WEIGHT HYPOGLYCEMIA NAUSEA

Efficacy Side effects

Basal insulin GLP-1 RA monotherapy GLP-1 RA/basal insulin combined in one pen

LixiLan-O

Key clinical findings

†Max. dose 60 U; Documented symptomatic hypoglycaemia with PG <70 mg/dL (3.9 mmol/L). Symptomatic hypoglycaemia = symptomatic hypoglycaemia

recorded on the dedicated eCRF and meeting protocol definition for severe, or documented, or probable symptomatic hypoglycaemia. eCRF, electronic Case Report Form; EOT, end of treatment; IGlar U100, insulin glargine U100; Lixi, lixisenatide; OAD, oral antidiabetic drug Rosenstock et al. Diabetes Care 2016;39:2026–35

• 1.6
• 1.3
• 0.9
• 1.8
• 1.6
• 1.4
• 1.2
• 1.0
• 0.8
• 0.6
• 0.4
• 0.2

0.0

p<0.0001 Change in HbA1c (%) IGlarLixi IGlar

U100† Lixi

p<0.0001

• 0.3

1.1

• 2.3
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 0.5 1.0 1.5

Change in weight (kg) p<0.0001 IGlarLixi IGlar U100† Lixi

1.4 1.2 0.3 0.0 0.5 1.0 1.5 2.0

Severe hypoglycaemia: 1 event with IGlar U100 Hypoglycaemia rate (events/patient-year) IGlarLixi IGlar U100† Lixi HbA1c Weight Confirmed symptomatic hypoglycemia

Baseline HbA1c 8.1% 8.1% 8.1% EOT HbA1c 6.5% 6.8% 7.3% Uncontrolled on OADs

Severe hypoglycaemia in four IGlarLixi patients and

• ne IGlar U100 patient
• 1.1
• 0.6
• 1.2
• 1.0
• 0.8
• 0.6
• 0.4
• 0.2

0.0

p<0.0001

• 0.7

0.7

• 0.8
• 0.6
• 0.4
• 0.2

0.0 0.2 0.4 0.6 0.8

Change in HbA1c (%) Change in weight (kg)

3.0 4.2 1 1 2 2 3 3 4 4 5 5

Hypoglycaemia rate (events/patient-year) IGlarLixi IGlar U100 (max. 60 U) IGlarLixi IGlar U100 (max. 60 U) IGlarLixi IGlar U100

(max. 60 U)

p<0.0001

LixiLan-L

Key clinical findings

Documented symptomatic hypoglycaemia with PG <70 mg/dL (3.9 mmol/L). Symptomatic hypoglycaemia = symptomatic hypoglycaemia recorded on the dedicated eCRF and meeting protocol definition for severe, documented or probable symptomatic hypoglycaemia eCRF, electronic Case Report Form; EOT, end of treatment; IGlar U100, insulin glargine U100 Aroda et al. Diabetes Care 2016;39:1972–80

HbA1c Weight Confirmed symptomatic hypoglycemia

Baseline HbA1c 8.1% 8.1% EOT HbA1c 6.9% 7.5% Uncontrolled on insulin

Diabetes Care Publish Ahead of Print, published online February 26, 2018

HbA1c over time

IDegLira (n=252) IGlar U100 + IAsp (n=254)

5.5 6.0 6.5 7.0 7.5 8.0 8.5

• 2

2 4 6 8 10 12 14 16 18 20 22 24 26

0.0 HbA1c (%) Time (weeks)

ETD: −0.02% [−0.16; 0.12]95% CI p<0.0001 for test for non-inferiority by 0.3%

6.7% 6.7%

Diabetes Care Publish Ahead of Print, published online February 26, 2018

Change in body weight over time

• 2
• 1

1 2 3 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (weeks)

IDegLira (n=252) IGlar U100 + IAsp (n=254) –0.93 kg 2.64 kg

Change in body weight (kg)

IDegLira IGlar U100 + IAsp ETD [95% CI] ∆Weight (kg) LSMean −0.93 2.64 −3.57 [-4.19; -2.95], p<0.0001

Diabetes Care Publish Ahead of Print, published online February 26, 2018

Severe or BG-confirmed symptomatic hypoglycemia over time

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 2 4 6 8 10 12 14 16 18 20 22 24 26

Number of episodes per subject

Treatment ratio: 0.11 [0.08; 0.17]95%CI p<0.0001

Time (weeks)

IDegLira (n=252) IGlar U100 + IAsp (n=253)

Diabetes Care Publish Ahead of Print, published online February 26, 2018

And 92% reduction in nocturnal hypoglycemia

Basal-Plus: Initiation and Advancing Therapy

• Choose a target meal to initiate prandial coverage
• Breakfast, largest meal of the day, or largest glucose excursion
• Start 4–6 units of a rapid-acting insulin analog (or 10% of basal dose) 10–15

minutes before the meal

• Adjust prandial insulin dose based on

– 2-h PPG target <180 mg/dL – Next preprandial or bedtime BG target <130 mg/dL

• If A1C remains above target, add second prandial dose
• Once on prandial insulin stop oral insulin secretagogues (sulfonylureas; DPP 4

inhibitors, glinides) and reduce or stop TZDs

• Basal – bolus treatment – usually 50% basal; 50% bolus

HS = at bedtime; PPG = postprandial glucose

Lankisch MR, et al. Diabetes, Obesity and Metabolism. 2008:10;1178-1185. Meneghini L, et al. Endocrine

• Practice. 2011;17; 727-736.

Physiologic insulin regimens with basal insulin plus rapid-acting insulin dosing before each meal

• Premeal insulin dosing by algorithmic scale or, preferably,

carbohydrate counting

• Carbohydrate counting or consistent carbohydrate intake
• Check blood glucose 4 to 6 times a day
• Record keeping: “monitoring” rather than just “checking”
• Surveillance and risk for hypoglycemia
• Likely recalculate doses when advancing from basal-plus,

not just adding another injection

Key points

Type 2 diabetes is a progressive disease – the majority of people with T2DM will ultimately require insulin Compared to NPH basal insulin analogues reduce

• hypoglycemia. The

newer basal insulin analogues are associated with even less hypoglycemia than the “older”

• nes

Basal insulin and GLP 1 RA are effective when used in combination and are associated with lower rates of hypoglycaemia compared to basal – prandial insulin

Key points

If prandial insulin is required, start by adding 1 dose at the biggest meal If that is still not effective advance to basal bolus treatment If possible adjust the dose of prandial insulin based on the pre meal glucose and amount of carbohydrate to be consumed at the meal