Main Pathophysiological Defects in T2DM “The Ominous...
Transcript of Main Pathophysiological Defects in T2DM “The Ominous...
Main Pathophysiological Defects in T2DM “The Ominous Octet”
Islet β-cell
Impaired Insulin Secretion
Neurotransmitter Dysfunction
Decreased Glucose Uptake
Islet α-cell
Increased Glucagon Secretion
Increased Lipolysis
Increased Glucose Reabsorption
Increased HGP
DecreasedIncretin Effect
Defronzo RA. Diabetes. 2009 Apr;58(4):773-95.
Injectable Therapies for T2DM and Obesity
This presentation will: • Explain the pathophysiological aspects of T2DM, and
how defects can be addressed with injectable therapies
• Outline incretin-based injectable therapies for T2DM and obesity management and discuss evidence from clinical trials
• Describe established and newly available insulin therapies for treatment of type 2 diabetes.
• Describe how to intensify insulin regimens to achieve glycemic targets
Abnormal Insulin and Glucagon Responses Contribute to Hyperglycemia in Type 2 Diabetes
Healthy (n = 11)Type 2 Diabetes (n = 12)
Mean ± SEData from Müller WA, et al. N Engl J Med. 1970;283:109-115
140
360
300
240Glucose (mg/dL)
0
120
60Insulin (mcU/mL)
100
120
140Glucagon (pg/mL)
80
-60 120 180 240
Time (min)
600
Meal
The Incretin Effect
Time, min
IR In
sulin
, m
U/L
nmol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 1200
Control Subjects (n=8)
Type 2 Diabetes(n=14)
Time, min
IR In
sulin
, m
U/L
nmol / L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 120 0
Incretin Effect
Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
GLP-1 Modulates Numerous Functions in Humans
GLP-1: Secreted upon the ingestion of food
Beta cells: Enhances glucose-dependent
insulin secretion
Brain promotes satiety and reduces appetite
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
Stomach: Helps regulate gastric
emptying
Liver: ↓ Glucagon reduces
hepatic glucose output
Alpha cells: ↓ Glucose-dependent
postprandial glucagon secretion
Glucose-Dependent Actions of GLP-1: Effect in Subjects With Type 2 Diabetes
Data are mean ± SE. *P<0.05 Adapted from: Nauck MA, et al. Diabetologia. 1993;36:741-744.
350
300
250
200
150
100
50
0
Insulin (pmol/L)
* ** * *
* * *
GLP-1/PBO infusion
Time (min)
-30 0 60 120 180 240
25
20
15
10
5
0
Glucagon (pmol/L)
Time (min)
-30 0 60 120 180 240
*** *
GLP-1/PBO infusion
GLP-1
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0
*
Glucose (mmol/L)
GLP-1/PBO infusion
***
** *
-30 0 60 120 180 240
Time (min)
Placebo
Strategies for Enhancing GLP-1 Action
• GLP-1 receptor agonists (injectable therapies) – Exenatide – Liraglutide – Albiglutide – Dulaglutide
• DPP-4 inhibitors (oral therapies) – Inhibit actions of DPP-4 – Sitagliptin, Saxagliptin, Linagliptin, Alogliptin
Characteristics of GLP-1 AgonistsExenatide, Liraglutide, Albiglutide, Dulaglutide
Mechanism Mimic prolonged action of GLP-1
EfficacyDecrease A1C levels 0.5%–2.0% (depends on entry of glucose into bloodstream from gut)
Dosing Once- or twice-daily injection, weekly *
Side effects Nausea, vomiting, weight loss
Main riskC-cell thyroid tumors**, long-term safety unknown
Associated with Pancreatitis possible
Nathan DM, et al. Diabetes Care. 2008;31:173-175; Drucker DJ, et al. Lancet. 2006;368:1696- 1705. Exenatide [package insert]. San Diego, CA; Amylin Pharmaceuticals; 2010.; Tanzeum (albiglutide) [prescribing information].
*Dosing depends on GLP-1 agonist **With liraglutide, in rodents only
A1C = glycated hemoglobin; GLP-1 = glucagon-like peptide-1
Marketed GLP-1 RAsCharacteristic Exenatide BID Liraglutide Exenatide ER Albiglutide Dulaglutide
Initial US approval 2005 2010 2012 2014 2014
Trade name Byetta Victoza Bydureon Tanzeum (U.S.) Eperzan (Europe)
Trulicity
Description
Synthetic exendin-4, a peptide identified in H. suspectum that activates the GLP-1 R and is resistant to DPP-4 degradation
GLP-1 modifieda to be resistant to DPP-4 degradation
Exenatide contained in a hydrolyzable polymer microspheres for extended release
An albumin fusion protein made of 2 copies of modified human GLP-1
A fusion protein with 2 disulfide-linked human GLP-1 analog sequence chains, connected by a small peptide linker to human immunoglobulin G4 (IgG4)
Administration Subcutaneous injection
Half-life 2.4 hours 13 hours > 1 week 5 days 5 days
Dosing 2 × daily, before meals
1 × daily, any time 1 × weekly 1 × weekly 1 × weekly
a Amino acid substitution and addition of acyl chain.
Byetta (exenatide) [prescribing information]; Victoza (liraglutide) [prescribing information]; Bydureon (exenatide extended-release for injectable suspension) [prescribing information].; Neumiller JJ. J Am Pharm Assoc. 2009;49(suppl 1):S16-S29.; DeYoung M, et al. Diabetes Technol Ther. 2011;13:1145-1154.; Tanzeum (albiglutide) [prescribing information]; Trulicity (dulaglutide) [prescribing information]; Kuritzky L, et al. PostGrad Med. 2014;126(6):60-72.
Liraglutide
• Liraglutide: 0.6 mg sc QD x 1 week then 1.2 mg sc QD increase to 1.8 mg sc QD if needed • Supplied in a pen • Use: 2-3 pens per month
*P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P=0.0015 vs glargine. †All liraglutide dosages shown are 1.8 mg QD.
1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.
Glucose Control With Liraglutide With/Without Oral Agents
Δ A
1C (%
)
-1.6
-1.2
-0.8
-0.4
0
0.4
-1.33-1.50
-1.13
-1.50
-1.00-1.14 -1.09
-0.5-0.44
-0.9-0.98
-0.51
-0.24
0.230.09
Monotherapy vs Glimepiride 52 Weeks1
Add-on to Metformin 26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Sulfonylurea 26 Weeks4
Add-on to Met + TZD 26 Weeks5
Add-on to Met + SU
26 Weeks6
N 746 1091 665 1041 821 581
Treatment Glim
Lir Met Glim +
Met
Lira +Met
Sit + Met
Lira +Met
SU Rosi +
SU
Lira +
SU
Rosi +
Met
Lira +
Rosi + Met
Met +SU
Glar + Met +
SU
Lira +
Met + SU
Baseline A1C (%)
8.4 8.3 8.4 8.4 8.4 8.5 8.4 8.4 8.4 8.5 8.4 8.6 8.3 8.2 8.3
*
****
***
******
*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU. †All liraglutide dosages shown are 1.8 mg QD.
1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.
-4
-3
-2
-1
0
1
2
3
-1.80-2.00
-0.20
-3.38-2.80-2.50
1.60
0.60
2.10
-0.96
1.001.10
-0.42-0.10
-1.50Δ W
eigh
t (kg
) Weight Reduction With Liraglutide: Mono
and Dual Combination Therapy
* ** **
*
*
***
Monotherapy vs Glimepiride 52 Weeks1
Add-on to Metformin 26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Sulfonylurea 26 Weeks4
Add-on to Met + TZD 26 Weeks5
Add-on to Met + SU
26 Weeks6
N 746 1091 665 1041 821 581
Treatment Glim
Lir Met Glim +
Met
Lira +Met
Sit + Met
Lira +Met
SU Rosi +
SU
Lira +
SU
Rosi +
Met
Lira +
Rosi + Met
Met +SU
Glar + Met +
SU
Lira +
Met + SU
*
*P<0.01 vs active comparator. †All liraglutide dosages shown are 1.8 mg QD.
1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.
Hypoglycemia With Liraglutide: Mono and Dual Combination Therapy
0
8
15
23
30
85
3
8
45
17
33
24
Monotherapy 52 Weeks1
Add-on to Metformin 26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Sulfonylurea 26 Weeks4
N 746 1091 665 1041
Treatment† Glim Lira Met Glim + Met
Lira +Met
Sit + Met
Lira +Met
SU Rosi +SU
Lira +SU
*
Pat
ient
s R
epor
ting
Hyp
ogly
cem
ia (%
)
**
Blood Pressure Changes With Liraglutide
-6
-4.5
-3
-1.5
0
1.5
-4.0
-5.6
-2.8
-0.7
-2.3
-3.6
0.5
-1.1-0.9-0.9
0.4
-0.7
-2.3-1.8
Δ S
ysto
lic B
P (m
mH
g)
**
**
Monotherapy vs Glimepiride 52 Weeks1
Add-on to Metformin 26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Sulfonylurea 26 Weeks4,5
Add-on to Met + TZD 26 Weeks6
Add-on to Met + SU
26 Weeks7
N 746 1091 665 1041 821 581
Treatment Glim
Lir Met Glim +
Met
Lira +Met
Sit + Met
Lira +Met
SU Rosi +
SU
Lira +
SU
Rosi +
Met
Lira +
Rosi + Met
Met +SU
Glar + Met +
SU
Lira +
Met + SU
*P<0.05 vs comparator. †All liraglutide dosages shown are 1.8 mg QD.
1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90.; 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.5. Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 7. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055
Liraglutide: Adverse Events
Adverse Events*
Patients (%)
Monotherapy + Met + Glim + Met + TZD
Lir (n=497)
Glim (n=248)
Lir (n=724)
PBO (n=121)
Lir (n=695)
PBO (n=114)
Lir (n=355)
PBO (n=175)
Nausea 28.4 8.5 15.2 4.1 7.5 1.8 34.6 8.6
Diarrhea 17.1 8.9 10.9 4.1 7.2 1.8 14.1 6.3
Vomiting 10.9 3.6 6.5 0.8 12.4 2.9
Constipation 9.9 4.8 5.3 0.9 5.1 1.1
Headache 9.1 9.3 9.0 6.6 8.2 4.6
Dyspepsia 5.2 0.9
*Adverse events of interest occurring in ≥5% of patients receiving liraglutide.
Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc. 2012.
Nausea Declined Over Time with Liraglutide Monotherapy
Patients (%)
0
3.5
7
10.5
14
Time (weeks)
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Liraglutide 1.2 mg (n=251)Liraglutide 1.8 mg (n=246)Glimepiride 8 mg (n=248)
Liraglutide Monotherapy vs SU
Liraglutide [package insert]. Princeton, NJ: Novo Nordisk Inc. 2010; Garber A et al. Lancet. 2009;373:473-481.
Liraglutide 3mg• Approved December 2014 for treatment of
overweight/obesity • Indications: adults with BMI ≥ 30 or BMI ≥ 27 with
one CV risk factor: hypertension, type 2 diabetes, hypercholesterolemia
• Approved with REMS: follow up and registry for MTC, breast cancer, CV safety
• Supplied as 3 mL pen, 6mg/mL (5 pens/mo.) • Dose titration: 0.6mg daily sc x 7 d; 1.2mg daily x
7 d; 1.6mg daily x 7 d; 1.8mg daily x 7 d; 2.4mg daily x 7 d; 3mg daily maintenance
Liraglutide 3mg QD• Phase 3 - 56-week trials: • Proportion of patients achieving weight loss:
≥ 5% ≥ 10%
Liraglutide 3mg 60.3 31.2
Placebo 24.4 8.7
*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.
1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.5. Buse JB, et al. Lancet. 2013;381:117-124.
Glucose Control With Exenatide ER
Δ A
1C (%
)
-1.9
-1.425
-0.95
-0.475
0
-1.5-1.53
-1.28-1.50
-1.20
-1.48
-1.90
-1.5-1.3
-0.9
-1.6-1.5
-1.15
Add-on to OAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Met +/- SU 26 Weeks4
Add-on to OAs†
26 Weeks5
N 258 820 514 456 911
Treatment Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
Glar + OAs
Exe ER + OAs
Lira + OAs
Exe ER + OAs
Baseline A1C (%)
8.3 8.3 8.5 8.5 8.6 8.5 8.5 8.5 8.6 8.3 8.3 8.4 8.5
P<0.001 P<0.0001P<0.01P=0.017 P=0.02
Exenatide ER• 2 mg sc every 7 days, w/ or w/o meals • 23G x 5/16” needle • Microsphere release; steady state: 6-7 wks • Not recom. as 1st line Rx or use w/insulin • Add on to metformin, SU, TZD, or combination • Less nausea vs exenatide BID • ↑ weight loss vs exenatide BID: 5.1 lb vs 3.1 lb
@24 wks
*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.
1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.
-4
-3
-2
-1
0
1
2
3
-2.3-2.0-2.7-2.6
2.8
-2.0
-3.7 -3.6
1.4
-0.8
1.5
-3.6
-0.8
Add-on to OAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Met +/- SU 26 Weeks4
Add-on to OAs†
26 Weeks5
N 258 820 514 456 911
Treatment (mg/day)
Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
Glar +
OAs
Exe ER + OAs
Lira +
OAs
Exe ER + OAs
P<0.0001
Δ W
eigh
t (kg
)
Weight Reduction With Exenatide ER
P<0.001P<0.001
*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.
1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.
0
10
20
30
40
1.05.2
11.013.0
1.04.15.4
8.9
31.0
3.03.76.1
3.1
Add-on to OAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin 26 Weeks3
Add-on to Met +/- SU 26 Weeks4
Add-on to OAs†
26 Weeks5
N 258 820 514 456 911
Treatment Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
Glar +
OAs
Exe ER + OAs
Lira +
OAs
Exe ER + OAs
Pat
ient
s re
porti
ng
hypo
glyc
emia
(%)
Hypoglycemia With Exenatide ER
Exenatide Extended Release: Adverse Events
Adverse Events*
Patients (%)
Monotherapy + Met + Met +/- SU
Exe ER (n=248)
Sit (n=163)
Pio (n=163)
Met (n=246)
Exe ER (n=160)
Sit (n=166)
Pio (n=165)
Exe ER (n=233)
Glar (n=233)
Nausea 11.3 3.7 4.3 6.9 24.4 9.6 4.8 12.9 1.3
Diarrhea 10.9 5.5 3.7 12.6 20.0 9.6 7.3 9.4 4.0
Injection site reaction 10.5 6.7 3.7 10.2 5.0 4.8 1.2 6.0 0
Constipation 8.5 2.5 1.8 3.3 6.3 3.6 1.2
Headache 8.1 9.2 8.0 12.2 9.4 9.0 5.5 9.9 7.6
Dyspepsia 7.3 1.8 4.9 3.3 5.0 3.6 2.4
Vomiting 11.3 2.4 3.0
Fatigue 5.6 0.6 3.0
*Adverse events of interest occurring in ≥5% of patients receiving exenatide extended release.
More Weekly GLP-1 Receptor Agonists
• Albiglutide (modified GLP-1 fused to albumin) • Dulaglutide (GLP-1 analog fused to IgG4) • Resistant to DPP-4 degradation • Similar efficacy as exenatide ER • A1c reduction 0.8 – 1.0% • Studied with metformin, SU, pioglitazone, basal
insulin • Not recommended as first-line therapy
Albiglutide
• 30 mg sc Qwk • Increase to 50 mg sc Qwk if needed • Supplied as single-dose prefilled pen
Dulaglutide
• 0.75 mg sc Qwk • Increase to 1.5 mg sc Qwk if needed • Supplied as single-dose prefilled pen
Safety: Medullary Thyroid Cancer Risk
• All GLP-1 RAs are contraindicated in patients with a personal or family history of MTC or MEN2 because of the occurrence of C-cell tumors in rodents.
• The C-cell tumor risk humans is unknown, because human relevance could not be determined in clinical trials.
• The value of routine calcitonin and/or ultrasound monitoring is uncertain.
Victoza® PI 2013.; Bydureon® PI 2013. Parks M, et al. N Eng J Med. 2010;362:774-777.
Safety: Renal Impairment
• Exenatide BID or ER is not recommended in those with severe renal impairment or end-stage renal disease (CrCl<30 mL/min) and all GLP-1 RAs should be used with caution in patients with renal transplantation or moderate renal impairment.
Johansen O, et al. Br J Clin Parmacol. 2008;66:568-569.;Weise WJ, et al. Diabetes Care. 2009;32:e22-e23. Ferrer-Garcia JC, et al. Diabetes Med. 2010;27:728-729. López-Ruiz A, et al. Pharm World Sci. 2010;32:559-561.
Safety: Pancreatitis
• Pancreatitis has been reported with all incretin-based therapies, although no causal relationship has been established.
• Patients should know signs and symptoms of pancreatitis and stop taking incretin-based therapies if signs and symptoms occur.
• If pancreatitis is confirmed, therapy should not be restarted.
Ahmad SR, et al. N Engl J Med. 2008;358:1970-1971.; Garg R, et al. Diabetes Care. 2010;33:2349-2354.; Byetta® PI 2013.; Victoza® PI 2013.; Bydureon® PI 2013.; Januvia® PI 2013.; Onglyza® PI 2013.; Tradjenta® PI 2013.; Nesina® PI 2013.
CV OUTCOME TRIALS with GLP-1RAs
ELIXA – Lixisenatide (not yet approved in the USA) No CV risk or benefit – Neutral effect No increase in CHF
Trials ongoing with the other drugs in the class
Synthetic Human Amylin AnalogPramlintide
Pramlintide [package insert]. San Diego, CA; Amylin Pharmaceuticals, Inc; 2008.
MechanismAmylin mimetic: !PPG, suppresses glucagon secretion, slows gastric emptying, promotes satiety
Efficacy Modest ( ! A1C 0.5%)
Advantages No dosage adjustment required in renal impairment
Disadvantages
Nausea, headaches, anorexia, vomiting, abdominal pain, fatigue, dizziness, risk of severe hypoglycemia with insulin Only approved in combination with prandial insulin but cannot be combined in the same syringe
ContraindicationsConfirmed diagnosis of gastroparesis, hypoglycemia unawareness
When To Start Insulin in T2DM
• When combination oral/injectable agents become inadequate
• Unacceptable side effects of oral/injectable agents
• Patient wants more flexibility • Special circumstances (i.e. steroid use,
infection, pregnancy) • Patients with hepatic or renal disease, • Patients with CAD, ↑TG
CAD=coronary artery disease; T2DM=type 2 diabetes mellitus; TG=triglycerides.
Holman et al. NEJM. 2009; 361:1736-1747; Lebovitz HE. Diabetes Rev. 1999;7(3):139-153
Key Points: Insulin Initiation• Diabetes is a progressive disease and many individuals with T2DM eventually need insulin to control their blood glucose
• There are cultural taboos and misconceptions regarding insulin therapy; it is important to understand and acknowledge patients' specific concerns and design individualized treatment plans that fit their needs
• Start with a simple regimen, such as a once-daily basal insulin analog, and up-titrate the dose based on FPG; if A1C remains high when FPG is in the target range, add a DPP-4 inhibitor, a GLP-1 RA, or mealtime insulin
T2DM=type 2 diabetes mellitus; FPG=fasting plasma glucose; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; RA=receptor agonist; A1C=glycated hemoglobin.
1. Garber AJ, et al. Endocr Pract. 2013;19:327-336. 2. Peragallo V. Diabetes Educ. 2007;33:60S–65S.
Key Points: Insulin Initiation• Allow patients to give the first injection during the
office visit (because the first injection is often the biggest hurdle)
• Alternately, to help diminish fear, give patient a mock shot as soon as insulin is discussed (this can be done before insulin is initiated)
• Insulin pens facilitate the initiation and acceptance of insulin
• PCP and/or nurse educator should provide ongoing, enthusiastic support, advice, and trouble-shooting
PCP=primary care provider.
Insulin Pens • More convenient than
traditional vial and syringe • More accurate, repeated
doses • Easier to use for those with
visual or fine motor skill impairment
• Less injection pain – Polished and coated needles are
not dulled by insertion into a vial of insulin before a second insertion into the skin
Gebel E, ADA. 2012 Insulin Pens. Jan. 2012 Available at, http://forecast.diabetes.org/magazine/features/2012-insulin-pens, accessed Oct. 5, 2013.
Insulin Therapy in Type 2 Diabetes Current Strategies
• Basal insulin therapy – Long-acting insulin analog once daily – Intermediate-acting NPH at bedtime
• Human or analog insulin (prandial or premixed w/ intermediate) - Once daily at largest meal - Twice daily (breakfast and dinner) - Three times daily (with each meal)
• Intensive insulin therapy - Basal + - rapid-acting analog insulin
- Once daily at largest meal - Twice daily at meals - Three times daily (with each meal)
• Insulin pump therapy
Holman R. New Engl J of Med. 2007 Oct 25;357(17):1716-30.
NPH=Neutral Protamine Hagedorn.
Insulin Analogs More Closely Match the Physiologic Insulin Profile Than Human Insulin
• Bolus (meal-related) insulin analogs – Rapid absorption – Peak action coincides with peak carbohydrate
absorption • Basal insulin analogs
– Slow and steady rate of absorption – Protracted action
Nathan DM, et al. Diabetes Care. 2006;29:1963-1972
Long-Acting Insulin Analogs vs NPH In Type 2 Diabetes
A Meta-Analysis
• Long-acting analogs provide comparable glycemic control to NPH
• Reduced risks of nocturnal and symptomatic hypoglycemia
• May be associated with less weight gain than NPH
1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.
NPH=Neutral Protamine Hagedorn.
Pitfalls and Caveats In the Use of Basal Insulin (BI)
PP=postprandial; BI=basal insulin; OHA=oral hypoglycemic agents; SU=sulfonylurea.
The Challenge The Solution
Uptitrating dose based on elevated pre-supper blood glucose → nocturnal hypoglycemia
• Post-lunch hyperglycemia is the culprit; only titrate BI based upon fasting blood glucose
Over-reliance on BI to control PP hyperglycemia when added to non-prandial agents (eg, metformin, thiazolidinediones)
• As both fasting and PP hyperglycemia are present, consider use of a prandial agent before/at time of BI addition
Delay in down-titration of BI with improved glycemia → hypoglycemia and pre-emptive eating
• Discuss this scenario with patient as glycemic control is re-established: “Less insulin is needed to maintain control than establish control”
• Reduction of OHAs, such as SUs or glinides, may also be required
At Some Point, Raising Basal Dose Alone Will Be Inadequate, Failing to Address PPG
Time4:00 16:00 20:00 24:00 4:00
Breakfast
Lunch Dinner
8:0012:008:00
Plasma Insulin
(µU/mL)
75
50
25
0
Mealtime insulin response is missing; high postprandial readings every meal
Basal insulin
This may lead to hypoglycemia if food changes or meals are missed
Adapted from: Unger, J. Initiating insulin therapy in patients with type 2 diabetes. Diabetes Management in Primary Care. Lippincott. 2008.
PPG = post prandial glucose; µU=micro units; mL=milliliter.
Incretin-Based Therapy in Combination With Basal Insulin A Promising Tactic for the Treatment of Patients With T2DM
• Consider non-insulin options with synergistic mechanisms of action and low hypoglycemia risk when intensifying regimens beyond basal insulin • DPP-4 inhibitors when A1C reductions of <1.0% are
needed • GLP-1 receptor agonists when A1C reductions ≥1.0%
are needed (and patients may benefit from possible weight loss)
• Insulin doses may be able to be – or may need to be – lowered
• Targets insulin deficiency and glucagon excess
42
DPP-4=dipeptidyl peptidase-4 ;GLP-1=glucagon-like peptide-1; A1C=glycated hemoglobin; T2DM=type 2 diabetes mellitus.
Vora J, et al. Diabetes Metab. 2013 Feb;39(1):6-15.
Mea
n be
twee
n-gr
oup
diff
eren
ce f
rom
ba
selin
e (u
nits
as
show
n)
-7
-4.75
-2.5
-0.25
2
ΔTDD (U/day) ΔA1C (%) ΔWt (kg) ΔHypo (EPY)
0.2
Adding a GLP-1 RA to Basal Insulin Therapy with or Without OADs in T2DM Improves Glycemic Control
a Hypo, BG < 54 mg/dL; major hypo, loss of consciousness or seizure or assistance required. b P < .05; c P < .001.
Mean duration of diabetes: 12 years.
1. Buse JB, et al. Ann Intern Med. 2011;154:103-112.
GLAR + EXE ± MET ± PIO vs GLAR + PBO ± MET ± PIO (30 weeks)
• Patients receiving EXE had 8%-33% more GI adverse events and headaches than patients receiving PBO
• 1 patient in the PBO group had 2 majora hypoglycemic episodes
N = 259
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; EXE=exenatide; PIO=pioglitazone; GLAR=glargine; PBO=placebo; MET=metformin; EPY=Events per-participant/per-year; Hypo=hypoglycemia; TDD=total daily dose; U=unit; kg=killigram; INS=insulin; A1C=glycated hemoglobin; Wt=weight; T2DM=type 2 diabetes mellitus; BG=blood glucose; mg=milligrams; dL=deciliters.
Options When Not at Goal with 1 Injection of Basal Insulin
• Basal Plus Add prandial insulin at main meal or • Switch to Premixed Insulin (if regular meal schedule)
or • Switch to Basal/Bolus or • Add an incretin-based therapy (DPP-4 inhibitor or
GLP-1 RA, if patient is not already on incretin therapy)
1. American Association of Clinical Endocrinologists. Endocrine Practice. 2011;17(S2):1-53. 2. Garber AJ, et al. Endocr Pract. 2013;19:327-336.
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; RA=receptor agonist
Meal-Time Insulin Rapid-Acting Analogs (Aspart, Glulisine, Lispro) vs Regular
Hours
Howey DC, et al. Diabetes. 1994;43:396–402.
10
8
6
4
2
00 1 2 3 4 5 6 7 8 9 10 1112
Insulin Activity
Regular Human Insulin
Timing of food
absorbed
Analog insulin
The Basal-Bolus Insulin Concept• Basal insulin
– Controls glucose production between meals and overnight
– Nearly constant levels – 50% of daily needs
• Bolus insulin (mealtime or prandial) – Limits hyperglycemia after meals – Immediate rise and sharp peak at 1-hour postmeal – 10% to 20% of total daily insulin requirement at each
meal • For ideal insulin replacement therapy, each component
should come from a different insulin with a specific profile
1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086; 2. Leahy JL et al. Insulin Therapy. Marcel Dekker, Inc. Burlington, VT: 2002.
0600 0800 18001200 2400 0600Time of day
20
40
60
80
100 B L D
Basal-Bolus Insulin Treatment with Insulin Analogs
µU=milli units; mL=milliliters; B=breakfast; L=lunch; D=dinner.
Glargine, Detemir or Degludec
Lispro, glulisine, or aspart
Normal pattern
Insulin (µU/mL)
1. Leahy JL et al. Insulin Therapy. Marcelle Dekker, Inc. Burlington, VT: 2002.
Effect of Adding 1, 2, or 3 Pre-meal Rapid-acting Insulin Injections To a Background of Basal Insulin Analog
Therapy in Patients Requiring Therapy Intensification
0
13
25
38
50
1 Injection 2 Injections 3 Injections
A1C <7.0%Hypo (%)
Davidson MB, et al. Endocr Pract. 2011;17:395-403.49
Pati
ents
(%
) Ach
ievi
ng
A1C
<7.
0% a
t W
eek
24
A1C=glycated hemoglobin.
Inhaled Human Insulin• Approved July 2014 • Dry powder, human regular insulin • Adsorbed onto Technosphere microparticles • Dissolves immediately when inhaled • Ultra-rapid acting: peak concentration at
12-15 minutes, back to baseline at 180 minutes
• Bioavailability: 21-30% of subcut. dose • Mealtime glycemic control • Need to use with basal insulin in type 1 DM
Inhaled Human Insulin• Adverse Effects/Contraindications
– Hypoglycemia: similar or lower than sc insulin – Decreased FEV1: small, occurs w/i first 3 months,
potentially reversible with discontinuation – Lung cancer: 2 cases in clinical trials-both heavy
smokers – Not recommended in smokers or recent stoppers – Contraindicated in COPD, asthma – REMS: baseline, 6 mo. and annual spirometry -5 year monitoring to assess risk of lung cancer, change in PFTs
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00Time
Plasma Insulin
Biphasic Analog Insulin (Premixed Insulin)
1. Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker; 2002:87. 2. Nathan DM. N Engl J Med. 2002;347(17):1342–1349.
Concentrated InsulinsApproved Conc Volume Supplied #units Admin. Features
Glargine U-300
February 2015 3X 1/3 Prefilled Pen
450 QD More compact sc depot with smaller surface area; “Flatter” insulin
Lispro U-200
May 2015 2X 1/2 Prefilled Pen
600 AC TID Bioequiv. to Lispro U-100; Similar time to max. conc.
Regular U-500
1952 (Beef) 1997 (Human)
5X 1/5 Vial (20 mL) 10,000 AC BID-TID
Prefilled pen approved Jan2016
Hypoglycemia: Clinical Consequences
Acute
• Symptoms (sweating, irritability, confusion)
• Accidents • Falls
Long-term• Recurrent hypoglycemia
and hypoglycemia unawareness
• Refractory diabetes • Dementia (elderly) • Cardiovascular events
– Cardiac autonomic neuropathy
– Cardiac ischemia – Fatal arrhythmia – Angina
1. Cryer PE, et al. Diabetes Care. 2003;26:1902-1912.; 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-S66; 3. Zammit NN, et al. Diabetes Care. 2005;28:2948-2961.
Real-World Choices Depend On the Patient
• Injection frequency preference − Some patients may prefer premix
• Frequency of self-monitoring of blood glucose • Variability of lifestyle, including meal timing and
carbohydrate content of meals • Presence of postprandial hyperglycemia • Patient’s ability to follow the prescribed regimen • Educational and emotional support available to patient • Cost of analogue insulin options may be nearly double
that of NPH or regular insulin
Monami M. Diabetes Obes Metab. 2009;11(4):372-8.
Summary• Many patients on basal insulin therapy will
ultimately require treatment intensification • Current options include:
– Addition of mealtime control via addition of prandial insulin, leading to multiple daily insulin therapy
– Switch to premix insulin – Add a SGLT-2 inhibitor, DPP-4 inhibitor or a
GLP-1 agonist
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
Garber AJ, et al. Endocr Pract. 2013;19:327-336.