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GLP-1 and Diabetes
Dr. Shashikiran Umakanth
Prof & Head, Medicine
Dr. TMA Pai Hospital, Udupi
MMMC, Manipal University
Microvascular changes
Macrovascular changes
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
RelativeChanges
β-cell failure
Years
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50
100
150
200
250
-15
Onset
diabetes
Glucose(mg/dL)
Diabetes
diagnosis
50
100
150
200
250
300
350
Fasting glucose
Prediabetes
(Obesity, IFG, IGT)
Postmeal Glucose
-10 -5 0 5 10 15 20 25 30-15
Years
Natural history of type 2 diabetes
Case
 A 58-year-old gentleman,
Mr Kumar, a building
contractor with
 Type 2 diabetes
 Hypertension
 Obesity
 Recurrent balanoposthitis
Mr Kumar
 He is on treatment with
 Metformin 1000mg 1-0-1
 Enalapril 10mg 1-0-0
 Rosuvastatin 0-0-1
 Vitamin supplements
 Complains of
 Nocturia
 Discomfort while passing
urine
 Abdominal bloating - “gas”
 Has very irregular eating
habits
 Examination
 Gen exam - normal
except abd obesity
 Eyes - normal
 CVS & RS - normal
 Abdomen - normal
 Nervous system -
absent ankle reflexes
 Pulse - 80/min, regular
 BP 130/80
 Weight - 84 kg
 BMI - 30.8
Mr Kumar
 Investigations
 FBS - 150
 PPBS - 265
 HbA1c - 8.7%
 Creatinine - 1.2
 Potassium - 4.1
 LFT - normal
 Lipid profile
 Cholesterol - 230
 Triglycerides - 215
 HDL - 32
 LDL - 155
 Urine
 8 WBCs/HPF
Mr Kumar
 Kumar doesn’t want to take an injection. Which
antidiabetic would you add to metformin?
1. Sulfonylurea
2. Pioglitazone
3. DPP-4 inhibitor
4. Voglibose
5. SGLT-2 inhibitor
6. Bromocriptine
Mr Kumar
GLP-1 and Diabetes Mellitus
In patients with type 2 diabetes and inadequate glycaemic control on
metformin monotherapy, the addition of sitagliptin or glimepiride led
to similar improvement in glycaemic control after 30 weeks.
Sitagliptin was generally well tolerated. Compared to treatment with
glimepiride, treatment with sitagliptin was associated with a lower
risk of hypoglycaemia and with weight loss versus weight gain
Treatment with metformin plus vildagliptin compared with
metformin plus sulphonylurea is expected to result in a
lower incidence of diabetes-related adverse events and to
be a cost-effective treatment strategy.
 Started on
 Vildagliptin 50mg 1-0-1
 Rosuvastatin 20mg 0-0-1
 Metformin and Enalapril continued
 Balanoposthitis treated
Mr Kumar - Progress
Glucagon-like peptide 1 (GLP-1)
GLP-1
 An incretin (hormone that increases insulin
secretion in response to a meal)
 30-amino acid peptide secreted in response to the
oral ingestion of nutrients by intestinal L cells
 GLP-1 receptors (GLP-1R) are located in islet cells,
central nervous system, and other organs
 GLP-1 is metabolized by the enzyme dipeptidyl
peptidase-4 (DPP-4)
SerumInsulin
Time (min)
Incretin Effect*
*
*
*
*
*
*
Oral Glucose
Intravenous Glucose
(Isoglycemic)
60 120 1800
Adapted from Circulation. 2011; 124: 2285-2289
First described in New Interpretation of Oral Glucose Tolerance. Lancet. 1964 Jul 4;2(7349):20-1.
A phenomenon whereby a
glucose load delivered orally
produces a much greater
insulin secretion than the same
glucose load administered
intravenously
Numerous functions of GLP-1
Stomach:
Helps regulate
gastric emptying
Promotes satiety and
reduces appetite
Liver:
 Glucagon reduces
hepatic glucose outputBeta cells:
Enhances glucose-dependent
insulin secretion
Alpha cells:
 Glucose-dependent
postprandial
glucagon secretion
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.
GLP-1: Secreted upon
the ingestion of food
GLP-1 preserves
human islet cell
morphology and
function in cultured
islets in vitro
Day 1
Day 3
Day 5
Control GLP-1 treated Farilla et al. Endocrinology. 2003 Dec;144(12):5149-58
Comparison of incretins
YesYesPromotes insulin biosynthesis
NoYesReduces food intake
NoYesDecreased secretion in T2DM
YesYesKnockout mice (result in IGT)
YesYes
Stimulates beta-cell
mass/growth
NoYesSlows gastric emptying
NoYes
Inhibits glucagon secretion
postprandially
Site of Production
GIP
K-cells
(Duodenum and Jejunum)
GLP-1
L-cells
(Ileum and Colon)
Microvascular changes
Macrovascular changes
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
RelativeChanges
β-cell failure
Years
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50
100
150
200
250
-15
Onset
diabetes
Glucose(mg/dL)
Diabetes
diagnosis
50
100
150
200
250
300
350
Fasting glucose
Prediabetes
(Obesity, IFG, IGT)
Postmeal Glucose
-10 -5 0 5 10 15 20 25 30-15
Years
Natural history of type 2 diabetes
Incretin effect is blunted in type 2 diabetes
Insulin(mU/L)
Time (min)
Healthy Subjects
Insulin(mU/L)
Time (min)
Type 2 Diabetes
N = 22; Mean (SE); *P0.05
Data from Nauck M, et al. Diabetologia 1986;29:46-52.
0
20
40
60
80
0 60 120 180
0
20
40
60
80
0 60 120 180
Intravenous (IV) Glucose
Oral Glucose
Reduced Incretin EffectIncretin Effect
*
*
*
*
*
*
*
**
*
GLP-1 has a short half-life - 2 min
Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
Lys
DPP-4
His Ala
7
37
9
Therapeutic potential of GLP-1
HOW DO WE LEVERAGE IT?
HbA1c Goals unmet in most
AACE/ACE recommended target (<6.5%)
ADA recommended target (<7%)
1. Data from Saydah SH, et al. JAMA 2004; 291:335-342.
2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20.
3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50.
4. Data from ACE. Endocrine Practice 2002.
8.0
9.5
HbA1c (%)
6.0
8.5
10.0
6.5
5.5
9.0
7.0
7.5
37.2% have A1C >8%
20.2% have A1C >9%
12.4% have A1C >10%
64.2% of patients with
type 2 diabetes have A1C 7%
Contribution of PPBS to HbA1c
%Contribution
HbA1c Range (%)
0
20
40
60
80
100
FPG (Fasting Plasma Glucose)
PPG (Postprandial Plasma Glucose)
>10.2
70%
30%
9.3-10.2
60%
40%
8.5-9.2
55%
45%
7.3-8.4
50%
50%
<7.3
30%
70%
Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.
Incretin based therapies
GLP-1 infusion restores glucose
homeostasis in type 2 diabetes
0
2
4
6
8
10
12
14
16
00:00 04:00 08:00 12:00 16:00
SnackLunchBreakfast
Glucose(mmol/L)
Time of day
Type 2 diabetes: Saline (n=8)
Type 2 diabetes: Exogenous GLP-1 (n=7)
Healthy subjects (n=6)
20:00
Continuous GLP-1 infusion
DPP-4
GLP-1
GLP-1R
Synthetic GLP-1R Agonists
DPP-4 inhibitors
Incretin based therapies
GLP-1 Analogues
o Exenatide
o Liraglutide
o Lixisenatide
o Albiglutide
o Dulaglutide
DPP-4 Inhibitors
o Sitagliptin
o Vildagliptin
o Saxagliptin
o Linagliptin
o Anagliptin
o Teneligliptin
o Alogliptin
o Trelagliptin
o Omarigliptin
GLP-1 secretion is reduced in type 2 diabetes
Natural GLP-1 is rapidly degraded by DPP-4
Parenteral, potent Oral, less potent
Exendin-4
 Gila monster: a species of
venomous lizard; Mexico
 Eats only 4 times a year
 When fasting, it shuts down
the pancreas, stopping insulin
 When its time to eat, it
restarts pancreas with
exendin-4 in its saliva -
a GLP-1R agonist
Exenatide is a synthetic
version of exendin-4
DPP-4 Inhibitors (Gliptins)
Saxagliptin
VildagliptinSitagliptin
Linagliptin
Incretin Based Therapies: DPP-4 Inhibitors
DPP-4 Inhibitors
o Sitagliptin
o Vildagliptin
o Saxagliptin
o Linagliptin
o Anagliptin
o Teneligliptin
o Alogliptin
o Trelagliptin
o Omarigliptin
Teneligliptin
Sitagliptin
 100 mg once/day
 79% eliminated
unchanged by the
kidney
 Slight increased risk
of pancreatitis (?)
 25-50mg/day in
renal failure
 in HbA1c vs Placebo = -0.65%
Placebo (n=224)
Sitagliptin 100 mg (n=453)
Add-on to Metformin Study
7.0
7.2
7.4
7.6
7.8
8.0
8.2
0 6 12 18 24
Time (weeks)
(%)
(P<0.001)
 in HbA1c vs Placebo = -0.70%
Add-on to Pioglitazone Study
Placebo (n=174)
Sitagliptin 100 mg (n=163)
7.0
7.2
7.4
7.6
7.8
8.0
8.2
0 6 12 18 24
Time (weeks)
HbA1c(%)
(P<0.001)
HbA1c
Charbonnel B et al Diabetes Care. 2006;29:2638-2643
Rosenstock J et al. Clin Ther. 2006;28:1556-1568
Vildagliptin
125
175
225
275
Glucose
(mg/dl)
60
80
100
120
–30 0 30 60 90 120
Time (min)
Glucagon
(pmol/l)
Placebo
Vildagliptin
 50mg twice/day
 79% eliminated
unchanged by the
kidney
 Slight increased risk
of skin lesions (?)
2
6
10
14
GLP-1
(pmol/l)
HbA1c /weight : FAS, hypoglycemia : safety set, insulin : randomized set .*P < 0.001.
.Diabetes Obes Metab. 2013 Mar;15(3):252-7. doi: 10.1111/dom.12020. Epub 2012 Nov 1.
Kothny W1, Foley J, Kozlovski P, Shao Q, Gallwitz B, Lukashevich V.
8.80
Vildagliptin 50 mg bid
Placebo
Between-treatment difference
Weight Change from BL to EP
227 221N =
Hypoglycemic Events
-0.77
-0.05
-0.72
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Meanchange(SE)inHbA1c,%
BL = 8.84
N = 215221
HbA1c Change from BL to EP
*
BL = 78.878.1
N = 215222
Meanchange(SE)
inbodyweight,kg
Vildagliptin add-on with insulin
Saxagliptin
Adjusted mean change in HbA1c from
baseline to wk 24
Adjusted mean change in HbA1c from
baseline versus placebo
*
*
*
*
#
Saxagliptin + TZDs Saxagliptin + Metformin  2.5-5 mg once/day
 Primarily
eliminated by the
kidney
 Most potent DPP-4i
 Increased risk of
heart failure
N Engl J Med 2013; 369:1317-1326
Linagliptin
 5 mg/day
 Entero-hepatic
excretion, 84.7%
eliminated in feces
 No dosage
adjustment in renal
disease
This 24-week, double-blind, placebo-controlled study randomized 791 individuals with T2
DM that were drug naïve with an A1c> 7.5% and <11% or that were using one oral
antidiabetic drug (metformin) with an A1c >7.0 and <10.5%.
Teneligliptin
Changes in a plasma glucose and b serum insulin levels in response to the oral
glucose tolerance test before and after 12 weeks of teneligliptin administration.
Data are expressed as mean ± standard error (SE). *p < 0.05, **p < 0.01, before
vs. after 12 weeks of teneligliptin administration. 12W 12 weeks
 20 mg/day
 Improves early
phase insulin
secretion too
 Slight increase in
free fatty acid
levels
 No dosage
adjustment in renal
disease
Ito R et al. Drugs R D (2015) 15:245–251
Limitations with some therapies with type
2 diabetes & renal impairment
GLP-1 receptor agonists
Metformin
Sulfonylurea
Pioglitazone
DPP-4 inhibitors
Insulin
Acarbose
SGLT-2 inhibitors
Renal function
Normal Mild RI Moderate Severe Terminal
GFR (mL/min) >90 60–90 <60 <30 <15
DPP-4 inhibitors in renal failure
Sitagliptin1
DPP-4 inhibitors
100 mg o.d. 50 mg o.d. 25 mg o.d.
Saxagliptin2
5 mg o.d.Linagliptin4
Vildagliptin5 50 mg o.d.50 mg b.i.d.
Creatinine
Clearance
(mL/min) 30
Mild RI Moderate RI Severe RI
50
2.5 or 5 mg o.d. 2.5 mg o.d.
1. Available at: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf; 2. Available at: http://www1.astrazeneca-us.com/pi/pi_onglyza.pdf#page=1;
3. Available at: http://general.takedapharm.com/content/file.aspx?FileTypeCode=NESINAPI&cacheRandomizer=7236cffb-eb6c-4b0a-ac79-26810425c89e;
4. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf;
5. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf
GLP-1 Receptor Agonists
GLP1 receptor agonists
 Short acting
 Exenatide
 Lixisenatide
 Lower PPBS levels
 By delaying of gastric emptying
 Stimulation of insulin secretion
 Long acting
 Albiglutide Dulaglutide
 Exenatide QW Liraglutide
 Lower blood glucose levels
 Stimulation of insulin secretion
 Reduction of glucagon levels
Comparison of short 7 long-acting GLP-1R agonists
Short Acting GLP-1RA Long Acting GLP-1RA
Compounds Exenatide
Lixisenatide
Albiglutide, Dulaglutide
Exenatide-QW, Liraglutide
Half-life 2-5 hr 12h - many days
HbA1c reduction Modest Strong
FBS reduction Modest Strong
PPBS reduction Strong Modest
Glucagon secretion Yes Yes
Gastric emptying Delayed No effect
Blood pressure Reduction Reduction
Heart rate No effect Modest increase (2-5bpm)
Weight reduction 1-5 kg 2-5 kg
Nausea 20-50%, slow attenuation 20-40%, quick attenuation
Route of administration Subcutaneous Subcutaneous
Short acting GLP-1 R agonists
 Exenatide
 S.C twice daily
 Rapid absorption, peak in ~2
hours
 Little metabolism in circulation
 Clearance is glomerular
filtration
 Liraglutide
 S.C once daily
 Peak in 8-12 hrs
 Elimination t½ is 12-14 hours
 Clearance is primarily through
the metabolic pathways of
large plasma proteins
Long-acting GLP-1R agonists
 Better glycemic control than the short-acting GLP-1 receptor
agonists
 Patients have higher insulin levels in the fasting state (and
presumably during the night)
 5–10% of patients discontinue treatment due to nausea &
vomiting
 Diarrhoea in ~10–20% of patients - more with long acting
compounds
 Few cases of acute pancreatitis have been reported
Meier J. Nat. Rev. Endocrinol. 8, 728–742 (2012);
Precautions with GLP-1 agonists
 Avoid in patients with prior history of pancreatitis
 In rats and mice, GLP-1 agonists were found to
increase medullary thyroid cancer (MTC)
 Not reported in humans so far
 Avoid in patients with history/ family history of MTC
 Avoid in patients with MEN-2 syndrome
Efficacy of GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Efficacy of GLP-1 Receptor
Agonists and DPP-4 Inhibitors:
A meta-analysis
Aroda VR et al. Clin Ther. 2012 Jun;34(6):1247-1258.e22
• 80 RCTs (≥12 weeks’ duration
in T2DM)
• Mean baseline HbA1c 7.4% -
10.3% (GLP-1RA studies) and
7.2% - 9.3% (DPP-4 inhibitor
studies)
• All incretin-based therapies in
the meta-analysis were
associated with significant
reductions from baseline in
HbA1c and FPG.
 HbA1c reduced from 8.7 to 7.6
 LDL reduced from 155 to 110
 Weight has remained same
 Balanoposthitis resolved
 Patient is willing to start an injectable if required, as he
wants to lose weight
Mr Kumar - 3 months later
 What is the best choice now?
1. Add sulfonylurea
2. Start long-acting insulin
3. Start basal-bolus insulin regimen
4. Stop gliptin and start GLP-1R agonist
5. Continue gliptin and start GLP-1R agonist
Mr Kumar
 Gliptin stopped
 Liraglutide 0.6mg/day SC started, and gradually
increased to 1.2, then 1.8mg/day
 Metformin continued
 Rosuvastatin increased to 40mg/day
Mr Kumar
 HbA1c is 6.9%
 LDL is 90 mg/dL
 Weight has reduced by 7 kg
Mr Kumar - 6 months later
Summary
GLP-1
Stomach:
Helps regulate gastric
emptying
Promotes satiety and
reduces appetite
Liver:
 Glucagon reduces
hepatic glucose outputBeta cells:
Enhances glucose-
dependent insulin
secretion
Alpha cells:
 Glucose-dependent
postprandial
glucagon secretion
GLP-1: Secreted upon
the ingestion of food
Enhanced understanding of the complicated physiological
mechanisms governing postprandial glucose homeostasis
Choice between DPP-4 inhibitors and GLP-1 agonists
 Elderly: Consider DPP-4 inhibitors because of
moderate effect on lowering blood glucose and
neutral effect on caloric intake
 Young diabetics, recent onset diabetes,
abdominal obesity: consider GLP-1 analogs
 Moderate-severe renal failure: DPP-4
inhibitors (in reduced doses) are safe, but GLP-
1 analogs are generally contraindicated
Diabetes Care May 2011. 34:Suppl 2; S276-8
Age
Weight
Compliance
Affordability
Thank you
Pathophysiology of Type 2 Diabetes
Insulin
Resistance
Relative Insulin
Deficiency
Hyperglycemia
(Diabetes)
Incretin Defect

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GLP-1 and Diabetes Mellitus

  • 1. GLP-1 and Diabetes Dr. Shashikiran Umakanth Prof & Head, Medicine Dr. TMA Pai Hospital, Udupi MMMC, Manipal University
  • 2. Microvascular changes Macrovascular changes Kendall DM, et al. Am J Med 2009;122:S37-S50. Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343. RelativeChanges β-cell failure Years -10 -5 0 5 10 15 20 25 30 Insulin resistance Insulin level 0 50 100 150 200 250 -15 Onset diabetes Glucose(mg/dL) Diabetes diagnosis 50 100 150 200 250 300 350 Fasting glucose Prediabetes (Obesity, IFG, IGT) Postmeal Glucose -10 -5 0 5 10 15 20 25 30-15 Years Natural history of type 2 diabetes
  • 3. Case  A 58-year-old gentleman, Mr Kumar, a building contractor with  Type 2 diabetes  Hypertension  Obesity  Recurrent balanoposthitis
  • 4. Mr Kumar  He is on treatment with  Metformin 1000mg 1-0-1  Enalapril 10mg 1-0-0  Rosuvastatin 0-0-1  Vitamin supplements  Complains of  Nocturia  Discomfort while passing urine  Abdominal bloating - “gas”  Has very irregular eating habits
  • 5.  Examination  Gen exam - normal except abd obesity  Eyes - normal  CVS & RS - normal  Abdomen - normal  Nervous system - absent ankle reflexes  Pulse - 80/min, regular  BP 130/80  Weight - 84 kg  BMI - 30.8 Mr Kumar
  • 6.  Investigations  FBS - 150  PPBS - 265  HbA1c - 8.7%  Creatinine - 1.2  Potassium - 4.1  LFT - normal  Lipid profile  Cholesterol - 230  Triglycerides - 215  HDL - 32  LDL - 155  Urine  8 WBCs/HPF Mr Kumar
  • 7.  Kumar doesn’t want to take an injection. Which antidiabetic would you add to metformin? 1. Sulfonylurea 2. Pioglitazone 3. DPP-4 inhibitor 4. Voglibose 5. SGLT-2 inhibitor 6. Bromocriptine Mr Kumar
  • 9. In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain
  • 10. Treatment with metformin plus vildagliptin compared with metformin plus sulphonylurea is expected to result in a lower incidence of diabetes-related adverse events and to be a cost-effective treatment strategy.
  • 11.  Started on  Vildagliptin 50mg 1-0-1  Rosuvastatin 20mg 0-0-1  Metformin and Enalapril continued  Balanoposthitis treated Mr Kumar - Progress
  • 13. GLP-1  An incretin (hormone that increases insulin secretion in response to a meal)  30-amino acid peptide secreted in response to the oral ingestion of nutrients by intestinal L cells  GLP-1 receptors (GLP-1R) are located in islet cells, central nervous system, and other organs  GLP-1 is metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4)
  • 14. SerumInsulin Time (min) Incretin Effect* * * * * * * Oral Glucose Intravenous Glucose (Isoglycemic) 60 120 1800 Adapted from Circulation. 2011; 124: 2285-2289 First described in New Interpretation of Oral Glucose Tolerance. Lancet. 1964 Jul 4;2(7349):20-1. A phenomenon whereby a glucose load delivered orally produces a much greater insulin secretion than the same glucose load administered intravenously
  • 15. Numerous functions of GLP-1 Stomach: Helps regulate gastric emptying Promotes satiety and reduces appetite Liver:  Glucagon reduces hepatic glucose outputBeta cells: Enhances glucose-dependent insulin secretion Alpha cells:  Glucose-dependent postprandial glucagon secretion 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. GLP-1: Secreted upon the ingestion of food
  • 16. GLP-1 preserves human islet cell morphology and function in cultured islets in vitro Day 1 Day 3 Day 5 Control GLP-1 treated Farilla et al. Endocrinology. 2003 Dec;144(12):5149-58
  • 17. Comparison of incretins YesYesPromotes insulin biosynthesis NoYesReduces food intake NoYesDecreased secretion in T2DM YesYesKnockout mice (result in IGT) YesYes Stimulates beta-cell mass/growth NoYesSlows gastric emptying NoYes Inhibits glucagon secretion postprandially Site of Production GIP K-cells (Duodenum and Jejunum) GLP-1 L-cells (Ileum and Colon)
  • 18. Microvascular changes Macrovascular changes Kendall DM, et al. Am J Med 2009;122:S37-S50. Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343. RelativeChanges β-cell failure Years -10 -5 0 5 10 15 20 25 30 Insulin resistance Insulin level 0 50 100 150 200 250 -15 Onset diabetes Glucose(mg/dL) Diabetes diagnosis 50 100 150 200 250 300 350 Fasting glucose Prediabetes (Obesity, IFG, IGT) Postmeal Glucose -10 -5 0 5 10 15 20 25 30-15 Years Natural history of type 2 diabetes
  • 19. Incretin effect is blunted in type 2 diabetes Insulin(mU/L) Time (min) Healthy Subjects Insulin(mU/L) Time (min) Type 2 Diabetes N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52. 0 20 40 60 80 0 60 120 180 0 20 40 60 80 0 60 120 180 Intravenous (IV) Glucose Oral Glucose Reduced Incretin EffectIncretin Effect * * * * * * * ** *
  • 20. GLP-1 has a short half-life - 2 min Glu Gly Thr Phe Thr Ser Asp Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ile Ala Trp Leu Val Lys Gly Arg Gly Val Ser Glu Phe Lys DPP-4 His Ala 7 37 9
  • 21. Therapeutic potential of GLP-1 HOW DO WE LEVERAGE IT?
  • 22. HbA1c Goals unmet in most AACE/ACE recommended target (<6.5%) ADA recommended target (<7%) 1. Data from Saydah SH, et al. JAMA 2004; 291:335-342. 2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20. 3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50. 4. Data from ACE. Endocrine Practice 2002. 8.0 9.5 HbA1c (%) 6.0 8.5 10.0 6.5 5.5 9.0 7.0 7.5 37.2% have A1C >8% 20.2% have A1C >9% 12.4% have A1C >10% 64.2% of patients with type 2 diabetes have A1C 7%
  • 23. Contribution of PPBS to HbA1c %Contribution HbA1c Range (%) 0 20 40 60 80 100 FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) >10.2 70% 30% 9.3-10.2 60% 40% 8.5-9.2 55% 45% 7.3-8.4 50% 50% <7.3 30% 70% Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.
  • 25. GLP-1 infusion restores glucose homeostasis in type 2 diabetes 0 2 4 6 8 10 12 14 16 00:00 04:00 08:00 12:00 16:00 SnackLunchBreakfast Glucose(mmol/L) Time of day Type 2 diabetes: Saline (n=8) Type 2 diabetes: Exogenous GLP-1 (n=7) Healthy subjects (n=6) 20:00 Continuous GLP-1 infusion
  • 27. Incretin based therapies GLP-1 Analogues o Exenatide o Liraglutide o Lixisenatide o Albiglutide o Dulaglutide DPP-4 Inhibitors o Sitagliptin o Vildagliptin o Saxagliptin o Linagliptin o Anagliptin o Teneligliptin o Alogliptin o Trelagliptin o Omarigliptin GLP-1 secretion is reduced in type 2 diabetes Natural GLP-1 is rapidly degraded by DPP-4 Parenteral, potent Oral, less potent
  • 28. Exendin-4  Gila monster: a species of venomous lizard; Mexico  Eats only 4 times a year  When fasting, it shuts down the pancreas, stopping insulin  When its time to eat, it restarts pancreas with exendin-4 in its saliva - a GLP-1R agonist Exenatide is a synthetic version of exendin-4
  • 30. Saxagliptin VildagliptinSitagliptin Linagliptin Incretin Based Therapies: DPP-4 Inhibitors DPP-4 Inhibitors o Sitagliptin o Vildagliptin o Saxagliptin o Linagliptin o Anagliptin o Teneligliptin o Alogliptin o Trelagliptin o Omarigliptin Teneligliptin
  • 31. Sitagliptin  100 mg once/day  79% eliminated unchanged by the kidney  Slight increased risk of pancreatitis (?)  25-50mg/day in renal failure  in HbA1c vs Placebo = -0.65% Placebo (n=224) Sitagliptin 100 mg (n=453) Add-on to Metformin Study 7.0 7.2 7.4 7.6 7.8 8.0 8.2 0 6 12 18 24 Time (weeks) (%) (P<0.001)  in HbA1c vs Placebo = -0.70% Add-on to Pioglitazone Study Placebo (n=174) Sitagliptin 100 mg (n=163) 7.0 7.2 7.4 7.6 7.8 8.0 8.2 0 6 12 18 24 Time (weeks) HbA1c(%) (P<0.001) HbA1c Charbonnel B et al Diabetes Care. 2006;29:2638-2643 Rosenstock J et al. Clin Ther. 2006;28:1556-1568
  • 32. Vildagliptin 125 175 225 275 Glucose (mg/dl) 60 80 100 120 –30 0 30 60 90 120 Time (min) Glucagon (pmol/l) Placebo Vildagliptin  50mg twice/day  79% eliminated unchanged by the kidney  Slight increased risk of skin lesions (?) 2 6 10 14 GLP-1 (pmol/l)
  • 33. HbA1c /weight : FAS, hypoglycemia : safety set, insulin : randomized set .*P < 0.001. .Diabetes Obes Metab. 2013 Mar;15(3):252-7. doi: 10.1111/dom.12020. Epub 2012 Nov 1. Kothny W1, Foley J, Kozlovski P, Shao Q, Gallwitz B, Lukashevich V. 8.80 Vildagliptin 50 mg bid Placebo Between-treatment difference Weight Change from BL to EP 227 221N = Hypoglycemic Events -0.77 -0.05 -0.72 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Meanchange(SE)inHbA1c,% BL = 8.84 N = 215221 HbA1c Change from BL to EP * BL = 78.878.1 N = 215222 Meanchange(SE) inbodyweight,kg Vildagliptin add-on with insulin
  • 34. Saxagliptin Adjusted mean change in HbA1c from baseline to wk 24 Adjusted mean change in HbA1c from baseline versus placebo * * * * # Saxagliptin + TZDs Saxagliptin + Metformin  2.5-5 mg once/day  Primarily eliminated by the kidney  Most potent DPP-4i  Increased risk of heart failure N Engl J Med 2013; 369:1317-1326
  • 35. Linagliptin  5 mg/day  Entero-hepatic excretion, 84.7% eliminated in feces  No dosage adjustment in renal disease This 24-week, double-blind, placebo-controlled study randomized 791 individuals with T2 DM that were drug naïve with an A1c> 7.5% and <11% or that were using one oral antidiabetic drug (metformin) with an A1c >7.0 and <10.5%.
  • 36. Teneligliptin Changes in a plasma glucose and b serum insulin levels in response to the oral glucose tolerance test before and after 12 weeks of teneligliptin administration. Data are expressed as mean ± standard error (SE). *p < 0.05, **p < 0.01, before vs. after 12 weeks of teneligliptin administration. 12W 12 weeks  20 mg/day  Improves early phase insulin secretion too  Slight increase in free fatty acid levels  No dosage adjustment in renal disease Ito R et al. Drugs R D (2015) 15:245–251
  • 37. Limitations with some therapies with type 2 diabetes & renal impairment GLP-1 receptor agonists Metformin Sulfonylurea Pioglitazone DPP-4 inhibitors Insulin Acarbose SGLT-2 inhibitors Renal function Normal Mild RI Moderate Severe Terminal GFR (mL/min) >90 60–90 <60 <30 <15
  • 38. DPP-4 inhibitors in renal failure Sitagliptin1 DPP-4 inhibitors 100 mg o.d. 50 mg o.d. 25 mg o.d. Saxagliptin2 5 mg o.d.Linagliptin4 Vildagliptin5 50 mg o.d.50 mg b.i.d. Creatinine Clearance (mL/min) 30 Mild RI Moderate RI Severe RI 50 2.5 or 5 mg o.d. 2.5 mg o.d. 1. Available at: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf; 2. Available at: http://www1.astrazeneca-us.com/pi/pi_onglyza.pdf#page=1; 3. Available at: http://general.takedapharm.com/content/file.aspx?FileTypeCode=NESINAPI&cacheRandomizer=7236cffb-eb6c-4b0a-ac79-26810425c89e; 4. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf; 5. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf
  • 40. GLP1 receptor agonists  Short acting  Exenatide  Lixisenatide  Lower PPBS levels  By delaying of gastric emptying  Stimulation of insulin secretion  Long acting  Albiglutide Dulaglutide  Exenatide QW Liraglutide  Lower blood glucose levels  Stimulation of insulin secretion  Reduction of glucagon levels
  • 41. Comparison of short 7 long-acting GLP-1R agonists Short Acting GLP-1RA Long Acting GLP-1RA Compounds Exenatide Lixisenatide Albiglutide, Dulaglutide Exenatide-QW, Liraglutide Half-life 2-5 hr 12h - many days HbA1c reduction Modest Strong FBS reduction Modest Strong PPBS reduction Strong Modest Glucagon secretion Yes Yes Gastric emptying Delayed No effect Blood pressure Reduction Reduction Heart rate No effect Modest increase (2-5bpm) Weight reduction 1-5 kg 2-5 kg Nausea 20-50%, slow attenuation 20-40%, quick attenuation Route of administration Subcutaneous Subcutaneous
  • 42. Short acting GLP-1 R agonists  Exenatide  S.C twice daily  Rapid absorption, peak in ~2 hours  Little metabolism in circulation  Clearance is glomerular filtration  Liraglutide  S.C once daily  Peak in 8-12 hrs  Elimination t½ is 12-14 hours  Clearance is primarily through the metabolic pathways of large plasma proteins
  • 43. Long-acting GLP-1R agonists  Better glycemic control than the short-acting GLP-1 receptor agonists  Patients have higher insulin levels in the fasting state (and presumably during the night)  5–10% of patients discontinue treatment due to nausea & vomiting  Diarrhoea in ~10–20% of patients - more with long acting compounds  Few cases of acute pancreatitis have been reported Meier J. Nat. Rev. Endocrinol. 8, 728–742 (2012);
  • 44. Precautions with GLP-1 agonists  Avoid in patients with prior history of pancreatitis  In rats and mice, GLP-1 agonists were found to increase medullary thyroid cancer (MTC)  Not reported in humans so far  Avoid in patients with history/ family history of MTC  Avoid in patients with MEN-2 syndrome
  • 45. Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors
  • 46. Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: A meta-analysis Aroda VR et al. Clin Ther. 2012 Jun;34(6):1247-1258.e22 • 80 RCTs (≥12 weeks’ duration in T2DM) • Mean baseline HbA1c 7.4% - 10.3% (GLP-1RA studies) and 7.2% - 9.3% (DPP-4 inhibitor studies) • All incretin-based therapies in the meta-analysis were associated with significant reductions from baseline in HbA1c and FPG.
  • 47.  HbA1c reduced from 8.7 to 7.6  LDL reduced from 155 to 110  Weight has remained same  Balanoposthitis resolved  Patient is willing to start an injectable if required, as he wants to lose weight Mr Kumar - 3 months later
  • 48.  What is the best choice now? 1. Add sulfonylurea 2. Start long-acting insulin 3. Start basal-bolus insulin regimen 4. Stop gliptin and start GLP-1R agonist 5. Continue gliptin and start GLP-1R agonist Mr Kumar
  • 49.  Gliptin stopped  Liraglutide 0.6mg/day SC started, and gradually increased to 1.2, then 1.8mg/day  Metformin continued  Rosuvastatin increased to 40mg/day Mr Kumar
  • 50.  HbA1c is 6.9%  LDL is 90 mg/dL  Weight has reduced by 7 kg Mr Kumar - 6 months later
  • 52. GLP-1 Stomach: Helps regulate gastric emptying Promotes satiety and reduces appetite Liver:  Glucagon reduces hepatic glucose outputBeta cells: Enhances glucose- dependent insulin secretion Alpha cells:  Glucose-dependent postprandial glucagon secretion GLP-1: Secreted upon the ingestion of food Enhanced understanding of the complicated physiological mechanisms governing postprandial glucose homeostasis
  • 53. Choice between DPP-4 inhibitors and GLP-1 agonists  Elderly: Consider DPP-4 inhibitors because of moderate effect on lowering blood glucose and neutral effect on caloric intake  Young diabetics, recent onset diabetes, abdominal obesity: consider GLP-1 analogs  Moderate-severe renal failure: DPP-4 inhibitors (in reduced doses) are safe, but GLP- 1 analogs are generally contraindicated Diabetes Care May 2011. 34:Suppl 2; S276-8 Age Weight Compliance Affordability
  • 55. Pathophysiology of Type 2 Diabetes Insulin Resistance Relative Insulin Deficiency Hyperglycemia (Diabetes) Incretin Defect

Editor's Notes

  • #20: The greater beta-cell response observed in subjects with type 2 diabetes during intravenous glucose administration is due to the higher glucose stimulus in subjects with diabetes.
  • #21: GLP-1 is inactivated by DPP-IV by N-terminal degradation of the peptide at position 2 alanine. GLP-1 half-life in man is in the order of 1-2 min with a high clearance of 4-10 L/min.