GLP-1 and Diabetes

Dr. Shashikiran UmakanthProf & Head, MedicineDr. TMA Pai Hospital, UdupiMMMC, 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.

Rel

ativ

e C

hang

es

β-cell failure

Years-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

0

50100

150200

250

-15

b-cell function

Onsetdiabetes

Glu

cose

(m

g/dL

)Diabetesdiagnosis

50100150200250300350

Fasting glucose

Prediabetes (Obesity, IFG, IGT)

Postmeal Glucose

-10 -5 0 5 10 15 20 25 30-15Years

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, regularBP 130/80Weight - 84 kgBMI - 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. Sulfonylurea2. Pioglitazone3. DPP-4 inhibitor4. Voglibose5. SGLT-2 inhibitor6. Bromocriptine

Mr Kumar

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)

Seru

m In

sulin

Time (min)

Incretin Effect*

*

**

* *

*

Oral Glucose

Intravenous Glucose(Isoglycemic)

60 120 1800

Adapted from Circulation. 2011; 124: 2285-2289First 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

postprandialglucagon 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)

YesYesStimulates beta-cell mass/growth

NoYesSlows gastric emptying

NoYesInhibits glucagon secretion postprandially

Site of ProductionGIP

K-cells(Duodenum and Jejunum)

GLP-1L-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.

Rel

ativ

e C

hang

es

β-cell failure

Years-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

0

50100

150200

250

-15

b-cell function

Onsetdiabetes

Glu

cose

(m

g/dL

)Diabetesdiagnosis

50100150200250300350

Fasting glucose

Prediabetes (Obesity, IFG, IGT)

Postmeal Glucose

-10 -5 0 5 10 15 20 25 30-15Years

Natural history of type 2 diabetes

Incretin effect

Incretin effect is blunted in type 2 diabetesIn

sulin

(mU

/L)

Time (min)

Healthy Subjects

Insu

lin (m

U/L

)Time (min)

Type 2 Diabetes

N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.

0

20

40

60

80

0 60 120 1800

20

40

60

80

0 60 120 180

Intravenous (IV) GlucoseOral 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-1HOW 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%

Con

trib

utio

n

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

Gluc

ose

(mm

ol/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 Analogueso Exenatideo Liraglutideo Lixisenatideo Albiglutideo Dulaglutide

DPP-4 Inhibitorso Sitagliptino Vildagliptino Saxagliptin o Linagliptino Anagliptino Teneligliptino Alogliptino Trelagliptino 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 Inhibitorso Sitagliptino Vildagliptino Saxagliptin o Linagliptino Anagliptino Teneligliptino Alogliptino Trelagliptino 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 24Time (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 24Time (weeks)

HbA

1c (%

)

(P<0.001)

HbA

1c

Charbonnel B et al Diabetes Care. 2006;29:2638-2643Rosenstock 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)

PlaceboVildagliptin

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 bidPlacebo Between-treatment difference

Weight Change from BL to EP

227 221N =

Hypoglycemic Events

-1.0

-0.8

-0.6

-0.4

-0.2

0.0 -0.05

-0.72

Mea

n ch

ange

(SE)

in H

bA1c

, %

BL = 8.84N = 215221

HbA1c Change from BL to EP

*

BL = 78.878.1N = 215222

Mea

n ch

ange

(SE)

in

bod

y w

eigh

t, kg

Vildagliptin add-on with insulin

Saxagliptin

Adjusted mean change in HbA1c from baseline to wk 24

Adjusted mean change in HbA1c frombaseline 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 functionNormal 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.

CreatinineClearance (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 agonistsShort Acting GLP-1RA Long Acting GLP-1RA

Compounds ExenatideLixisenatide

Albiglutide, DulaglutideExenatide-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 sulfonylurea2. Start long-acting insulin3. Start basal-bolus insulin regimen4. Stop gliptin and start GLP-1R agonist5. 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/dayMetformin continuedRosuvastatin increased to 40mg/day

Mr Kumar

HbA1c is 6.9%LDL is 90 mg/dLWeight 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

postprandialglucagon 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