What is NEW in T2DM?

Anil Bhansali

Department of Endocrinology PGIMER, Chandigarh

Recents in T2DM

Prevalence Pathogenesis Diagnosis Treatment -Targets - Incretins - Novel Insulin - Newer Drugs Novel therapies Conclusions

Prevalence of DMRank 2000 2030

1 India 31.7 India 79.4

2 China 20.8 China 42.3

3 US 17.7 US 30.3

4 Indonesia 8.4 Indonesia 21.3

5 Japan 6.8 Pakistan 13.9

6 Pakistan 5.2 Brazil 11.3

7 Russian Fed. 4.6 Bangladesh 11.1

8 Brazil 4.6 Japan 8.9

9 Italy 4.3 Philippines 7.8

10 Bangladesh 3.2 Egypt 6.7

Wild et al Diabetes Care 2004

Wang et al NEJM 2010China 2010- 92.4 million adults

State Pre-diabetes Diabetes

Maharashtra 12.8 8.4

Tamilnadu 8.3 10.4

Jharkhand 8.1 5.3

Chandigarh 14.6 13.6

PATHOPHYSIOLOGY

Two Defects of T2DM

Insulin resistance Insulin deficiency

AJM 2000

Three Defects of T2DM

Insulin resistance Insulin deficiency Incretin deficiency

-Impaired insulin secretion

-Impaired glucose-glucagon axis

Iso-glycaemic profilesG

luco

se c

once

ntra

tion

0 10 20 30 40 50 60 70 80 90minutes

Glucose given orally

Glucose given intravenously to achieve the same profile

Iso-glycaemic profiles

Insu

lin c

once

ntra

tion

0 10 20 30 40 50 60 70 80 90minutes

Glucose given orally

Glucose given intravenously to achieve the same profile

Incretin effect

Incretins

Enteroendocrine cells (K/L cells): GIP and GLP-1

Released in response to mixed meal/ glucose Potentiate the glucose induced insulin secretion Insulin secretion is glucose dependent Contributes 60% of prandial insulin release Inhibits glucagon

Glucose-Glucagon Axis

Normally rising glucose levels inhibits glucagon and vice versa

In T2DM, glucose mediated inhibition of α- cells is impaired

GLP-1

-Stimulating insulin (Intra-islet insulin)

-Direct inhibition of α-cells

-Restores glucose sensitivity to α-cells

Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin/Glucagon Ratio)

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitusAdapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.

CHO meal

0

NGTT2DM

-60Time (min)

0 60 120 180 240

Glucose100

200

300

400

mg

/dL

0

Insulin50

100

150

μU

/mL

NGTT2DM

Glucagon

75

100

125

150

pg

/mL

NGTT2DM

Pancreatic Islet Dysfunction Leads to Hyperglycemia in T2DM

↑ Glucose

Fewer -cells

-cellsHypertrophy

Insufficient Insulin

Excessive Glucagon

–+

↓ Glucose Uptake

↑ HGO

+

The Ominous OctetIslet b-cell

ImpairedInsulin Secretion

NeurotransmitterDysfunction

Decreased GlucoseUptake

Islet a-cell

IncreasedGlucagon Secretion

IncreasedLipolysis

Increased GlucoseReabsorption

IncreasedHGP

DecreasedIncretin Effect

Diagnosis of DM

Diagnosis FPG 126 mg/dl 2h PG 200 mg/dl (75 gm anhydrous glucose) RPG 200 mg/dl with symptoms Reconfirmation on subsequent days

Limitations Ensure fasting Influenced by exercise and activity Analytical variability Intra-individual variations

Glycated Hb (HbA1c)

Diagnosis of DM HbA1c 6.5% FPG ≥126mg/dl, RPG > 200 mg/dl with

symptoms Confirm with a repeat HbA1c

Prediabetes (IFG, IGT)- HbA1c 5.7 - 6.4%

Glycated Hb (HbA1c)

Single estimation Any time of the day Better index of overall glycemic exposure Substantially less biologic variability Better pre-analytic stability Denotes risk of long term complications Standardized and aligned to the

DCCT/UKPDS

Total no. people approached -2368

Included in the study - 2245

123 (non responders), Refused = 48

Out of station = 64, Sickness = 9

Pregnancy = 2

18 Excluded – 2hr PG-Not available

Refused to take glucose = 7, Taken

tea/food and later refused = 5

Under took physical activity = 3

Not available on 2 consecutive visits = 2Finally evaluable in the study - 2227 - 2245

HbA1c not available = 255

HbA1c available - 1972

Flow summary of study subjects

JCEM, Bhansali et al 2010

HbA1c for diagnosis of diabetes

Cut-off level Sensitivity Specificity5.7 92 63

5.8 92 68

6.0 83 77

6.1 81 81

6.2 76 84

6.3 73 86

6.4 70 87

6.5 65 88

6.6 62 89

6.9 47 91

7.0 42 92

JCEM, Bhansali et al 2010

SE

HbA1c and Pre-diabetes

Both the ADA and IEC

HbA1c cut-offs under-diagnosed the presence of pre-diabetes in 38% and 64% of these subjects

Bhansali et al. Diab Med Dec 2012

Management Algorithms

At insulin initiation, the average patient had: 5 years with A1C >8% 10 years with A1C >7%

Standard Approaches to Therapy Result inProlonged Exposure to Elevated Glucose

Brown JB, et al. Diabetes Care. 2004;27:1535-1540.

Sulfonylurea or Metformin

Monotherapy

ADA Goal <7%

CombinationTherapy

Diet/Exercise

Mea

n A

1C a

t L

ast

Vis

it

YearsDiagnosis 2 3 4 5 6 7 8 9 10

9.6%

9.0%8.6%

6%

7%

8%

9%

10% Insulin

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedioneAACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007; 13 (Suppl 1): 16–34.

American Association of Clinical Endocrinologists: algorithm for patients with T2DM

Drug-naïve patientsHbA1c 6%–7%

Initiate monotherapyMetformin, TZD, secretagogues, DPP-4 inhibitors, α-glucosidase inhibitors

HbA1c 7%–8% Initiate combination therapySecretagogue + metformin, TZD, or α-glucosidase inhibitor TZD + metforminDPP-4 + metformin or TZDSecretagogue + metformin + TZD Fixed-dose combinationsInsulin

As aboveExenatide may be combined with oral therapies in patients not achieving goals

Patients currently pharmacologically treated

HbA1c 8%–10% Intensify combination therapyTo address fasting and postprandial glucose levels

HbA1c >10% Initiate / intensify insulin therapy

Lif

esty

le C

han

ges

WHAT SHOULD BE TARGETED ?

Fasting plasma glucose Post prandial glucose

Post-prandial hyperglycaemia

Post-prandial hyperglycaemia contributes HbA1c ~1%

B=breakfast; L=lunch; D=dinner.Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.

Pla

sma

glu

cose

(m

g/d

L)

300

200

100

0

Time of day (h)6 12 18 24 6

Uncontrolled Diabetes HbA1c 8%

Fasting hyperglycaemia

Basal hyperglycaemia contributes ~2%

B

L

D

NormalHbA1c ~5%

Basal vs Post-Prandial Hyperglycemia – A1c

INCRETINS

DPP-IV Inhibitors

VildagliptinIC50DPPIV 3nmol/LDPPIV specificity 32-250Glucagon ↓ ↓ ↓Intact GLP-1 levels ↑ ↑T½ 3 hrsMetabolism 85%hydrolyzed

in liverHbA1c reduction 0.4-0.9%Infections ↑With insulin ApprovedRenal insufficiency Moderate to severeHepatic dysfunction Caution

Sitagliptin 18 nmol/L >2600 ↓ ↓ ↑ 12.4 hr 80% excreted by kidneys 0.4-0.9% ↑ Not approved Mild to moderate Use with caution

Saxagliptin 26 nmol/L NA ↓ ↓ ↑ 2 hr 33-60% by kidney 40 -67% hepatic 0.43 – 0.54 % ↑ Not approved Mild to moderate Use with caution

Linagliptin New class of DPP-IV inhibitor Exclusively metabolized through entero-

hepatic route Safe in renal and liver failure HbA1c reduction by 0.6-0.8% Reduces albuminuria independent of

glycemic control Can be given OD or BID

All GLP-1 Analogues are Same !

All GLP-1 receptor agonists are not the same

Meier Nat Rev Endocrinol 2012

Liraglutide

Native human GLP

Lixisenatide, exenatide

PDY10931: effects of lixisenatide and liraglutide on post-prandial glucose and insulin

Source: www.clinicaltrial.gov NCT01175473, IDF 2011 D-0740, Sanofi internal data

Lixisenatide (D-1)

Lixisenatide (D28)

Meal 451 kcal

Glucose (mg/dL)

Time (minutes)

p<0.0001

0

0

40

60

70

2702109030

50

30

20

60 150

Meal 451 kcal

Insulin free (µIU/mL)

Time (minutes)

Liraglutide (D-1)

Liraglutide (D28)

Newer concepts of GLP-1 analogues

Nat.Rev.Endocrinol Sep 2012

Effect of Incretin on Islet cell Mass

Novel Insulin (Degludec) Ultra long acting basal insulin- insulin Degludec Extreme dosing intervals of 8–40 h Daily injection time of IDeg can be varied without

compromising glycemic control or safety Less hypoglycemia, particularly nocturnal hypoglycemia

Diabetes care Jan 2013

Feb 12, 2013 FDA rejected approval of Degludec

Need of additional CVS safety data

Ann Phar. 2013

SGLT2 Inhibitors

Abdul-Ghani ; Endo Rev 2011

SGLT2 Inhibitor (Dapagliflozin)

Abdul-Ghani ; Endo Rev 2011

Glucokinase Activator (Piragliatin)

Glucokinase Activator (Piragliatin) Pre-clinical studies

Increases insulin secretion, Decreases HGO

Concerns Hypoglycemia, Fatty liver, Hyperlipidemia

Matschinsky F et al Diabetes care 2012

GPR 40 Modulator(TAK 875)

TAK-875 50–200-mg OD reduced A1C similar to 1 mg glimepiride OD

HbA1c reduction was 0.65%-1.37% with increasing doses

Kaku K Diabetes Care 2013

Stem Cells Dev. 2009 Dec;18(10):1407-16

Efficacy Of Autologous Bone Marrow Derived Stem Cell Transplantation In Patients With Type 2 Diabetes Mellitus.

Bhansali A, Upreti V, Khandelwal N, Marwaha N, Gupta V, Sachdeva N, Sharma RR, Saluja K, Dutta P, Walia R, Minz R, Bhadada S, Das S, Ramakrishnan S.

PGIMER , Chandigarh,

BASELINE PARAMETERS

N=10 (8 men) Mean age: 57.5± 5.9 years Mean duration of DM: 14.6 ± 7.5 years Mean duration of insulin therapy: 5.6 ± 3 years Mean dose of insulin: 69.4 ± 6.6 units/day Mean weight : 74.5 ± 11.6 kg Mean BMI: 26.5 ± 3.4 kg/m2 Mean waist circumference: 93.2 ± 7.8 cm

RESULTS

Primary end points Reduction in insulin requirement by ≥ 50% Improvement in glucagon stimulated C– peptide

levels at the end of 6 months Secondary end points

Change in weight, HbA1c and insulin- glucose homeostasis

Responders :7, Nonresponders:3

RESULTS Parameters Baseline 6 months p value

INSULIN REQUIREMENT/ DAY (U)*

Group 69.4±6.6 28.2±7.4 0.007

Responders 75.3± 8.2 18.9± 7.4 0.02

Non-responders 55.7± 6.2 50± 9.9 0.29

FPG (mg/dl)

Group 136.5± 25.1 119.1± 21.3 0.059

Responders 133.9± 28.8 112.3± 4.6 0.063

Non-responders 142.7± 16.1 134.7± 37.8 0.59

HbA1c*Group 8.4 ± 0.6 7.3 ± 0.8 0.009

Responders 8.1 ± 0.2 7.3 ± 0.4 0.04

Non–responders 8.9 ± 0.2 7.5 ± 0.2 0.11

RESULTSParameters Baseline 6 months p value

STIMULATED C- PEPTIDE (ng/ml)*

Group 1.1± 0.2 2.1± 0.3 0.03

Responders 1.2± 0.1 2.6± 0.3 0.03

Non–responders 0.8± 0.7 0.9± 0.6 0.99

HOMA- B

Group 46.1± 14.0 174.5± 52.9 0.02

Responders 37.7± 18.4 154.5±74.3 0.04

Non–responders 67.3±9.8 224.5± 2.8 0.18

HOMA- IR

Group 4.74±1.4 3.37± 0.95 0.74

Responders 5.14± 1.94 3.86± 1.27 0.89

Non–responders 3.75±1.75 2.15± 0.75 0.66

Bariatric surgery- an option or ultimate solution

HbA1c> 7.5% inspite of optimal therapy

Endocrine Pract 2013

Outcomes

Wt Loss

Diabetes Remission

Co-morbidities

At 2 years, diabetes remission in no patients in the medical-therapy group

75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group

NEJM 2012

Future

Motto of ADA “Living with diabetes” With bariatric surgery: “LIVING WITHOUT

DIABETES”

Conclusions

Enormous advances have been made in understanding of the disease , diagnosis and

treatment. Treatment of diabetes should be tailor-made

and needs to be individualized Future is pregnant with many possibilities

Thank You