new in type 2 diabetes mellitus
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TRANSCRIPT
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