AN UPDATE ON DIABETES MANAGEMENT
Dr.Seenaj Chandran.MD(Med),Dip.Diab
Sr.Physician & Diabetologist
KIMS Hospital,Cochin

What are we going to do Today ?

Diabetes Today
The Ominous Octet-Type 2
Decreased Glucose
Uptake
Increased
Lipolysis
Increased Glucose
Reabsorption
Increased
HGP
Decreased
Incretin Effect

Hypoglycaemia
& Weight gain
HbA1c
The challenge of tight glucose control
4

Hypoglycemia and Weight Gain are linked

5
Foley Jl. Vasc Health Risk Manag. 2010:6 541–548
Hypoglycemia leads to Defensive eating

“HYPOGLYCEMIA”
A TOP PRIORITY
IN NEWER GUIDELINES
Favors the use of GLP-1 agonists /DPP-4 inhibitors with higher priority: Effectiveness and overall safety profiles.
Sulfonylureas - lower priority: Risks of Hypo, weight gain, and improved glycemic for relatively short period (1-2 years).
GLP-1 agonists/ DPP-4i: Important agents in regimen
TZDs: Effective BUT lower priority: ↑CV risks and bone #
AGIs & glinides: Lower priority – limited efficacy.

Hypoglycaemia in T2DM:
A possible link to increased CV risk/events
Haemodynamic changes:
- activation of autonomic nervous system
10-50 fold increased secretion of
adrenaline & noradrenaline
Haemorheological changes:
- platelet activation
- increased viscosity
ECG changes:
- longer QT interval
- hypokalemia

POSSIBLE MECHANISMS:
Hypoglycemia as link to tissue ischemia:
Study of 72-h continuous glucose monitoring and simultaneous cardiac Holter monitoring in patients with T2DM treated with insulin and history of frequent hypoglycaemia and coronary artery disease (n=19). 54 episodes of hypoglycaemia reported (BGL <3.9 mmol/L)
Desouza C, et al. Diabetes Care. 03; 26: 1485–1489.
*P <0.01 vs episodes during hyperglycaemia and normoglycaemia.BGL=blood glucose level; T2DM=type 2 diabetes mellitus.
1Diabetes Research & Clinical Practice 87 (2010) 204-210
2Cryer PE. Diabetologia. 2002; 45: 937–948.
Symptoms of Hypoglycemia :  medication non-adherence by 76 % 1
Hypoglycaemia makes clinicians less likely to implement glycaemic targets2

Weight gain in T2DM:
A common side effect post treatment
The vicious circle of type 2 diabetes
Weight gain is a common side effect
of diabetes treatments
OAD=oral antidiabetic drug;
SU=sulfonylurea;
TZD=thiazolidinedione
1Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2002. 4Malone M. Ann Pharmacother 2005; 39: 2046–2055. 5Actos [package insert]. Indianapolis, Ind:
Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005.
7Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004.
8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004.
9Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005

Consensus of 14 highly experienced clinicians, clinical researchers, practitioners, and academicians and is based on the AACE/ ACE Diabetes Guidelines & the recent medical literature.
Objective: Practical algorithm for management of patients with
type 2 diabetes mellitus that considers “currently approved
Classes” of medications and emphasizes “safety and efficacy”

Therapy Targets in diabetes:
“Moving beyond conventional”
11
Changing Targets

Current therapeutic options
Biguanides-Phenformin,Metformin
Sulfonylureas-Glemepride,glipizide etc
Meglitidines-Repaglinide,Nateglinide
Thiazolidinediones-Pioglitazone
Alpha-glucosidase inhibitors-Acarbose,Voglibose
DPP-4 Inhibitors-Sitagliptin,vildagliptin,Saxagliptin,Lanagliptin
Insulins

The New class-DPP-4 Inhibitors
What is DPP-4-Dipeptydyl Peptidase-4
What is the significance
What are the PK properties
Different gliptins available
Comparison
Yet to come

IV=intravenous
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
Oral Glucose Tolerance Test and Matched IV Infusion
Plasma Glucose (mg/dL)
Plasma Insulin (pmol/L)
0
100
200
300
400
–30
0
30
60
90
120
150
180
210
Time (min)
Proof of a Gastrointestinal ‘Incretin Effect’: Different Responses to Oral vs IV Glucose
50 g Glucose
N=6
14

Incretins
Intravenous glucose fails to increase insulin response as effective as oral glucose intake.
This is due to existence of Gut hormones in the enteroinsular axis which can increase insulin liberation by many folds following oral administration.
They are collectively called as incretins
Example of incretins: Glucagon like Peptide-1
GLP–1 is highly peptidase sensitive. So peptidase resistant incretins can be tried as a treatment of DM.

The Incretins
16
Y
A
E
G
T
F
I
S
D
Y
S
I
A
M
D
K
I
H
Q
Q
D
F
V
N
W
L
L
A
Q
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G
K
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D
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K
H
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T
I
GIP: Glucose-dependent Insulinotropic Peptide
H
A
E
G
T
F
T
S
D
V
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S
Y
L
E
G
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A
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GLP-1: Glucagon-like Peptide-1
Amino acids shown in orange are homologous with the structure of glucagon.

Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; JANUVIA Local Physician Circular, MSD Pharmaceuticals Private Limited, INDIA.
The Incretins

L-cell
(ileum)
Proglucagon
GLP-1 [7–37]
GLP-1 [7–36 NH2]
K-cell
(jejunum)
ProGIP
GIP [1–42]
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.
GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake
18

HGO= Hepatic Glucose Output
Adapted from Unger RH. Metabolism. 1974;23:581.
 Insulin
 Glucagon
IMPROVED
GLYCEMIC CONTROL
Incretin Activity Prolonged
Improved islet function
DPP-4 Inhibitor
DPP-4 Inhibition enhances the physiological effects of incretin hormones

FPG=fasting plasma glucose; GLP-1=glucagon-like peptide-1; PPG=postprandial glucose; T2DM=type 2 diabetes mellitus
Zander M, et al. Lancet. 2002; 359: 824–830; Nauck MA, et al. Diabetologia. 1993; 36: 741–744.
GLP-1 Demonstrates Multiple Metabolic Effects in Patients with T2DM
GLP-1 decreases PPG and FPG by:
improving - and -cell sensitivity to glucose
delaying gastric emptying
reducing appetite and food intake
20
Evolving Paradigms for Diabetes Management

-cell Mass
-cell Proliferation
-cell Apoptosis
GLP-1=glucagon-like peptide-1
*GLP-1 infused at 30 pmol/kg/min over 2 days.
Adapted from Farilla L, et al. Endocrinology. 2002; 143: 4397–4408.
GLP-1 Improves -cell Mass in Zucker
Diabetic Fatty Rats
N=16
21

Insulin or Incretin Mimetic
Joshi SR, APICON ‘09
Indian Algorithm for T2DM
Incretins based therapies first time in guidelines

ADA/EASD 2009
23
Incretins based therapies first time in guidelines

doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester
10.1002/ddr.20138, von Geldern, Trevillyan

Harnessing Incretins for Improved Glucose Control
GI = gastrointestinal
Two Approaches to Prolonging Incretin Activity

History of Development of Gliptins
1967, DPP-4 enzyme was discovered.
The first inhibitors were characterized in the late 1980s and 1990s.
Ferring Pharmaceuticals filed for patent on two potent and stable substrate like inhibitors DPP-4 inhibitors which they published in 1995.
1995, Edwin B. Villhauer at Novartis started to explore substrate like inhibitors.
Vildagliptin (Galvus) was first synthesized in May 1998 and was named after Edwin B. Villhauer.
1999: Merck started a drug development program on DPP-4 inhibitors.
Merck stopped working on compounds from the α-amino acid series related to isoleucyl thiazolidide due to lack of selectivity but identified a potent and selective triazolopiperazine series
Optimization of these compounds finally led to the discovery of Sitagliptin.

Drugs belonging to DPP4 inhibitor class
Sitagliptin (FDA approved 2006, marketed by Merck & Co./MSD as Januvia, Ono in Japan as Glactiv)
Vildagliptin (marketed in the EU and elsewhere by Novartis as Galvus)
Saxagliptin (FDA approved in 2009, marketed as Onglyza by BMS and Astra Zeneca)
Linagliptin (being developed by Boehringer Ingelheim),
Dutogliptin (being developed by Phenomix Corporation)
Gemigliptin (being developed by LG Life Sciences,Korea)
Alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently suspended as of June 2009, awaiting Japanese approval)
ABT 341 (Abbott Labs)
Melogliptin (Glenmark) currently dropped.
Denagliptin (GSK) suspended
MK-3102 (Merck/MSD) Once weekly Gliptin, Phase I

Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its anti-hyperglycemic activities, Gemifloxacin was one of the drug candidates for the development of DPP4 inhibitors

All the DPP4 Inhibitors stands True on the above parameters

But

do all have same degree of Efficacy & safety......

Probably Not

The family of Incretin-based therapies
Today we have four DPP4 Inhibitors
& many in line

Important mechanistic lessons from 1st Gliptin discovered
1st DPP4 inhibitor discovered
Large evidence of Mechanistic data
Highly selective DPP-4 inhibitor
VILDAGLIPTIN
X-ray crystallographic structure of vildagliptin (green) bound to the active site (yellow) of human DPP-4
DPP-4=dipeptidyl peptidase-4

Mechanistic difference among Gliptins:
Differences in the way in which gliptins interact with DPP4 enzymes
31
1 = http://www.pearsonhighered.com/mathews/ch02/c02cv.htm
2 = Deacon etal Diabetes, Obesity and Metabolism 13: 7–18, 2011
Type of bonding with DPP4 enzyme
2-step binding with Vilda & Saxa :

Substrates like Vildagliptin bind fast & dissociate slowly
GLP-1 may remain active for longer duration
For GLP-1 to stay active the DPP4 inhibitor has to stay bound to DPP4 so that GLP-1 stays active
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.
* Compared to sitagliptin Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009
** Deacon etal Diabetes, Obesity and Metabolism 13: 7–18, 2011
GLP-1 may remain longer with substrates than competitive inhibitors

Inhibition of DPP-IV by sitagliptin was reversible as evident from the fast relieving of the enzyme activity indicating the fast dissociation of the inhibitor.
In contrast, the enzyme activity was recovered very slowly in the case of vildagliptin pre-treatment suggesting the slow dissociation of the inhibitor from the complex.

Relative fluorescence units (RFU) ia a unit for measuring Dissociation
Davis JA etal, Indian J Pharmacol. 2010 August; 42(4): 229–233.
Vildagliptin bind rapidly & dissociate slowly as compared to sitagliptin which binds rapidly but also dissociates rapidly
GLP-1 may remain active for longer duration with vildagliptin

34
Sustained high intact GLP-1 level & Higher glucagon suppression
Possible tighter glucose control with vildagliptin
*P <0.05 vs vildagliptin group. Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. 1He YL, et al. Clin Pharmacokinet. 2007; 46: 577–588; 1Herman GA, et al. Clin Pharmacol Ther. 2005; 78: 675–688; 2Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009.
Note :
Marfella study was statistically powered to measure inter- group differences for measuring intact GLP-1

OPTIMA study : Vildagliptin vs Sitagliptin
Optimized glycemic control: Signifi cantly better with vildagliptin on all parameters of glycemic exposure & circadian glycemic control: mean of 24h, time spent in ideal range, AUC in hyperglycemia (≥140 & ≥180 mg/dL) & control of basal & total hyperglycemia
Results from the randomized Optima study. Diabetes Metab (2012), http://dx.doi.org/10.1016/j.diabet.2012.06.001
Though Similar improvement versus baseline in glycemic variability in both the groups

36
Vildagliptin induced significant improvements from baseline in time spent within ideal glycemic range (70-140mg/dL) and added 222 minutes more from baseline which was statistically significant.
OPTIMA
Main results – Time spend in ideal range
Results from the randomized Optima study. Diabetes Metab (2012), http://dx.doi.org/10.1016/j.diabet.2012.06.001

Results from the randomized Optima study. Diabetes Metab (2012), http://dx.doi.org/10.1016/j.diabet.2012.06.001
37% reduction in overall hyperglycemia with Vildagliptin from baseline which was statistically significant and it was driven by reduction in basal hyperglycemia.
Post-prandial hyperglycemia reduction after 8 weeks was observed with both Vildagliptin and Sitagliptin.
Basal hyperglycemia was reduced by 41 % with Vildagliptin which was statistically significant ,however no improvement was seen with Sitagliptin
Vildagliptin had better reduction in hyperglycemia, especially during night
OPTIMA
Main results – Overall, PP and Basal hyperglycemia

Does the Mechanistic differences result in better Clinical Outcomes ?

Let’s look at the Efficacy of Gliptins

Twice Daily versus Once daily Gliptins:
Sustained Overnight effect due to the evening dose with prolonged DPP4 inhibition & tight binding
39
Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c & fasting plasma glucose.
50 mg OD vildagliptin Approx – 0.7% HbA1c drop
50 mg BD vildagliptin Approx – 1.1 % drop (with 50 vilda BD + 500 met BD)
Approx – 1.8 % drop (with 50 vilda BD + 1000 met BD)

Ahren etal, Diabetes, Obesity and Metabolism 13: 193–203, 2011

Comparison of agents – A1c Reductions


 



 
Vildagliptin comes out better than any other DPP-4 inhibitor as has similar potency to exenatide
Aroda VR et al. Clinical therapeutics 2012 34(6) 1247-56

Comparison of agents – Fasting Plasma Glucose
Aroda VR et al. Clinical therapeutics 2012 34(6) 1247-56
The mean changes in FPG with the DPP-4 inhibitors were 0.97, 1.04, 0.73, 0.87, and 1.57 (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, respectively) with vildagliptin demonstrating a broad range of FPG reductions.

12-month observational, multicentre, post-authorisation, prospective cohort study
Patients with T2DM aged >18 years and taking OAD monotherapy were prescribed a new add-on OAD by the physician based on patients’ needs and were assigned to one of two cohorts
*Vildagliptin cohort: T2DM patients newly initiating vildagliptin as add-on dual therapy or newly initiating vildagliptin/metformin (fixed-dose) from non-vildagliptin monotherapy.
**Comparator OAD cohort: T2DM patients newly initiating therapy with oral anti-diabetic therapies other than vildagliptin (defined as SU, metformin, TZDs, metiglinides, α-glucosidase inhibitors as add-on dual therapy) except as add-on to vildagliptin, other DPP-4 inhibitors, or GLP-1 mimetics/analogues.
AEs, Adverse events; BL, baseline; OADs, oral anti-diabetic drugs; T2DM, type 2 diabetes mellitus; TZDs, thiozolidinediones

42
EDGE: Study design

Vildagliptin, N 26610 8083 14803 8559 7942 10800 13405 Comparator, N 14631 4188 8249 5094 5039 6129 7827
EDGE Results: Overall time course of HbA1c
Time (weeks)
CI, confidence intervals; SE, standard error

EDGE: Responder rates and HbA1c drop
(Proportion at goal (HbA1c <7.0%), no hypos, no weight gain)
CI, confidence intervals; hypos, hypoglycemic events
44

Safety of DPP4 inhibitors
Hypoglycemia risk with different DPP4 inhibitors
45
John Gerich, D i a b e t e s R e s e a r c h and C l i n ic a l Prac t i c e 9 0 ( 2 0 1 0 ) 1 3 1– 1 4 0
Aschner P etal, Diabetes Care 2006; 29:2632-9
Rosenstock J etal, Curr Med resp Opin 2009; 25:2101-11
Pi Sunyer Fx etal Diabetes res Clin Pract 2007; 76:132-8
Schweizer A etal, Diabetes Medicine 2007; 24:955-61
Prescribing Information – Vildagliptin ; Saxagliptin ; Sitagliptin ; Linagliptin
Hermansen etal, Diabetes, Obesity and Metabolism, 9, 2007, 733–745 ;
Garber etal, Diabetes, Obesity and Metabolism, 11, 2009, 157–166
%

46

Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine , IL-6 , and IL-18 than sitagliptin treatment which is statistically significant.…..because Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE

DPP-4 physiologically cleaves cytokines, chemokines & neuropeptides involved in inflammation, immunity & vascular function due to which DPP-4 inhibitors hold promise for cardiovascular protection
Reduce Inflammation
IL-6 ; TNF-α ; MCP-1

Cleaves Neuropeptides
NPY ; SP

GLP 1 action
Action on pancreas & GI tract

eNOS stimulation
Reduce blood pressure

Gian Paolo Fadini, Vascular Parmacoloy 2011
Vascular protection
Myocardial protection

DPP4 inhibitors had a reduced risk of Major Cardiovascular events (MACE)
49
DPP4i, compared with placebo or other treatment, were associated with a reduced risk of :
major cardiovascular events (MACE) (MH-OR 0.689 [0.528–0.899], p+0.006
Current Medical Research & Opinion Vol. 27, No. S3, 2011, 57–64

bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin.
*Vs all comparators=placebo, metformin, gliclazide, acarbose, rosiglitazone, pioglitazone and glimepiride. All-study safety population.
#Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, US Department
of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.
Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494.
Vildagliptin Reference M-H RR
n / N (%) n / N (%) (95% CI)

Vilda 50 mg qd* 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11)

Vilda 50 mg bid* 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14)


Risk ratio
Incidences and odds ratios for adjudicated CV events by treatment
Vildagliptin better
Vildagliptin worse
0.1
1
10
#Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set by the US Food and Drug Administration [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)]
Pooled Meta-analysis of 25 Phase III studies of Vildagliptin showed no increased cardiovascular risk vs comparators.
Data on cardiac safety being now established:

Vildagliptin Long term renal safety

original article
One-year safety, tolerability and efficacy of vildagliptin in patient with type 2 diabetes and moderate or severe renal impairment
W. Kothny1, Q. Shao1, P.-H. Groop2,3 & V. Lukashevich1

Aim: Assess long-term safety and efficacy of the dipeptidlyl peptidase-4 (DPP-4) inhibitor vildagliptin in 369 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI).
Methods: Double-blind, randomized, parallel-group, 52-week clinical trial comparing safety and efficacy of vildagliptin (50 mg qd, n=216) and placebo (n=153) added to ongoing stable antihyperglycaemic treatment, in patients with T2DM and moderate or severe (glomerular filtration rate [GFR] ≥30 to <50 ml/min/1.73 m2and<30 ml/min/1.73 m2) RI.
Conclusions: In patients with T2DM and moderate or severe RI, vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo during 1-year observation. Furthermore, relative to placebo, a clinically significant decrease in A1C was maintained throughout 1-year treatment with vildagliptin

Hindawi Publishing Corporation
Experimental Diabetes Research
Volume 2012, Article ID 892706, 11 pages
doi:10.1155/2012/892706
Clinical Study
Dipeptidyl Peptidase 4 Inhibition May Facilitate Healing of Chronic Foot Ulcers in Patients with Type 2 Diabetes
RaffaeleMarfella,1 Ferdinando Carlo Sasso,2 Maria Rosaria Rizzo,1 Pasquale Paolisso,1 Michelangela Barbieri,1 Vincenzo Padovano,3 Ornella Carbonara,2 Pasquale Gualdiero,1 Pasquale Petronella,3 Franca Ferraraccio,4, 5 Antonello Petrella,4, 5 Raffaele Canonico,3Ferdinando Campitiello,3 Angela Della Corte,3 Giuseppe Paolisso,1 and Silvestro Canonico3

1Department of Geriatrics and Metabolic Diseases, Second University of Naples, 80138 Naples, Italy
2Department of Internal and Experimental Medicine, Center of Cardiovascular Excellence, Second University of Naples,
80138 Naples, Italy

3Department of Geriatric Surgery, Second University of Naples, 80138 Naples, Italy
4Department of Biochemistry, Section of Pathology, Second University Naples, 80138 Naples, Italy
5Department of Pharmaceutical Sciences, University of Salerno, Salerno 84084, Italy
Correspondence should be addressed to Raffaele Marfella, raffaele.marfella@unina2.it

Received 1 June 2012; Revised 12 September 2012; Accepted 12 September 2012
Academic Editor: N. Cameron

Safety conserns & Adverse events

55
AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily;
SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators
(all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.
Vildagliptin better
Vildagliptin worse
Vildagliptin Reference Peto odds ratio
n / N (%) n / N (%) (95% CI)

Hepatic AEs
Vilda 50 mg qd* 15 / 1502 (1.00) 14 / 1662 (0.84) 1.29 (0.61–2.70)

Vilda 50 mg bid* 83 / 6116 (1.36) 84 / 4872 (1.72) 0.87 (0.64–1.19)

Hepatic SAEs
Vilda 50 mg qd* 2 / 1502 (0.13) 2 / 1662 (0.12) 1.08 (0.15–7.76)

Vilda 50 mg bid* 6 / 6116 (0.10) 5 / 4872 (0.10) 1.13 (0.35–3.67)


Odds Ratio
0.01
0.1
1
10
100
According to the Prescribing information, vildagliptin should not be used in patients with
hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN).
Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should
be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.
Ligueros-Saylan M, et al. Diabetes, Obesity and Metabolism 12: 495–509, 2010.

Vildagliptin Relative to All Comparators:
Not associated with increased risk of Hepatic AEs and SAEs
No liver injury seen

Vildagliptin better
Vildagliptin worse
Vildagliptin Reference Peto odds ratio n / N (%) n / N (%) (95% CI)
ALT / AST ≥3 × ULN
Vilda 50 mg qd* 6 / 1406 (0.43) 4 / 1574 (0.25) 1.60 (0.46–5.49)
Vilda 50 mg bid* 51 / 5874 (0.87) 32 / 4597 (0.70) 1.24 (0.80–1.93)

ALT / AST ≥3 × ULN and bilirubin >ULN    
Vilda 50 mg qd* 0 / 1400 (0.00) 1 / 1571 (0.06) 0.21 (<0.01–6.54)
Vilda 50 mg bid* 5 / 5863 (0.09) 3 / 4588 (0.07) 1.19 (0.29–4.90)
Odds ratio
ALT=alanine aminotransferase; AST=aspartate aminotransferase; bid=twice daily; CI=confidence interval; qd=once daily; ULN=upper limit of normal; vilda=vildagliptin. *Vs all comparators=placebo, metformin, gliclazide, acarbose, rosiglitazone, pioglitazone and glimepiride. All-study safety (including open-label) population. Data show persistent mild hepatic enzyme elevations. Persistent elevations are those which met the criterion at consecutive on-treatment measurements or at last on-treatment visit.
0.01
0.1
1
10
100
According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment,
including patients with pre-treatment ALT or AST >3x ULN. Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.
Ligueros-Saylan M, et al. Diabetes Obes Metab. 2010; 12: 495–509.
Vildagliptin: safety data shows no significant increased risk of persistent hepatic enzyme elevations vs comparators

Summary
Diabetes management Guidelines had evolved over a period of time since 2007 to 2013
In 2009 for the First time incretin based therapies included in the guidelines
DPP-4 inhibitors provide an alternative treatment strategy that has a very low risk of hypoglycemia & are weight Neutral
DPP-4 inhibitors address the core defects in the pathophysiology of type 2 diabetes
Vildagliptin is a potent and selective inhibitor of DPP4 inhibitor and delivers effective glucose control while also addressing clinical and physiological challenges of type 2 diabetes
Based on A1c & ABCD parameters, physicians should select the strategy with minimum risk and maximum benefit for each individual
Diabetes Obesity & Metabolism 12: 648-658, 2010 ; Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131 ; Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009
John Gerich, D i a b e t e s R e s e a r c h and C l i n ic a l Prac t i c e 9 0 ( 2 0 1 0 ) 1 3 1– 1 4 0 ; Aschner P etal, Diabetes Care 2006; 29:2632-9
Paolo Pozzilli etal, Diabetes Metab Res Rev 2010; 26: 239–244

Case Study - I

CASE STUDY -1
50 years
Profession: HR Manager
Infrequent healthcare visits
Last visit 3 years ago
Family history of cardiovascular risk
Father: 75 years with high blood pressure
Mother: died at 68 years from “heart disease”
Sister: 50 years; obese with no other known health problems

Current treatment
Metformin 850 mg twice daily
General health
He feels well and denies symptoms of hyperglycemia, including polydipsia, polyuria and blurred vision
He has also been diagnosed with lipid disorders and hypertension

Weight: 100 kg
Height: 1.8 m
Body mass index (BMI): 30.9 kg/m2
Blood pressure (seated): 166 / 92 mm Hg
Lab:
Fasting glucose: 150 mg/dL/8.3 mmol/l
Glycated hemoglobin (A1c): 7.7%.
Lipids
Total cholesterol: 230 mg/dL
Triglycerides (TGs): 243 mg/dL
High-density lipoprotein cholesterol (HDL-C): 37 mg/dL
Low-density lipoprotein cholesterol (LDL-C; calculated): 144 mg/dL
Creatinine: 1 mg/dL
Liver function assessment: ALT/AST/bb: within the normal range

This patient has many risk factors, including lipid disorders, OBESITY, HTN and family history of CVD
Low compliance to treatment
He is only 50 years old and needs to be treated to targets ASAP to prevent long-term complications
His HbA1C is 7.7%. Hypoglycemia may be a serious AE since he drives many hours a day

Therefore
The treatment should reduce HbA1C without risk of hypoglycemia
Be at least neutral for each one of the risk factors
Good tolerability to facilitate compliance

What we did and results
Increased the metformin to 1 gm bd
Added clopidogrel 75 mg and Atorvastatin 10 mg as once daily
Added vildagliptin 50 mg bd
Referred for Diet councelling and calorie counts
Ensured 30 mins of walk
Added 5 mg of Enalapril for Hypertension 1

After 10 weeks
Weight: 96 kg
Blood pressure (seated): 140 / 80 mm Hg
Lab:
Fasting glucose: 110 mg/dL/
Glycated hemoglobin (A1c): 6.7%.
Lipids
Total cholesterol: 194 mg/dL
Triglycerides (TGs): 162 mg/dL
High-density lipoprotein cholesterol (HDL-C): 42 mg/dL
Low-density lipoprotein cholesterol (LDL-C; calculated): 90 mg/dL
Creatinine: 1 mg/dL

Case Study - II

Case 2
45 Yr old man
Ex smoker
5 yr History of T2DM and Stable Angina
At referral his treatment regimen consisted of MF (1000mg BID), Simvastatin 40mg given in the evening, beta blocker and oral nitrates.
His HbA1c was 8.3%,
FBS 150mg/dl,
PBS 230
BP 136/78 mmHg,
TG 152mg/dl, LDL 85mg/dl, HDL 36mg/dl

Priorities before considering another Anti-hyperglycemic agent for this patient
Avoidance of hypoglycemia
Although the exact cause of excess mortality in ACCORD is not likely to be known with certainty, the most plausible cause during intensive therapy is Iatrogenic hypoglycemia
CGMS studies show that some patients with diabetes have definite ECG abnormalities during hypoglycemia suggestive of cardiac ischemia.
Low cardiac risk
Hypoglycemia may cause serious morbidity , provoking major vascular events such as stroke, myocardial infarction, acute cardiac failure and ventricular arrhythmia.
Other risk factors such as fluid retention and weight gain
Potential drug interaction with cardiac medication
Zammit et. Al diabetes care, 2005
Philip Cryer, Diabetes 2008

Issues with Type 2 DM Therapies
Avandia full prescribing information
Amaryl Full prescribing information

Vildagliptin
Highly selective Potent and reversible DPP-4 inhibitor that enhances the secretion and synthesis of insulin as well as glucagon suppression in a glucose dependant manner.
Low risk of hypoglycemia
No cardiac risk associated with vildagliptin
No meaningful drug interactions
Sitagliptin full prescribing information

Patient added with vildagliptin to Metformin
After 3 Months:
FBS: 85
PBS: 120
HbA1C: 6.2
No symptoms of hypoglycemia

Case 3
64 year old male, Arab origin
On
Inj. Mixtard 30/70: 96 -0-60
T. Gliclazide SR 30 4-0-0
T. Metformin 1 gm 1-1-1
BMI: 43, c/o weight gain
HbA1c: 14.1
FBS: 396
PPBS: 275
Complaints of hypos prompting him to eat sugars.
Blames it on insulin.

Case 4 (Contd…)
Treatment modified
Inj. Glargine 60 -0- 60
T. vildagliptin 50 mg 1-0-1
T. Metformin 1 gm 1-0-1
Finally after one month
FBS: 116
PPBS: 132
No hypo symptoms reported. Patient satisfied with therapy

Mrs. Saraswathy
55 years
Profession: University Lecturer
Health-conscious and proactive in seeking healthcare support
Family history:
Father: 79 years with high blood pressure
Mother: died aged 63 years of “heart failure”

Mrs. Sharma’s Perspective on her Diabetes
“I’m so frustrated with my diabetes... I’ve been careful to eat healthily and exercise regularly but its still not enough. The metformin doesn’t seem to be working any more. I want to get my diabetes under control so I can get on with my life.”

Diagnosed with type 2 diabetes 1.5 years ago
Current treatment
Metformin 850 mg twice daily
Higher-dose metformin was not tolerated due to GI adverse events
General health
Feels well and denies symptoms of hyperglycemia
She is active and plans further activity to prevent potential bone problems
She is also following a strict diet because she does not want to gain more weight
Menstrual activity ceased 5 years ago
no symptoms apart from gaining 4 kg in the last 5 years; no hormone replacement
Assessments
A1c has been measured every three months during the first year of her diabetes
Values have always been below 7.4% during the first year, but the most recent measurement was 8%

Weight: 78 kg
Height: 1.65 m
Body mass index (BMI): 28.6 kg/m2
Blood pressure (seated): 138 / 85 mm Hg

Lab:
Fasting glucose: 162 mg/dL
Glycated hemoglobin (A1c): 8.0%.
Lipids
Total cholesterol: 200 mg/dL
Triglycerides (TGs): 160 mg/dL
High-density lipoprotein cholesterol (HDL-C): 42 mg/dL
Low-density lipoprotein cholesterol (LDL-C; calculated): 126 mg/dL
Creatinine: 1.1 mg/dL
Liver function assessment: ALT/AST/bb: within the normal range

She needs something more than Met (high-dose Met is intolerant)
To prevent CV events, early prevention is required
She is post-menopausal, starting to gain despite of her exercise, and will face the risk of osteoporosis
She wants to have active and healthy life
Her liver function is within the normal range
She visits hospital regularly

What we did
Shifted her to vilda 50 mg + metformin combination which she tolerated well
After 8 weeks her status
Fbs-92
Ppbs-148 mg/dl,
No hypos

Take home messages
Hypoglgeamia is a key factor in present scenario
DPP-4 inhibitors is a good option
Vildagliptin do have added advantages
Adverse effects are low
Economic burden is a problem
Be aware of the Pancreatitis issue
Kindly do a baseline LFT

THANK YOU FOR YOUR PATIENCE

ACKNOWLEDGEMENTS:
AMERICAN DIABETES ASSOCIATION
AND
OUR PATIENTS AND TEACHERS WHO TAUGHT US
THE ART OF MEDICINE