Some of the recent advances in diabetes mellitus including newer insulin preparations and other oral hypoglycaemic agents.

1. Dr Udupa
RECENT ADVANCES IN THE TREATMENT OF
DIABETES MELLITUS

2. Dr Udupa 11/5/2011
INTRODUCTION
 Definition:
“Metabolic disorder characterized by
hyperglycemia, glycosuria, hyperlipemia, negative
nitrogen balance and sometimes ketonemia.”
 Classification: ( Expert Committee,2003)
Type I - IDDM (Insulin Dependant)
Type II - NIDDM (Non- Insulin Dependant)
Type III - Others (MODY)
Type IV - Gestational
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3. Dr Udupa 11/5/2011
PHARMACOTHERAPY OF DM
 Non-pharmacologic Rx:
 Diet
 Exercise
 Pharmacological Rx:
 Insulins
 Oral anti-diabetic drugs
 Recent developments
 Emerging non-pharmaco. Rx:
 Islet cell transplant
 Gene therapy
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4. Dr Udupa
4 11/5/2011
CURRENT THERAPY OF DIABETES MELLITUS
 Drugs increase insulin release OR reduce
glucose absorption/increase utilisation. Don’t
alter overactivity of glucagon & other
hormones that increase hepatic glucose
output.
 Insulin.
 OHA
 Insulin secretogogues- sulfonylureas &
meglitinides
 Biguanides
 Thiazolidinediones
 α-glucosidase inhibitors

5. Dr Udupa
5 11/5/2011
NEED FOR NEWER THERAPIES
 Inadequate control of post prandial
hyperglycemia(with sulfonylureas, metformin,
TZDs )
 Weight gain( sulfonylureas, meglitinides,
TZDs & insulin )
 Loss of efficacy ( all agents )
 Pathophysiology of insulin resistance
remains unaltered
 Insulin- Hypoglycemia , Resistance

6. Dr Udupa 11/5/2011
RECENT ADVANCES IN INSULIN THERAPY
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7. Dr Udupa 11/5/2011
LIMITATIONS OF REGULAR HUMAN INSULIN
 Slower onset of activity
 Patient inconvenience
 Safety concerns
 Prolonged duration of action
 Late post-prandial hypoglycemia
 Risk of hyperinsulinemia
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8. Dr Udupa 11/5/2011
HIGHLY PURIFIED INSULIN PREPARATIONS
 Why purified ?
 Single peak Insulins:
50-200 ppm proinsulin
Actrapid, Lentard
 Monocomponent Insulins: 20 ppm proinsulin
Actrapid MC, Monotard MC
 Advantages of Monocomponent Insulins:
Immunogenicity similar to human insulin greater
stability less allergic
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9. Dr Udupa 11/5/2011
HUMAN INSULINS
 By recombinant DNA technology
 Benefits- more water soluble
more rapid absorption
 Special indications-
insulin resistance
allergy
inj. site lipodystrophy
short time crisis
during pregnancy
 Examples: Human Actrapid, Human
Insulitard. 9

10. Preparation Source
Dr Udupa
11/5/2011
Rapid-acting insulins
Insulin Lispro, Human analog
Insulin Aspart Human analog
Insulin Glulisine Human analog
Short-acting insulins
Regular Human Insulin Human
Intermediate-acting insulins
NPH Humulin Human
Premixed insulins (% NPH/ % regular)
Humulin 70/30 and 50/50
Human
(Lilly)
50/50 NPL, Lispro (Lilly) Human analog
Long-acting insulins
Insulin detemir, Human analog
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Insulin glargine, Human analog

11. NEWER INSULINS
Insulin Onset peak Duration
Rapid acting: 5-15 min 30-90 min 5 hrs
-lispro
-aspart
-glulisine
Short acting: 30-60 min 2-3 hrs 5-8 hrs
-Reglar ins.
Long acting: 2-4 hrs peakless 20-24 hrs
-glargine
Inhaled insulin
Oral / rectal insulin
11/5/2011 Dr Udupa 11

12. Dr Udupa 11/5/2011
INSULIN LISPRO (HUMALOG)
 Ist commercially available analogue
 At posn 28 of β-chain– lysine
 At posn 29 of β-chain– proline
 By s.c., 15 min before meal
 Rapid absorption from s.c.
due to dissociation into
monomers –shorter duration
 Glucose control significantly
improved
 Available as 100 U/ ml.
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13. Dr Udupa 11/5/2011
INSULIN ASPART (NOVOLOG)
 At position 28 of β-chain – aspartate replaces
proline
 Produced by rDNA from saccharomyces
cerevisiae
 Similar effects as that of lispro
 Faster onset & shorter duration
 Given 10 min before meal by s.c.
 C/I: hypoglycemia & hypersensitivity.
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14. Dr Udupa 11/5/2011
INSULIN GLULISINE (APIDRA)
 By rDNA technology from E. coli (k-12).
 At position 29 – glutamate for lysine
 At position 3 - lysine for asparagine
 Given 15 min before meal by s.c. , peak in 1
hr.
 ADR: gen. well tolerated
hypoglycemia, comprised cardiac
disease.
 Approved for use in type 1 & 2 DM.
 Used in combination with basal insulin 14

15. Dr Udupa 11/5/2011
INSULIN GLARGINE (LANTUS)
 First long acting insulin analogue approved
 At position 21 of A-chain- asparagine by
glycine
 2 arginine added to c- terminus of β-chain
 Has acidic pH of 4
 Results in less hypoglycemia & sustained
“peakless” absorption profile
 No effect of exercise & site of injection on
absorption
 C/I: hypersensitivity 15

16. Dr Udupa 11/5/2011
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17. Dr Udupa 11/5/2011
NEWER INSULIN DELIVERY DEVICES
 Insulin syringes
 Pen devices
 Jet injectors
 Insulin pumps-CSII
 Implantable pumps
 Buccal insulin
 Insulin patch
 External artificial pancreas
 Inhaled insulin
 Liposome entrapped insulin
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18. Dr Udupa 11/5/2011
INHALED INSULIN (EXUBERA)
 Inhalable insulin was available from
September 2006 to October 2007 in the
United States
 Pharmacological properties:
 more rapid increase in insulin conc.
 faster onset than s.c. peak at 2 hrs: duration
 6 hrs- intraindividual reproducibility of glycemic
response
 decrease in s. triglyceride levels
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19. Dr Udupa 11/5/2011
EFFICACY & SAFETY
 HbA1c values < 8% in 83% pts
 Mean HbA1c values were reduced & maintained
 Hypoglycemia
 Weight gain
 Greater decline in
pulmonary function
 Cough within seconds
of inhalation
 Lung Cancer concerns
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20. Dr Udupa 11/5/2011
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21. Dr Udupa 11/5/2011
NEWER INSULIN DELIVERY METHODS
 Jet Injector: High-pressure narrow jet of the
injection liquid instead of a hypodermic
needle to penetrate the epidermis.
 Buccal spray launched in India in 2009.
Claims to get absorbed through the buccal
mucosa.
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22. Dr Udupa 11/5/2011
NEWER INSULIN DELIVERY METHODS
 Insulin patch
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23. Dr Udupa 11/5/2011
INSULIN PUMPS
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24. Dr Udupa 11/5/2011
RA IN ORAL HYPOGLYCAEMIC THERAPY
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25. Dr Udupa 11/5/2011
INCRETIN MIMETICS
 Insulin has been shown to be released more
effectively through an oral glucose load than
intravenously and this is known as the
incretin effect.
 Enhance the incretin pathway in two ways
 ↑ Glucagon-like Polypeptide 1 (GLP-1)
 ↓Dipeptidyl peptidase (DPP-IV)
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26. Dr Udupa 11/5/2011
GLP-1 MODULATES NUMEROUS FUNCTIONS IN HUMAN
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27. Dr Udupa 11/5/2011
Human ileum, GLP-1
producing L-cells
Capillaries, DPP-IV (Di-
Peptidyl Peptidase-IV)
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28. Dr Udupa 11/5/2011
GLUCAGON-LIKE POLYPEPTIDE 1 ANALOGUES
 Exenatide:
 Saliva of the Gila monster
 1 st Incretin therapy. Approved as SC injection, to
treat Metformin/sulfonylurea treated T2DM, getting
suboptimal response
 Suppresses high glucagon  suppress hepatic
glucose output
 Preserves β-cell reserves
 Central loss of appetite. Control of bodyweight
 Reduces HbA1c by 1-1.3% S.C. inj. b.d. for 1
year
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29. Dr Udupa 11/5/2011
EXENATIDE- A D R
 Nausea in 44%, Vomiting, Diarrhea.
 Combination with Insulin/secretogogue leads
to Hypoglycemia.
 C/I : T1DM, T2DM with Beta Cell Failure,
Diabetic ketoacidosis , Renal impairment ,
GIT disease , Pregnancy , Lactation.
 Pancreatitis .
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30.  National Institute for Health and Clinical
Dr Udupa 11/5/2011
Excellence (NICE) Guidelines:
 Exenatide is not recommended for routine use in
T2DM
 Individual Fulfils One Of The Following Criteria:
 Has a body mass index (BMI) > 35 kg/m2
 Has specific problems of a psychological,
biochemical or physical nature arising from high
body weight
 Has inadequate glucose control (HbA1c >7.5%)
with conventional oral agents
 If another high cost medication such as a TZD or
insulin would otherwise be started.
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31. Dr Udupa 11/5/2011
PRAMLINTIDE- GLP-1 AGONIST
 Synthetic analogue of a Gut Hormone, Amylin
 Pramlintide suppresses Glucagon release.
 Approved Pre-Prandially [with Insulin] in T1&T2, is
a PP Glucose modulator.
 Delays Gastric Emptying.
 Central Anorectic effects.
 Reduces HbA1c by 0.39-0.62% [6 weeks]
 Peak action 20 Min. Duration-150 Min.
 Mealtime Insulin Dose reduced by 50%.
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32. Dr Udupa 11/5/2011
LIRAGLUTIDE EXENATIDE
Once daily Twice daily
Peakless Peak
Good effect on HbA1c & FBG Good effect on HbA1c & FBG
Weight loss Weight loss
No antibodies antibodies
No inj site reactions Inj site reactions
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33. Dr Udupa 11/5/2011
DIPEPTIDYL PEPTIDASE INHIBITORS
 This class of agent works by enhancing the
sensitivity of β-cells to glucose, which causes
enhanced glucose dependent insulin
secretion. It has also been shown to improve
markers of β cell function.
 Can be used in combination with metformin,
sulfonylureas, or even as monotherapy
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34. Dr Udupa 11/5/2011
VILDAGLIPTIN
 Expands β-cell mass
 Decreases fasting & PP BGL
 Reduces HbA1c in T2DM by 0.50-1% &
controls Glucose Levels in poorly controlled
 Addition of Insulin can lead to
Hypoglycemia.
 Single dose reduces Glucose by inhibiting
EGP [Endogenous glucose production] .
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35. Dr Udupa 11/5/2011
VILDAGLIPTIN
 Absorbed rapidly [Tmax = 1Hr ]
 Bioavailability 85% T1/2=90 Min But DPP-
4 Inhibition continued for 10 Hrs , Hence
OD/BD administration.
 Glucose Excursions significantly reduced
with Vildagliptin & Insulin levels increased.
 ADR
 Headache , Dizziness , Increased sweating ,
Nasopharingitis ,Cough .
 Hyperinsulinemic hypoglycemia .
 Nesidioblastosis
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36. Dr Udupa 11/5/2011
GLP-1 AGONISTS VS DPP-4 INHIBITORS
 Parenteral .Twice daily  Oral , Once daily .
 Alternative to Insulin  1st line/Add on
 HbA1c Reduction  HbA1c Reduction.
 Weight loss  Prevent Weight gain
,independent
 Predominantly Nausea  Nausea Absent
 GLP-1 R stimulation  All above due to
depends on Agonist modest stabilisation of
[Exenatide] level PP levels of GLP-
 Slow Gastric Emtying 1[Vildagliptin]
 No Effect
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37. Dr Udupa 11/5/2011
CANNABINOID-1 RECEPTOR BLOCKERS
 Cannabinoid-1 receptors appear to regulate
energy balance and body composition
 Blocking the action of these receptors is an
attractive target for treating obesity, diabetes,
and the metabolic syndrome
Jbilo O, et al, Faseb J, 2005;19:1567-1569
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38. Dr Udupa 11/5/2011
RIMONABANT
 Weight loss and improved insulin sensitivity
 20 mg once a day before breakfast
 Phase 3 trials and is licensed for use in
patients who have a BMI >30 kg/sqm or BMI
>27 kg/sqm with an additional risk factor
such as dyslipidaemia
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39. Dr Udupa 11/5/2011
PPAR MODULATORS
 PPAR alpha- increases HDL cholesterol
 PPAR gamma- insulin sensitization
 PPAR beta/delta- inflammation/ obesity
 Dual PPAR agonists:
 Muraglitazar
 Naveglitazar
 Tesaglitazar
 Farglitazar
 Pan- PPAR Activator- Bezafibrate
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40. RATIONALE FOR DUAL PPAR -α/γ
Dr Udupa 11/5/2011
AGONISTS
Muraglitazar TZDs : Rosiglitazone;
; Pioglitazone
Tesaglitazar
PPARg
PPARa
(liver, vascular wall) (fat, muscle)
 “Master Regulation: of
 Reduced triglycerides
adipocyte differentiation
 Increases circulating HDL
 Modulates glucose
 Improved LDL buoyancy
metabolism & insulin
sensitivity
Glucose intolerance
Dyslipidemia and
Type 2 diabetes
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41. Dr Udupa 11/5/2011
DUAL PPAR AGONISTS: SAFETY ISSUES
 Several earlier glitazars were discontinued
because of serious safety issue
 Includes ragaglitazar and farglitazar, among others
 Safety issues were different for each drug1
 Muraglitazar
 Increased risk of death, nonfatal MI, and nonfatal
stroke2
 Unlikely that further studies will be done
 Tesagalitazar
 Increased serum creatinine and decreased glomerular
filtration rate
 Development discoutinued May 2006 41

42. Dr Udupa 11/5/2011
SGLT2 INHIBITORS
 Sodium Glucose Co-transporter (SGLT)-2
inhibitors
 SGLT2 mediates 90% of filtered glucose
reabsorption in the convoluted segment of the
proximal renal tubule
 Dapagliflozin
 Canagliflozin
 Remogliflozin etabonate
 Sergliflozin
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43. Dr Udupa 11/5/2011
 Potential Clinical Advantages
 SGLT2 is expressed exclusively in the kidney
 SGLT2 function is independent of insulin
 Increased GLUCOSE EXCRETION Negative
energy balance Weight loss
 Improvement in both FBG and PPB
 Low incidence of hypoglycemia
 Predicted Clinical Limitations
 Increasedurine volume
 Sodium loss
 Long-term safety not yet studied
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44. Dr Udupa 11/5/2011
CLINICAL DATA FOR DAPAGLIFLOZIN
 Orally effective
 SGLT-2 selective
 Half life= 11.2-16.6hrs…. Suitable for once
daily dosing
 Dose dependent increase in glycosuria
 BSL and HbA1c reduction comparable to
metformin;
 Weight loss more than metformin
 Effective in combination with metformin
and other antidiabetics 44

45. Dr Udupa 11/5/2011
RUBOXISTAURIN (ARXXANT)
 Protein kinase C- β inhibitor drug under
investigation
 To reduce occurrence of vision loss in patients with
non-proliferative diabetic retinopathy.
 DRUGS ACTING ON INTERMEDIARY
METABOLISM TO ↓ HEP. GLUCOSE OUTPUT:
Acipimox, bezafibrate- ↓ FA levels
Etomoxir- ↓ FA oxidation
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46. Dr Udupa 11/5/2011
ALDOSE REDUCTASE INHIBITORS
 Enhanced polyol pathway – diabetic
peripheral neuropathy
 ARI blocks polyol pathway
 Delays progression & ameliorate symptoms
of diabetic neuropathy
 Examples :
 Epalrestat
 Ranirestat
 Fidarestat
 Zinarestat
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47. Dr Udupa 11/5/2011
PEGAPTINIB (MACUGEN) & RANIBIZUMAB
Pegaptinib:
 Selective Vascular Endothelial Growth Factor
antagonist (VEGF Antagonist)
 For Rx of age related macular degeneration
associated with diabetes
 0.3 mg every 6 weeks intravitreous inj
 ADR: anterior chamber inflammation, cataract,
blurred vision, endophthalmitis
Ranibizumab- recombinant humanised
monoclonal antibody that neutralizes all active
forms of VEGF-A 47

48. Dr Udupa 11/5/2011
OTHER EMERGING DRUGS
 Glucagon antagonist: skyrin, oxyskyrin,
octreotide
 β-3 adrenoreceptor agonists
 Endogenous cannabinoid modulator-
Rimonabant
 Protein kinase C inhibitors : Calphostin,
staurosporine
 Insulin like growth factors (IGF)
 Morpholinoguanidine
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49. Dr Udupa 11/5/2011
MISCELLANEOUS THERAPIES
 INGAP (Islet NeuroGenesis Assisted Protein)
 Thyroxyl insulin
 Phosphodiesterase inhibitors
 Growth hormone fragments
 RXR (Retinoid X Receptor ) agonist
 Glucose 6 phosphatase inhibitors
 Trace elements: vanadium (decreases EGF),
zinc, chromium, magnesium,selenium
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50. Dr Udupa 11/5/2011
HERBAL REMEDIES
 Gymnema sylvestre
 Pterocarpous marsupium (vijaysar) – trials by
ICMR
 Momordica charantia (karela)
 Trigonella faenum (methi)
 Marine product- CDR-MOES-D123
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51. Dr Udupa 11/5/2011
GYMNEMA SYLVESTRE
 Indian ayurvedic
plant vastly studied
 Also called gur-mar =
sugar destroyer
 Active ingredient
gymnemic acid
 As sugar controller &
insulin secretagogue
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52. Dr Udupa 11/5/2011
STEM CELL THERAPY AND TRANSPLANTATION
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53. Dr Udupa 11/5/2011
GENE AND CELL-REPLACEMENT THERAPY IN
THE TREATMENT OF TYPE 1 DIABETES
 Gene Therapy
 (Insulin) gene therapy will  introduction of a
foreign gene into any cell type in the body, allowing
it to produce insulin
 May be:
 insulin gene itself, perhaps under control of a
tissue-specific promoter
 a gene encoding a factor that in turn activates the
insulin gene
 Induction of stem-cell differentiation into ß-cells
by means of molecular intervention 53

54. Dr Udupa 11/5/2011
GENE AND CELL-REPLACEMENT THERAPY IN
THE TREATMENT OF TYPE 1 DIABETES
 Challenges:
 To ensure adequate insulin response after glucose
load
 Any newly created insulin-secreting cell will have to
be able to adapt to alterations in insulin
requirements that accompany changes with
exercise, body weight, and aging
 Ensure that newly created or implanted (surrogate)
ß-cells are protected in some way from recognition
by the immune system and in particular from
autoimmune destruction
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55. Dr Udupa 11/5/2011
ISLET CELL TRANSPLANTATION
 Average-size person (70 kg), a typical
transplant requires about one million islets,
isolated from two donor pancreases
 Donor pancreas isolated enzymatically
digested purified infused via the portal vein
into the liver.
 Daclizumab, Sirolimus And Tacrolimus
 Limitations:
 Low donor pool
 High incidence of failure of immunosuppressive
regimen 55

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