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2. Contents
1. Introduction
2. Classification
3. Current therapy of DM
4. Limitations of current therapy
5. Newer Drugs and their status in DM therapy
6. Newer potential targets
7. Future Prospects
8. Summary
3. 250 BC- Apollonius of Memphis coined the name "diabetes”
meaning “siphon- to pass through”
Thomas Willis in 1675 added "mellitus" to the word
"diabetes”
1869- Paul Langerhans, a German medical student, discovered
islet cells in the pancreas
1910- Sharpey-Shafer of Edinburgh suggested a single
chemical was missing from the pancreas. He proposed calling
this chemical "insulin.”
1922, Leonard Thompson became the first human to be
successfully treated for diabetes using insulin.
4. 1921- Frederick G. Banting and Charles H. Best successfully
purified insulin from a dog's pancreas
1923- 1st Nobel prize for insulin
5. World diabetes day
14th November of every year:
to mark the birthday of
Frederick Banting
6. Burden of disease
Around 7% of Indian Adults
Most of the world’s Diabetics dwell in India
Population of Diabetics-
2010 (285 Million)
India
51
Million
China
43
Million
USA
26
Million
Rest of
the
world
165
Million
Prevalence of Diabetes -2010
Countries Prevalence
INDIA 7.1%
CHINA 4.5%
USA 12.3%
Source: International
Diabetes federation
7. Etiological classification
Type 1 DM: β-cell destruction
a. Immune-mediated
b. Idiopathic
2. Type 2 DM
3. Other specific types of diabetes:
a. Genetic defects of β cell function: MODY
b. Genetic defects in insulin action
c. Diseases of the exocrine pancreas
d. Endocrinopathies
e. Drug- or chemical-induced
f. Infections
4. Gestational diabetes mellitus (GDM)
8. IDDM and NIDDM
Type 1 and Type 2
Age is not a criterion in the classification system
5 and 10% of individuals who develop DM after age 30 have
type 1 DM
Type 2 DM more typically develops with increasing age but is
now being diagnosed more frequently in children and young
adults, particularly in obese adolescents.
10. Type 3 Diabetes
Insulin resistance in the brain associated with Alzheimer’s
Disease.
Impaired glucose metabolism in the brain plays a role in the
development of Alzheimer’s by depriving cells of energy.
Evidence
Tau gene expression and phosphorylation are regulated through insulin and insulin-
like growth factor (IGF) signaling cascades.
Amyloid beta in pancreas which is similar to the protein deposits found in the brain
tissue of Alzheimer’s.
11. Type 4 Diabetes
Not associated with insulin deficiency or obesity
Has been discovered in lean mice
Abnormally high levels of
immune cells called
T regulatory cells (Tregs) inside their fat tissue.
Age-related insulin resistance that occurs in lean,
Elderly people.
21. Why newer Insulin…..?
Lipodystrophy
Insulin allergy
Antibody related insulin resistance
Hypoglycaemia due to prolonged circulation of injected
insulin.
Immune complex deposition
22.
23.
24.
25. Type Onset Peak (Hr) DOA (Hr)
Rapid acting • Lispro
• Aspart
• Glulisine
5-15 min
10-15 min
5-15 min
1
1
1
3-5
3-5
5-6
26. Type Onset Peak (Hr) DOA (Hr)
Rapid acting • Lispro
• Aspart
• Glulisine
5-15 min
10-15 min
5-15 min
1
1
1
3-5
3-5
5-6
Long acting • Glargine
• Detemir
• Degludec
1-2 hrs
2-3 hrs
1-2 hrs
No peak
6-8 hrs
No peak
24 hrs
≈ 24 hrs
>24 hrs
27. Insulin Detemir
New Long-acting insulin analogue
Threonine in B30 replaced by Myrsitic acid.
28. Self aggregation in subcutaneous tissue.
Bound to albumin in circulation.
Smooth time action profile with no peak.
Onset of action: 1–2 hrs.
Duration of action: <24 hrs.
Given twice a day.
29. Why detemir……?
Glycemic control is similar to NPH(1.9% vs 1.8%) after 24 weeks.
Hypoglycaemia less frequent( vs NPH).
Lesser Nocturnal hypoglycemia when given as bolus basal
therapy(aspart + detemir).
Lesser or minimal weight gain as compared to NPH.
32. T ½- (25-40 hr).
In blood it is bound to albumin.
Administered anytime of the day or thrice weekly.
Unlike Glargine, it is effective at physiological pH.
Unlike Glargine & Detemir, it can be mixed with other
insulins.
High incidence of hypoglycemia in clinical trials.
33. Inhalational insulin
Inhalable insulin is a powdered form of insulin, delivered with a nebulizer
into the lungs where it is absorbed.
Advantages and Disadvantages of nasal route.
PK:
Depends hugely on properties of inhaler device, breathing.
manoeuvre & local pathology/physiology.
Bioavailability: 9-22%.
Tmax: 7 to 90 minutes.
High clearance: less incidence of hypoglycemia.
34. Inhalational insulin ……..contd….
Adverse reactions:
Insulin acting as a local Growth Factor.
Local alveolar membrane morphological changes.
However much alteration was NOT noted with PFT.
Anti-insulin IgG antibodies.
Contraindications:
Smokers and ex-smokers (6 months).
Patients with poorly controlled lung disease.
Allergic patients.
35. Afrezza
Approved FDA in 2014.
Meal time insulin.
Rapid-acting inhaled insulin.
Starts to work immediately after inhalation, peaks in about 12 mins, and wanes
off by 3 hrs.
Monomeric formulation is reputed to more closely mimic the natural insulin
response of healthy individuals.
Decreases the risk of hypoglycemia and weight gain.
C/I- asthma, active lung cancer or COPD.
37. Exubera vs Afrezza
Hexameric form
Peaks in 50 mins
Titration in mg
Size of inhaler
Needs training
Starts acting after 12 mins
Action goes off by 6 hrs.
Needs cleaning every week
Monomeric form
Peaks in 12 mins
Dosage in units
Easy to use
Afrezza works instantly
Fast acting
Action goes off by 2-3 hrs.
No cleaning needed
40. Continuous Subcutaneous Insulin
Infusion (CSII)
Portable infusion devices with S.C cannula.
Only rapid or regular insulins are used.
Programmed to deliver at low basal rates ( 1U/hr.) &
premeal bolus (4-10 times of basal rate).
No definite advantage over multidose S.C inj has been seen
in the trials.
41. CSII
Indications
Inadequate glycaemic control despite
optimized multiple daily injection (MDI)
therapy.
High glucose variability.
Elevated A1C.
Recurrent or unpredictable hypoglycaemia.
Nocturnal hypoglycaemia.
Dawn phenomenon.
Pregnancy.
Erratic schedule & Varied work shifts.
Inconvenience of multi MDI.
Limitations
Cost
Strict adherence to diet
Site infection
Malfunctioning/ pump failure.
Scar
Allergic reactions
44. Dawn
DOWN INSULIN
Somogyi
SO MUCH INSULIN
Cause Less amount of Endogenous Insulin
(HbA1c = 7%)
More amount of Exogenous Insulin
Mechanism Surge of hormones body produces
during 4-5 AM
Surge because of hypoglycaemia at
night
Hormone GH (Type I and IIDM) Cortisol and epinephrine.
Age More severe when GH is at peak –
Adolescents and young adults
Type I DM
T/T Increase dose of Insulin Decrease Dose of Insulin
50. Drug MoA Advantages Disadvantages
Sulfonylureas K+ ATP channel blocker
Insulin secretion
Inexpensive Hypoglycaemia (at any
glucose conc.)
Weight gain
Meglitinide ↑ Insulin secretion Fast onset of action,
Short lasting,
lower postprandial
glucose
Hypoglycaemia
Dyspepsia, wt. gain
Arthralgia
Need to be administered
before each meal
Metformin ↓ Hepatic glucose
Production
↑glucose utilization
Weight neutral
No hypoglycaemia
Inexpensive
Diarrhoea, nausea,
Lactic acidosis
TZD ↓Insulin resistance
↑glucose utilization
Lower insulin
requirements
Peripheral oedema, CHF,
weight gain, fractures,
macular oedema
α- Glucosidase inhibitor
↓ GI glucose
absorption
Reduce postprandial
glycemia
GI flatulence,
loose stools,
liver enzymes rises
51. Why need newer drugs…..?
Limitations of existing drugs:
Insulins:
Repeated injections
Lipodystrophy, insulin resistance
Can’t mimic the physiological nature of insulin
release
OHAs:
Adverse effect profile-unacceptable: weight gain.
Abd. distention and flatulence with acarbose
Basic pathology is left unaltered
No strategy available to protect beta cells
54. Incretins
Incretins: GIT Hormones produced in response to incoming nutrients that
contribute to glucose homeostasis.
The Incretin Effect is defined as the increased stimulation of insulin secretion elicited
by oral as compared with intravenous administration of glucose under similar plasma
glucose levels.
Two hormones:
Gastric inhibitory polypeptide [also known as Glucose-dependent Insulinotropic
Polypeptide] (GIP)
Glucagon-like peptide-1 (GLP-1)
55.
56. GLP - 1
30-amino acid peptide secreted by L cells in ileum & colon.
GLP-1 receptors seen in islets and CNS.
Increases glucose-dependent insulin secretion.
Inhibits glucagon secretion.
Increases satiety.
Slows gastric emptying.
In animal studies shown to increase beta-cell mass.
Source: Diabetes Care.
2003;26:2929-40.
57. The problem with GLP - 1
GLP-1 is metabolized rapidly by the enzyme Dipeptidyl Peptidase 4 (DPP 4)
Very short plasma T1/2: 1-2 mins
Continuous iv infusion
Solution:
Long-acting GLP-1 analogues: Exenatide, Liraglutide
DPP4 inhibitors: Gliptins
58. GLP – 1 Analogues : Exenatide
Naturally occurring peptide from the saliva of the Gila Monster.
PK:
Injectable, SC
Resistant to DPP4 inactivation
Plasma T ½ of 10 hrs.; Renal clearance
Therapeutic dose: 5-10 mcg twice daily before meals
Adverse effects: nausea, vomiting, diarrhea, weight loss; necrotizing and haemorrhagic
pancreatitis.
Contraindications: severe renal impairment (creatinine clearance <30 mL/min) or ESRD.
Safety in pregnancy not studied.
59. Exenatide: Current Status
Approved by the FDA on April 2005 as adjunctive therapy for T2DM pts not well-
controlled on other oral medication (Metformin, Sulfonylurea, TZD, Metformin+SU,
Metformin+TZD).
Not approved as Monotherapy
Not approved in T1DM
Exenatide LAR(2013)
Cost Factor
60. Newer GLP - 1 Analogues
LIRAGLUTIDE:
Approved by the European Medicines Agency (EMEA) on July 2009; FDA in 2015.
Adjuctive therapy
Longer T ½ (11 hrs.): Once daily, SC
0.6 mg SC OD for 1 week initially then increase to 1.2 mg OD & can increase to 1.8
mg OD.
61. Injection site and time of administration can be changed without dose adjustment
& independent of meals.
Good glycemic control & wt. loss.
S/E- Nausea, Diarrhea, Vomiting,Constipation.
Hypoglycaemia with other therapy.
Black box warning for thyroid cancer MEN syndrome.
Approved for OBESITY by the FDA December 23, 2014.
In Leader trial (2016) the rate of the first occurrence of death from cardiovascular
causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2
diabetes mellitus was lower with liraglutide than with placebo.
62. DPP – 4 Inhibitors
DPP4 inhibition causes increase in levels of both GIP & GLP-1.
Intrinsic membrane glycoprotein & a serine exopeptidase.
63. Sitagliptin
Approved by FDA as a monotherapy and in combination with Metformin or TZD.
PK:
Oral, 87% bioavailable.
T ½ 8-14 hrs.; Hepatic clearance
Therapeutic dose: 100 mg Once daily
Weight-neutral
A/E- Nasopharyngitis, Diarrhea, Headache, Peripheral oedema, Osteoarthritis
Contraindications: ESRD
Safety in children<18 yrs & pregnancy not established
Dose to be reduced in renal failure
64. Vildagliptin
Less protein bound, less T ½ than Sitagliptin
Therapeutic dose: 25-100 mg, twice a day
Current Status:
FDA approval pending.
Has been approved by EU in Feb’08 as a combination therapy with SU, TZD or Metformin.
FDC with Metformin is also EU-approved.
S/E : Headache, nasopharyngitis, cough, constipation & increased sweating.
C/I in liver/ renal failure.
65. Other DPP – 4 Inhibitors
Saxagliptin:
Therapeutic dose: 2.5-5 mg once a day.
Approved by FDA in July’09 as Monotherapy or in combination with
SU/TZD/Metformin.
Alogliptin: FDA approved in 2013, risk of heart failure ( FDA 2016).
Linagliptin: Phase III trials.
Anagliptin : Phase III trials.
Dutogliptin : Phase III trials.
67. Amylin
Also known as IAPP.
Secreted from Beta cells in response to meals.
Actions:
Suppresses endogenous glucagon production.
Reduces postprandial hepatic glucose production.
Delays gastric emptying.
Induces satiety: Centrally mediated.
Amylin secretion is diminished (or even absent) in patients with Diabetes.
68.
69. Pramlintide
Synthetic Analogue of Amylin.
FDA approved 2005.
PK:
SC, T ½ around 50 min.
Metabolized in kidney: active metabolite.
Therapeutic dose:
T2DM: 60-120 mcg.
T1DM: 15-60 mcg.
To be given immediately prior to meals.
Adverse effects:
Nausea.
Hypoglycaemia.
70. Pramlintide contd….
Adjuvant: to decrease the insulin dose.
Not to be mixed with insulin in the same syringe.
Can also be used in pts on SU/Metformin.
Contraindications:
Gastroparesis, Hypersensitivity
73. Dual PPAR agonists: Current status
Saroglitazar –
Only drug approved till date for DIABETIC DYSLIPIDAEMIA.
Indigenously developed NCE by any Indian company.
Approved for use in India by the DCGI in 2013.
Phase II trials for NASH in US ( june,2016).
Diabetic dyslipidaemia and hypertriglyceridemia in T2DM not controlled by
statin therapy.
2 mg & 4 mg OD orally before meals.
Phase III trials- NASH in India.
A/E- weight gain, edema & gastritis.
74. Newer agents
Muraglitazar
Meta-analysis of the phase 2 and 3 clinical trials revealed that it was
associated with a greater incidence of MI, stroke, TIA and CHF when
compared to placebo or pioglitazone.
Aleglitazar: currently in phase II.
Tesaglitazar: no longer studied, discontinued: renal toxicity.
76. From Victim to Ally : Kidney in DM
Role of SGLT-2 in renal tubules
SGLT 2 is expressed almost exclusively in the proximal tubule of the kidney.
An adjunct to diet and exercise to improve glycemic control in adults with
Type 2 DM.
Canagliflozin
Dapagliflozin
Empagliflozin
77. Inhibition of SGLT2, and thus inhibition of renal glucose
reabsorption, has the potential to reduce hyperglycemia in
patients with DM.
78. Drug Approval Dose Adverse effect Comments
CANAGLIFLOZIN 2013 100 – 300 mg OD UTI
Hypotension
LDL ↑
↑ risk of DKA
↑ risk of Stroke
↓bone density and ↑
fracture
Amputation of toe??
DAPAGLIFLOZIN 2014 5 – 10 mg OD UTI
Candidiasis
Rapid wt. loss
Tiredness
Rash
Sore throat
Not used in moderate
renal failure or ESRD
Bladder cancer ??
EMPAGLIFLOZIN 2014 10 – 25 mg OD UTI,
Candidiasis
Dizziness
Not used in moderate
renal failure or ESRD
Reduces CVS mortality
??
REMOGLIFOZIN Phase 2 trial 1000 mg T2DM, NASH
TOFOGLIFLOZIN Phase 3, approved in
Japan.
20 – 40 mg OD T2DM
79. From March 2013 to October 2015
FDA received reports of 101 confirmable cases* of
AKI some requiring hospitalization and dialysis, with
canagliflozin or dapagliflozin use.
80. SGLT – 2 Inhibitors : Caution
Pregnant or are breast-feeding..
Renal problems, low or high blood pressure, or high cholesterol.
History of UTI, candidiasis.
Dehydrated or have low blood volume.
Drug interactions:
Insulin or other insulin secretagogues- risk of hypoglycemia.
Diuretics.
Possible challenge:
Increase in incidence of UTI.
Hypotension.
Bladder cancer, amputations, fractures.
81. Bile acid – Binding Resins
The only bile acid sequestrant approved for T2DM is COLESEVELAM.
The mechanism by which bile acid – binding resins and removal from enterohepatic
circulation lowers, blood glucose has not been established.
It reduce intestinal glucose absorption , although there is no direct evidence .
It is provided powder for oral solution.
Dose 625mg tab. , 3 tablets BD before lunch and dinner.
A/E – Constipation, Dyspepsia , Abdominal pain, Nausea.
Cautiously use in patients with inherited hypertriglyceridemia.
It is approved for t/t of Hypercholesterolemia and may be use in T2DM as an adjunct to diet
and exercise.
82. Hypothalamus and Insulin Resistance
Migrating birds developed seasonal insulin resistance; dopamine????
Seasonal circadian rhythm.
Non - existent in humans.
Decreased hypothalamic dopaminergic tone involved in the
pathogenesis of insulin resistance.
Effect of Dopaminergic stimulation of Hypothalamus.
83.
84. Bromocriptine
Centrally acting D2 agonist.
FDA approved in May’09 for T2DM.
PK:
Oral, Extensive first-pass metabolism in the liver.
T ½ : 2 - 8 hours.
Dose in T2DM:
0.8 mg daily.
Increased in 0.8 mg increments weekly until the target range (1.6 - 4.8 mg) or till
maximal tolerance is reached.
Once daily dosing within two hours of waking and with food.
88. 1. Activation Downstream of IRTK
Activation of IRS-1, Akt (protein kinase B), and GSK-3, which was
independent of IRTK phosphorylation.
Vanadate analogues.
Phase II trial for AKP-020.
89. 2. Protein Tyrosine Phosphatase 1B (PTP1B)
Inhibitors
Endoplasmic reticulum protein - negative regulator
of insulin and leptin (dephosphorylating activated
IRTK and IRS, JAK2).
Mice lacking PTP1B have enhanced insulin sensitivity,
did not gain weight.
Synergistic effects on glucose/lipid levels and food
intake.
Potential targets : Anti-obesity, DM II.
90. 3. Glycogen Synthase Kinase-3 (GSK3b)
Inhibitors
GS is the rate-limiting step in glycogen synthesis and is inactivated by
phosphorylation by GSK3b.
Two isoforms.
GSK3b favors IR by its proinflammatory and GS inhibitory effects.
Pre- clinical stages.
93. 1. Glucokinase (GK) Activators
Enzymes of the glycolytic
pathway that converts glucose
to glucose-6-phosphate.
Glucose sensor.
Upregulating insulin (from
pancreas).
Promoting glucose storage as
glycogen .
94.
95. Piragliatin - Phase 2
Possible concern –
Increased hepatic glycogen, lipid deposition in liver and
muscle.
96. 2. Fructose-1,6-Bisphosphatase (FBP)
Inhibitors
(FBP) is the Gluconeogenesis enzyme
that catalyses the reverse conversion
(F1,6P to F6P).
FBPi - decrease Hepatic Glucose
Production.
Efficacy has been an issue.
Phase 2 - MB07803.
97. 3. Glycogen Phosphorylase (GP) Inhibitors
Glycogenolysis is a substantial
contributor to hyperglycaemia.
GP produces glucose-1-phosphate
converted to glucose-6-phosphate
which feeds into glycolysis.
GP(a) inhibition of the liver isoform in
a selective fashion is important.
Ingliforib - phase 1
99. 1. Beta3-Adrenergic Receptor (β3-AR)
Agonists
Activate the uncoupling protein (UCP) which causes the expenditure of
metabolic calories as heat.
Preclinical stages.
Lipolysis & β oxidation.
Low bioavailability.
Efficacy is less.
Is it suitable?? β3AR stimulated thermogenesis to expend excess energy in
human diabetic patients is still undefined.
101. 3. GPR40 /(Free Fatty Acid Receptor 1
(FFAR1)) Ligands
FFAR1 facilitates glucose-stimulated insulin secretion from pancreatic β-cells.
GPR 40 regulates the secretion of glucagon-like peptide-1 in the intestine, as
well as increases insulin sensitivity.
Potential therapeutic targets for type 2 DM.
Chronic exposure impairs β-cell function (lipotoxicity).
Phase II : TAK-875.
Source: Diabetes care
2013 Aug 2:S175-9
102. Otelixizumab
Humanized Anti-CD3 Monoclonal Antibody Inhibition of autoimmune attack on β-
cells.
Phase 3- DEFEND (Durable-response therapy Evaluation For Early or New onset
type 1 Diabetes).
Evaluate whether a single course of otelixizumab, administered within 90 days after
the initial diagnosis, would reduce the amount of administered insulin required to
control blood glucose levels by inhibiting the destruction of beta cells.
Failed to show efficacy.
Orphan drug status by FDA.
S/E- infusion reactions, headache, vomiting.
103. Teplizumab
Anti-CD3 monoclonal antibody.
New-onset type 1 diabetes.
Minimize cytokine release and prevent the progressive destruction of β-
cells.
Phase 3.
104. Recombinant Human Glutamic Acid
Decarboxylase-65 (rhGAD65)
Vaccine.
Phase 3.
Antibodies against GAD - 80–90% type 1 DM.
Induces immunotolerance and may thereby slow or prevent
autoimmune destruction of pancreatic islet cells.
106. Future Prospects: Artificial Pancreas
FDA approved it on 30 sept 2016.
Components:
Continuous Glucose Sensor.
Insulin Infusion Pump.
An Algorithm to determine amount of insulin to be delivered.
Barricades:
Sensor: needle site infections.
Pumps: Need for changing the pump often; INSULIN.
Algorithm: complexity.
Cost.
Patient Compliance, understanding.