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RECENT ADVANCES IN THE
TREATMENT OF DIABETES
MELLITUS
- Dr. Chandini
- Moderator: Dr. Princy Pallatty
1
OVERVIEW
 Introduction
 Evolution of diabetes management
 Current therapeutic approaches
 Newer drugs & delivery systems
 Potential/emerging therapies
 Conclusion 2
INTRODUCTION
• Diabetes mellitus - complete/relative lack of
insulin/insulin resistance
 hyperglycemia
• ↑ prevalence (8.3%) – upto 35% by 2050
max in low & middle income countries.
• 3rd leading cause of death in older adults
3
4
• 46.3% still undiagnosed
• ICMR survey:
China – leading (98.4 million)
India – 2 (65.1 million)
• Ethnic factors:
Asian Indians - ↑ insulin resistance
greater abdominal adiposity
Etiological classification
1. Type 1 DM (IDDM) a. Idiopathic
b. Immune-mediated
2. Type 2 DM (NIDDM)
3. Other specific types:
a. Genetic defect (β cell function, insulin action)
b. Endocrinopathies
c. Drug- or chemical-induced
d. Infections
e. Diseases of exocrine pancreas
5
EVOLUTION OF DIABETES MANAGEMENT
• 20th C: Rx of diabetes understood
experimentally
• 1921: Discovery of insulin by
Banting & Best
6
7
• Role of diet.
• 1st gen sulphonylureas (SUs) – successful oral
replacement of insulin in T2 DM.
- Cardiovascular risk
2nd gen SUs
(glibenclamide, glipizide, glimepiride)
- risk of hypoglycaemia, ↑ weight
• Late 70s:
Phenformin – 1st biguanide launched,
withdrawn d/t lactic acidosis
Metformin – much safer
currently preferred 1st line GLD &
in combination therapy.
• Beginning of this century:
Thiazolidinediones – 1st true insulin sensitizers
CV risk (Rosiglitazone withdrawn,
Pioglitazone – limited use)
8
CURRENT THERAPEUTIC
APPROACHES
 Non-pharmacological
 Insulins
 Oral Hypoglycemic agents.
9
NON PHARMACOLOGICAL MEASURES
 Medical Nutrition Therapy (MNT)
 Dietary fiber
 Artificial Sweeteners
 Fruits ( avoid sweet fruits & juices)
 Alcohol, tobacco & salt restriction
 Physical activity
10
PHARMACOTHERAPY
Oral hypoglycemic drugs
3 categories –
1. Insulin secretagogues - stimulate insulin
secretion
2. Insulin sensitizers – sensitize tissues (liver &
adipose) to the action of insulin
3. Affect absorption of glucose
11
INSULIN SECRETAGOGUES
1. Sulfonylureas
Primarily stimulate insulin release by binding
to sulfonylurea rceptor
o 1st gen – Tolbutamide, Chlorpropamide,
Tolazamide, Acetohexamide
o 2nd gen - Glyburide, Glipizide, Glimepiride,
Gliclazide
12
INSULIN SENSITIZERS
2. Meglitinide analogs
Repaglinide, Mitiglinide
3. D-Phenylalanine derivative
Nateglinide
1. Biguanides
Metformin, Phenformin
2. Thiazolidinediones
Pioglitazone, Rosiglitazone, Troglitazone 13
DRUGS AFFECTING GLUCOSE ABSORPTION
o Alpha-glucosidase inhibitors
Competitively inhibit the intestinal α-glucosidase
enzymes
Eg. Acarbose, Voglibose, Miglitol
14
Insulins
• Insulin is the only Rx available for T1 DM.
• Human insulin -
- by rDNA technology,
- soluble in aqueous solution.
Conventional insulins –
 Rapid acting: Lispro, aspart, glulisine.
 Short: Regular
 Intermediate: NPH, lente
15
Why need newer drugs?
o Limitations of existing drugs:
Insulins:
• Repeated injections
• Lipodystrophy,
• insulin resistance
• Can’t mimic the physiological nature of insulin
release
16
OHAs:
• Adverse effect profile-unacceptable:
weight gain
• Abdominal distention & flatulence with
acarbose
Basic pathology is left unaltered
• No strategy available to protect beta cells
17
NEWER DRUGS
18
INCRETIN MIMETICS
• Incretins –
- insulinotropic hormones
- secreted from specialized neuroendocrine
cells in small intestinal mucosa
- stimulate insulin secretion.
• Eg. GLP-1 and GIP.
• GLP-1: successful drug target.
19
• Main effect: enhance insulin secretion
(glucose-dependent)
avoids hypoglycaemia
• Inhibits glucagon release
• Delays gastric emptying
• ↓ food intake, & normalizes fasting &
postprandial insulin secretion.
• t1/2 extremely short – rapidly metabolized by
dipeptidyl peptidase-4 (DPP-4)
20
GLP-1 analogs
• ↑ GLP-1 actions upto 10-fold.
• divided into –
Short acting: Exenatide & lixisenatide
(better post-prandial glucose control)
long-acting: Liraglutide, albiglutide,
dulaglutide, & semaglutide (under trial)
21
• Mechanism of action:
Activation of the GLP-1 receptor (class B GPCRs).
- Expressed in β cells.
Activation of cAMP-PKA pathway
22
Exenatide –
• 1st synthetic agent (exendin-4)
• SC, 5 or 10 mcg, as pens
• More stable than GLP-1.
Not metabolized by DPP-4
• BD (before 1st & last meal)
• Extended release – once a week (2mg)
• Use:
T2 DM - along with metformin +/- SU
- also basal insulin
23
Gila monster
24
Adverse effects/Drug interactions –
• IV or subcut GLP-1  nausea & vomiting
Rarely hypoglycaemia
• CNS receptors  delay gastric emptying
GLP-1 agonists – alter PK of drugs that
require rapid GI absorption (OCPs &
antibiotics)
• Exenatide avoided in mod-severe renal
failure & pancreatitis.
DIPEPTIDYL PEPTIDASE-4 (DPP-4)
INHIBITORS
• Competitively inhibit DPP-4 enzyme
↓
inhibit the degradation of GIP and GLP-1
↓
enhance incretin effect
↓
insulin secretion & glucagon inhibition.
• Eg. Sitagliptin, saxagliptin, linagliptin &
alogliptin (US), Vildagliptin (EU)
25
• ↓ A1c levels by 0.8%
• Use: Add-on drug for chronic glucose control
• Dose: BD
Dose ↓ in renal
dysfunction
- dose ↓ when
coadministered with CYP3A4 inhibitors
• No a/e noted in clinical trials 26
Alogliptin 25mg
Linagliptin 5mg
Vildagliptin 50mg
Sitagliptin 100mg
Saxagliptin 5mg
NA+/GLUCOSE TRANSPORTER 2 INHIBITORS
• 80-90% of renal retention of glucose in non-
diabetic persons
• Phlorizin - SGLT inhibitor
• Specific inhibitors  ↑ urinary glucose loss
• MonoRx ↓ A1c by 0.7-1%, also ↓ wt.
• Canagliflozin, dapagliflozin, empagliflozin –
clinical use
• Available in combination with metformin &
DPP-4 inhibitors
• Combined SGLT1/SGLT2 inhibitor - under
investigation.
27
• Dose:
• A/E: UTI, hypotension, ↑ risk of fractures (affect
mineral balance, Vit D & PTH levels),
lower extremity amputation (canagliflozin)
• Avoided in renal failure (> stage 3)
• Empagliflozin & canagliflozin ↓ CV risk 28
Dapagliflozin 5 & 10 mg
Canagliflozin 100 & 300mg
Empagliflozin 10 & 25 g
AMYLIN MIMETICS
Amylin –
• glucoregulatory polypeptide
• act centrally  induce satiety,
slow gastric emptying,
suppress pancreatic glucagon secretion,
apoptotic cell death (GPCR)
• absent in T1 DM, concn altered in T2 DM
• Analogs – both in T1 & T2 DM as an adjunct
to meal-time insulin
29
Pramlintide
• Acts via amylin Rs in hind brain.
• Subcut inj before meals
• Dose -
T1 DM: 15 mcg  60 mcg (max)
T2 DM: 60 mcg  120 mcg
• M/C side effect – nausea & hypoglycaemia
GI motility disorders
• Pregnancy C category
• can be used in moderate renal disease
• weight loss drug for non-diabetics ? 30
BILE ACID BINDING RESINS
• Only approved drug for T2 DM – Colesevelam
• MOA –
- Bile acid metabolism abnormal in T2 diabetics
- Bile acids bind to & remove blood glucose
from enterohep circulation
• Colesevelam
– powder (oral solution), or 625 mg tabs
( 3 tabs bd before lunch & dinner/ 6 tabs before
largest meal)
31
• A/E –
GI (constipation, dyspepsia, abdominal
pain, nausea)
↑ plasma triglycerides
(avoided if plasma TGs > 200 mg/dl)
Pregnancy Cat .B
• D/I –
Phenytoin, warfarin,verapamil, I-thyroxine,
fat-soluble vitamins
• Use – T2 DM; adjunct to diet & exercise.
32
Bromocriptine:
• D2 receptor agonist
• long known to improve insulin sensitivity &
glycemic control in T2 DM.
• MonoRx or adjunct - ↓ HbA1c by 0.5 – 1.2%
• Dose: 1.6 – 4.8 mg, taken with food, morning
33
Newer PPAR agonists -
• Dual PPAR α and γ agonists – Glitazars
(aleglitazar, muraglitazar)
• May treat both hyperglycemia &
dyslipidemia
• Devoid of s/e of thiazolidinediones &
glitazars
34
Glucokinase activators
• Glucokinase
↓
glucose phosphorylation
Glycogen synthesis Insulin synthesis
(liver) (β cells)
↓
↑ insulin concn
↓ glucose concn
• Also ↑ hep glucose metabolism
35
GA
Eg. Piragliatin
PDEIs
• β - cell expresses several PDEs  degrade
cAMP  ↓ insulin release
• Transient inhibition of PDEs (PDE-3B)
- possible intervention.
β- 3 agonists:
• shown to stimulate insulin release & improve
glycemic control in obese diabetic rodents
• adequate efficacy in humans ?
36
11B Hydroxysteroid Dehydrogenase Type
1 (11BHSD1) inhibitor
• Glucocorticoid antagonists
• ↑ glucocorticoid  truncal obesity,
insulin resistance
hyperglycemia
• Potential Rx – osteoporosis
Metabolic syndrome (T2 DM)
37
Anti-CD3 monoclonal Ab
• Otelixizumab –
- a humanized anti-CD3 monoclonal Ab
- currently being evaluated in patients with
T1 DM (immune-mediated).
- blocks function of effector T cells
mistakenly destroying β cells.
- Orphan drug status
38
Histamine H3 receptor agonist –
• H3 receptors - presynaptic membranes of
histamine neurons.
• Proxyfan – central agonist
- significantly improve glucose excursion by
↑ plasma insulin levels
(glucose -independent mech)
• Therapeutic potential in Rx of obesity & DM.
39
Vitamins and Minerals:
• Vit C, E & β-carotene
• Vit D3 - insulin production, secretion &
action.
(diabetics deficient in Vit D3)
• Vit D supplementation – glycemic control.
• Zn, Li, Se, Mb, Hg & Ca – insulin like
anti-diabetic effects.
40
Lipoic acid, isoferulic acid & ACEIs
• α - lipoic acid
- antioxidant
↑ insulin sensitivity – Rx of diabetic
neuropathy
• Isoferulic acid
- ↑ GLUT-4 & ↓ gluconeogenesis
• ACEIs – modest ↑ in insulin sensitivity
(↑ bradykinin)
41
NEWER INSULINS
• Long-acting
• Eg.
1. Insulin glargine
2. Detemir
3. Degludec
42
INSULIN GLARGINE
• Long-acting analogue of human insulin
• Clear solution; pH = 4
• Prolonged, predictable absorption from inj site.
• Cannot be mixed with short-acting insulin
preparations.
43
• Advantages over NPH insulin
- Sustained absorption  more predictable
24-h insulin coverage than NPH insulin (OD)
- lower risk of hypoglycemia (overnight)
- Administered anytime during the day
- Doesn’t accumulate after several inj
• Dose - 100 U/ml, 300 U/ml
• Basiglar - glargine biosimilar
44
INSULIN DETEMIR
• Myristoylated insulin - addition of a saturated fatty
acid to the ε amino group of LysB29
• SC inj  binds to albumin (via FA chain)
• T1 DM: BD
• Smoother action &
↓ prevalence of
hypoglycemia
• Glargine & detemir
absorption profiles
similar.
45
INSULIN DEGLUDEC
• 1 amino acid deleted (threonine at position B30)
& conjugated, at lysine at position B29.
• Active at physiologic
pH  forms
multihexamers after SC inj.
• Less severe
hypoglycemia than glargine
46
47
NEW & IMPROVED INSULIN DELIVERY
DEVICES
 Insulin pens
Eg. Novopen
 Insulin jets
48
 Continuous Subcutaneous Insulin Infusion.
• Insulin pumps available
• Constant basal infusion of insulin
• Option of diff infusion rates during day & night
• Only short acting insulins used.
• More physiological profile of
insulin replacement
during exercise
 less hypoglycemia
• Rapidly evolving
49
 Insulin inhalers –
• Contains powdered form of insulin,
• Delivered with a nebulizer
• More rapid absorption.
• Exubera – 1st product (2006)
discontinued.
• Afrezza – only FDA approved
inhaled insulin (2014)
Rapid-acting human insulin
50
51
POTENTIAL INTERVENTIONS
52
Pancreatic and islet cell transplantation:
• Whole organ transplantation:
In T1 DM + end stage diab nephropathy
(renal transplantation)
• Risk of graft rejection & s/e of
immunosuppression
• Islet cell transplantation - promising
Rx option for T1 DM
- donor β-cells injected into host portal vein
53
54
Stem cell technology
• Stem cells: totipotent  β cells
• Useful in T1 DM
• Eg. Mesechymal Stem cell (MSC) Rx
(immunomodulatory effects)
Hematopoeitic stem cell Rx
Embryonic stem cell Rx
• Limitations: absence of reliable methods
immunological rejection
uncontrolled proliferation
CONCLUSION
• Diabetes 1 of the most challenging health
problems globally
• Conventional drugs effective – drawbacks +
• Emerging: Leptin Rx
Mucoadhesive delivery (glipizide)
Gene Rx
Nanotechnology
Vaccines (RHGAD65)
55
REFERENCES -
1) The Pharmacological basis of therapeutics – Goodman &
Gilman
2) Rang & Dale’s pharmacology
3) Woldu MA, Lenjisa JL, Satessa GD (2014) Recent
Advancements in Diabetes Pharmacotherapy. Biochem
Pharmacol (Los Angel) 2014;143(3)
4) Mohammed AG, Kotwal S. Recent Advances in
Management of Diabetes Mellitus. JIMSA. 2012;25(30)171-
175
5) Tiwari P. Recent Trends in Therapeutic Approaches for
Diabetes Management: A Comprehensive Update. Journal
of Diabetes Research. 2015
6) Aschner P. Recent advances in understanding/managing
type 2 diabetes mellitus. F1000Research. 2017;6:F1000
Faculty Rev-1922
56

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Recent advances in the treatment of diabetes mellitus

  • 1. RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS - Dr. Chandini - Moderator: Dr. Princy Pallatty 1
  • 2. OVERVIEW  Introduction  Evolution of diabetes management  Current therapeutic approaches  Newer drugs & delivery systems  Potential/emerging therapies  Conclusion 2
  • 3. INTRODUCTION • Diabetes mellitus - complete/relative lack of insulin/insulin resistance  hyperglycemia • ↑ prevalence (8.3%) – upto 35% by 2050 max in low & middle income countries. • 3rd leading cause of death in older adults 3
  • 4. 4 • 46.3% still undiagnosed • ICMR survey: China – leading (98.4 million) India – 2 (65.1 million) • Ethnic factors: Asian Indians - ↑ insulin resistance greater abdominal adiposity
  • 5. Etiological classification 1. Type 1 DM (IDDM) a. Idiopathic b. Immune-mediated 2. Type 2 DM (NIDDM) 3. Other specific types: a. Genetic defect (β cell function, insulin action) b. Endocrinopathies c. Drug- or chemical-induced d. Infections e. Diseases of exocrine pancreas 5
  • 6. EVOLUTION OF DIABETES MANAGEMENT • 20th C: Rx of diabetes understood experimentally • 1921: Discovery of insulin by Banting & Best 6
  • 7. 7 • Role of diet. • 1st gen sulphonylureas (SUs) – successful oral replacement of insulin in T2 DM. - Cardiovascular risk 2nd gen SUs (glibenclamide, glipizide, glimepiride) - risk of hypoglycaemia, ↑ weight
  • 8. • Late 70s: Phenformin – 1st biguanide launched, withdrawn d/t lactic acidosis Metformin – much safer currently preferred 1st line GLD & in combination therapy. • Beginning of this century: Thiazolidinediones – 1st true insulin sensitizers CV risk (Rosiglitazone withdrawn, Pioglitazone – limited use) 8
  • 9. CURRENT THERAPEUTIC APPROACHES  Non-pharmacological  Insulins  Oral Hypoglycemic agents. 9
  • 10. NON PHARMACOLOGICAL MEASURES  Medical Nutrition Therapy (MNT)  Dietary fiber  Artificial Sweeteners  Fruits ( avoid sweet fruits & juices)  Alcohol, tobacco & salt restriction  Physical activity 10
  • 11. PHARMACOTHERAPY Oral hypoglycemic drugs 3 categories – 1. Insulin secretagogues - stimulate insulin secretion 2. Insulin sensitizers – sensitize tissues (liver & adipose) to the action of insulin 3. Affect absorption of glucose 11
  • 12. INSULIN SECRETAGOGUES 1. Sulfonylureas Primarily stimulate insulin release by binding to sulfonylurea rceptor o 1st gen – Tolbutamide, Chlorpropamide, Tolazamide, Acetohexamide o 2nd gen - Glyburide, Glipizide, Glimepiride, Gliclazide 12
  • 13. INSULIN SENSITIZERS 2. Meglitinide analogs Repaglinide, Mitiglinide 3. D-Phenylalanine derivative Nateglinide 1. Biguanides Metformin, Phenformin 2. Thiazolidinediones Pioglitazone, Rosiglitazone, Troglitazone 13
  • 14. DRUGS AFFECTING GLUCOSE ABSORPTION o Alpha-glucosidase inhibitors Competitively inhibit the intestinal α-glucosidase enzymes Eg. Acarbose, Voglibose, Miglitol 14
  • 15. Insulins • Insulin is the only Rx available for T1 DM. • Human insulin - - by rDNA technology, - soluble in aqueous solution. Conventional insulins –  Rapid acting: Lispro, aspart, glulisine.  Short: Regular  Intermediate: NPH, lente 15
  • 16. Why need newer drugs? o Limitations of existing drugs: Insulins: • Repeated injections • Lipodystrophy, • insulin resistance • Can’t mimic the physiological nature of insulin release 16
  • 17. OHAs: • Adverse effect profile-unacceptable: weight gain • Abdominal distention & flatulence with acarbose Basic pathology is left unaltered • No strategy available to protect beta cells 17
  • 19. INCRETIN MIMETICS • Incretins – - insulinotropic hormones - secreted from specialized neuroendocrine cells in small intestinal mucosa - stimulate insulin secretion. • Eg. GLP-1 and GIP. • GLP-1: successful drug target. 19
  • 20. • Main effect: enhance insulin secretion (glucose-dependent) avoids hypoglycaemia • Inhibits glucagon release • Delays gastric emptying • ↓ food intake, & normalizes fasting & postprandial insulin secretion. • t1/2 extremely short – rapidly metabolized by dipeptidyl peptidase-4 (DPP-4) 20
  • 21. GLP-1 analogs • ↑ GLP-1 actions upto 10-fold. • divided into – Short acting: Exenatide & lixisenatide (better post-prandial glucose control) long-acting: Liraglutide, albiglutide, dulaglutide, & semaglutide (under trial) 21
  • 22. • Mechanism of action: Activation of the GLP-1 receptor (class B GPCRs). - Expressed in β cells. Activation of cAMP-PKA pathway 22
  • 23. Exenatide – • 1st synthetic agent (exendin-4) • SC, 5 or 10 mcg, as pens • More stable than GLP-1. Not metabolized by DPP-4 • BD (before 1st & last meal) • Extended release – once a week (2mg) • Use: T2 DM - along with metformin +/- SU - also basal insulin 23 Gila monster
  • 24. 24 Adverse effects/Drug interactions – • IV or subcut GLP-1  nausea & vomiting Rarely hypoglycaemia • CNS receptors  delay gastric emptying GLP-1 agonists – alter PK of drugs that require rapid GI absorption (OCPs & antibiotics) • Exenatide avoided in mod-severe renal failure & pancreatitis.
  • 25. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS • Competitively inhibit DPP-4 enzyme ↓ inhibit the degradation of GIP and GLP-1 ↓ enhance incretin effect ↓ insulin secretion & glucagon inhibition. • Eg. Sitagliptin, saxagliptin, linagliptin & alogliptin (US), Vildagliptin (EU) 25
  • 26. • ↓ A1c levels by 0.8% • Use: Add-on drug for chronic glucose control • Dose: BD Dose ↓ in renal dysfunction - dose ↓ when coadministered with CYP3A4 inhibitors • No a/e noted in clinical trials 26 Alogliptin 25mg Linagliptin 5mg Vildagliptin 50mg Sitagliptin 100mg Saxagliptin 5mg
  • 27. NA+/GLUCOSE TRANSPORTER 2 INHIBITORS • 80-90% of renal retention of glucose in non- diabetic persons • Phlorizin - SGLT inhibitor • Specific inhibitors  ↑ urinary glucose loss • MonoRx ↓ A1c by 0.7-1%, also ↓ wt. • Canagliflozin, dapagliflozin, empagliflozin – clinical use • Available in combination with metformin & DPP-4 inhibitors • Combined SGLT1/SGLT2 inhibitor - under investigation. 27
  • 28. • Dose: • A/E: UTI, hypotension, ↑ risk of fractures (affect mineral balance, Vit D & PTH levels), lower extremity amputation (canagliflozin) • Avoided in renal failure (> stage 3) • Empagliflozin & canagliflozin ↓ CV risk 28 Dapagliflozin 5 & 10 mg Canagliflozin 100 & 300mg Empagliflozin 10 & 25 g
  • 29. AMYLIN MIMETICS Amylin – • glucoregulatory polypeptide • act centrally  induce satiety, slow gastric emptying, suppress pancreatic glucagon secretion, apoptotic cell death (GPCR) • absent in T1 DM, concn altered in T2 DM • Analogs – both in T1 & T2 DM as an adjunct to meal-time insulin 29
  • 30. Pramlintide • Acts via amylin Rs in hind brain. • Subcut inj before meals • Dose - T1 DM: 15 mcg  60 mcg (max) T2 DM: 60 mcg  120 mcg • M/C side effect – nausea & hypoglycaemia GI motility disorders • Pregnancy C category • can be used in moderate renal disease • weight loss drug for non-diabetics ? 30
  • 31. BILE ACID BINDING RESINS • Only approved drug for T2 DM – Colesevelam • MOA – - Bile acid metabolism abnormal in T2 diabetics - Bile acids bind to & remove blood glucose from enterohep circulation • Colesevelam – powder (oral solution), or 625 mg tabs ( 3 tabs bd before lunch & dinner/ 6 tabs before largest meal) 31
  • 32. • A/E – GI (constipation, dyspepsia, abdominal pain, nausea) ↑ plasma triglycerides (avoided if plasma TGs > 200 mg/dl) Pregnancy Cat .B • D/I – Phenytoin, warfarin,verapamil, I-thyroxine, fat-soluble vitamins • Use – T2 DM; adjunct to diet & exercise. 32
  • 33. Bromocriptine: • D2 receptor agonist • long known to improve insulin sensitivity & glycemic control in T2 DM. • MonoRx or adjunct - ↓ HbA1c by 0.5 – 1.2% • Dose: 1.6 – 4.8 mg, taken with food, morning 33
  • 34. Newer PPAR agonists - • Dual PPAR α and γ agonists – Glitazars (aleglitazar, muraglitazar) • May treat both hyperglycemia & dyslipidemia • Devoid of s/e of thiazolidinediones & glitazars 34
  • 35. Glucokinase activators • Glucokinase ↓ glucose phosphorylation Glycogen synthesis Insulin synthesis (liver) (β cells) ↓ ↑ insulin concn ↓ glucose concn • Also ↑ hep glucose metabolism 35 GA Eg. Piragliatin
  • 36. PDEIs • β - cell expresses several PDEs  degrade cAMP  ↓ insulin release • Transient inhibition of PDEs (PDE-3B) - possible intervention. β- 3 agonists: • shown to stimulate insulin release & improve glycemic control in obese diabetic rodents • adequate efficacy in humans ? 36
  • 37. 11B Hydroxysteroid Dehydrogenase Type 1 (11BHSD1) inhibitor • Glucocorticoid antagonists • ↑ glucocorticoid  truncal obesity, insulin resistance hyperglycemia • Potential Rx – osteoporosis Metabolic syndrome (T2 DM) 37
  • 38. Anti-CD3 monoclonal Ab • Otelixizumab – - a humanized anti-CD3 monoclonal Ab - currently being evaluated in patients with T1 DM (immune-mediated). - blocks function of effector T cells mistakenly destroying β cells. - Orphan drug status 38
  • 39. Histamine H3 receptor agonist – • H3 receptors - presynaptic membranes of histamine neurons. • Proxyfan – central agonist - significantly improve glucose excursion by ↑ plasma insulin levels (glucose -independent mech) • Therapeutic potential in Rx of obesity & DM. 39
  • 40. Vitamins and Minerals: • Vit C, E & β-carotene • Vit D3 - insulin production, secretion & action. (diabetics deficient in Vit D3) • Vit D supplementation – glycemic control. • Zn, Li, Se, Mb, Hg & Ca – insulin like anti-diabetic effects. 40
  • 41. Lipoic acid, isoferulic acid & ACEIs • α - lipoic acid - antioxidant ↑ insulin sensitivity – Rx of diabetic neuropathy • Isoferulic acid - ↑ GLUT-4 & ↓ gluconeogenesis • ACEIs – modest ↑ in insulin sensitivity (↑ bradykinin) 41
  • 42. NEWER INSULINS • Long-acting • Eg. 1. Insulin glargine 2. Detemir 3. Degludec 42
  • 43. INSULIN GLARGINE • Long-acting analogue of human insulin • Clear solution; pH = 4 • Prolonged, predictable absorption from inj site. • Cannot be mixed with short-acting insulin preparations. 43
  • 44. • Advantages over NPH insulin - Sustained absorption  more predictable 24-h insulin coverage than NPH insulin (OD) - lower risk of hypoglycemia (overnight) - Administered anytime during the day - Doesn’t accumulate after several inj • Dose - 100 U/ml, 300 U/ml • Basiglar - glargine biosimilar 44
  • 45. INSULIN DETEMIR • Myristoylated insulin - addition of a saturated fatty acid to the ε amino group of LysB29 • SC inj  binds to albumin (via FA chain) • T1 DM: BD • Smoother action & ↓ prevalence of hypoglycemia • Glargine & detemir absorption profiles similar. 45
  • 46. INSULIN DEGLUDEC • 1 amino acid deleted (threonine at position B30) & conjugated, at lysine at position B29. • Active at physiologic pH  forms multihexamers after SC inj. • Less severe hypoglycemia than glargine 46
  • 47. 47
  • 48. NEW & IMPROVED INSULIN DELIVERY DEVICES  Insulin pens Eg. Novopen  Insulin jets 48
  • 49.  Continuous Subcutaneous Insulin Infusion. • Insulin pumps available • Constant basal infusion of insulin • Option of diff infusion rates during day & night • Only short acting insulins used. • More physiological profile of insulin replacement during exercise  less hypoglycemia • Rapidly evolving 49
  • 50.  Insulin inhalers – • Contains powdered form of insulin, • Delivered with a nebulizer • More rapid absorption. • Exubera – 1st product (2006) discontinued. • Afrezza – only FDA approved inhaled insulin (2014) Rapid-acting human insulin 50
  • 51. 51
  • 52. POTENTIAL INTERVENTIONS 52 Pancreatic and islet cell transplantation: • Whole organ transplantation: In T1 DM + end stage diab nephropathy (renal transplantation) • Risk of graft rejection & s/e of immunosuppression
  • 53. • Islet cell transplantation - promising Rx option for T1 DM - donor β-cells injected into host portal vein 53
  • 54. 54 Stem cell technology • Stem cells: totipotent  β cells • Useful in T1 DM • Eg. Mesechymal Stem cell (MSC) Rx (immunomodulatory effects) Hematopoeitic stem cell Rx Embryonic stem cell Rx • Limitations: absence of reliable methods immunological rejection uncontrolled proliferation
  • 55. CONCLUSION • Diabetes 1 of the most challenging health problems globally • Conventional drugs effective – drawbacks + • Emerging: Leptin Rx Mucoadhesive delivery (glipizide) Gene Rx Nanotechnology Vaccines (RHGAD65) 55
  • 56. REFERENCES - 1) The Pharmacological basis of therapeutics – Goodman & Gilman 2) Rang & Dale’s pharmacology 3) Woldu MA, Lenjisa JL, Satessa GD (2014) Recent Advancements in Diabetes Pharmacotherapy. Biochem Pharmacol (Los Angel) 2014;143(3) 4) Mohammed AG, Kotwal S. Recent Advances in Management of Diabetes Mellitus. JIMSA. 2012;25(30)171- 175 5) Tiwari P. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update. Journal of Diabetes Research. 2015 6) Aschner P. Recent advances in understanding/managing type 2 diabetes mellitus. F1000Research. 2017;6:F1000 Faculty Rev-1922 56