Recent advances in the treatment of diabetes mellitus include newer drug classes and delivery methods. Newer drug classes target the incretin system through GLP-1 agonists and DPP-4 inhibitors, sodium-glucose transporters with SGLT2 inhibitors, and amylin signaling with pramlintide. Improved insulin formulations include long-acting insulins glargine and degludec. Novel delivery methods involve insulin pumps for continuous subcutaneous delivery and inhaled formulations. Emerging therapies aim to preserve beta cell function through stem cell technology, anti-CD3 antibodies, and gene therapies.

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
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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
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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withdrawn d/t lactic acidosis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CV risk (Rosiglitazone withdrawn,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
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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
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18. NEWER DRUGS
18

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
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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
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52. POTENTIAL INTERVENTIONS
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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
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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
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