RECENT_ADVANCES_IN_TREATMENT_DIABETES_MELLITUS_BY_DR_SIDDIQUE_REHMAN.pptx

2. CONTENTS
 Introduction
 Current therapy of DM
 Limitations of current therapy
 Newer Drugs and Their status in the DM
therapy
 Newer Potential Drugs Targets

3. Introduction
 Diabetes mellitus (DM), is a group of metabolic
diseases characterized by hyperglycemia resulting
from defects in insulin secretion, insulin action, or
both.

4. World Diabetes Day
 14TH November of every year
to mark the birthday of
Frederick Banting

5. Burden Of The Disease
 2021 Diabetes Atlas Numbers (IDF)
Globally, more than 1 in 10 adults aged 20-79 years (over half
a billion people) now live with diabetes (both type 1 and type
2).
This number has more than tripled since 2000 from an
estimated 151 million to 537 million.
Pakistan ranked at first place for having
the highest comparative diabetes prevalence rate in 2023 at
30.8%.- “World of Statics”

6. Current Therapy OF DM
NON-PHARMACOLOGICAL PHARMACOLOGICAL
1. WEIGHT REDUCTION
2. REGULAR PHYSICAL
ACTIVITY
3. NUTRATION THERAPY
4. TOBACO SMOKING
CESSATION
1. INSULINS
2. ORAL
HYPOGLYCAEMIC
AGENTS
3. INSULIN ANALOGUES

7. Conventional Insulins
 Short Acting
 Regular Insulin
 Semilente
 Intermediate Acting
 Lente
 Isophane (NPH)
 Long Acting
 Ultra Lente
 Protamine zinc Insulin (PZI)

8. Why We Need Newer Drugs ?
Due to limitations of conventional Insulins.
Limitations:
1. Delayed Onset of effect (1/2 -1 hrs) Post Prandial
Hyperglycemia
2. Prolonged time of peak action(5-8hrs) Late post Prandial
hyperglycemia
 Conventional insulins cause mismatch between need and
availability of bolus insulin and do not mimic the
physiological bolus insulin secretion

9. Why We Need Newer Drugs ?
Other limitations of conventional Insulins.
 Lipodystrophy- multidose forms
 Insulin allergy
 Antibody related insulin resistance
 Immune complex deposition
 Hypoglycemia due to prolonged
circulation of injected insulin

10. So…. What are the insulin analogues??
Molecules produced by genetic engineering wherein
the amino acids sequence in human insulin is changed
to alter its pharmacokinetics.
However, they bind to insulin receptors in the same way
as human insulin and produce similar effects
Designer Insulins
Democratic Insulins
Also
termed as

11. Merits of Insulin Analogues
1. Better mimicking of physiological insulin secretion
2. Better control of Post Prandial blood glucose levels
3. Better control of glucose levels in fasting, interdigestive
period
4. Lesser risk of hypoglycemia particularly nocturnal
hypoglycemia
5. They do not have to be injected half an hour before meals
6. Compliance is improved with long acting analogues as once
a day or weekly insulins
7. The need for snakes between meal may be reduced with short
acting analogues

12. Hence
 Insulin analogues overcome the limitations of
conventional insulins
Ultrashort acting analogues overcome
limitations of short acting insulins (regular)
Long acting analogues overcome the
limitations of long/intermediate acting insulins (NPH)

13. Classification

14. Ultrashort Analogues…
 Less propensity to form hexamers, hexamers formed dissociate
rapidly into monomers and rapidly absorbed, compare to
regular insulins.
Rapid onset of action 10 to 20 mins
Peak action 1 to 2 hrs
Duration of action 4 to 5 hrs
 Mimcs physiological bolus secretion.
 Can be taken just before or just after meals – allows adjustment
of insulins dose with size of meal
 Onset of action & peak action independent of dose/site of
injection / exercise (as of Regular Insulin)
Better control of
postprandial glucose
Decreased risk of late
postprandial
hypoglycemia

15. Lispro Vs Regular

17. Insulin Detemir
 New long acting analogue insulin
 Myristoulated insulin – addition of a saturated fatty acid to the
“e” amino group of LysB29
 PK
 SC inj  binds to albumin (via FA chain)
 Smoother time acton profile with no peak
 Glargine & determir absorption profiles are similar n
 Onset of action 1-2 hrs
 Duration > 24 hrs
 Given once or twice a day
 Approved for use during
pregnancy

18. Advantages Over NPH
 Hypoglycemia less frequent than NPH
 Less Nocturnal hypoglycemia when given basal bolus
therapy (aspart + detemir)
 Lesser or minimal wt gain compare to NPH

19. Insulin Degludec
 New long acting analogue insulin with plasma half life 25-40 hrs
 1 amino acid deleted ( threonine at position B300) & lysine is conjugated at
position B29 with hexdeconic acid .
 SC inj forms multihexamers which forms SC deposits thus slowly and
continuously absorbed into the bloodstream.
 Administered anytime of the day once or twice
 Unlike Glargine, it is effective at physiological PH
 Unlike Glargine it can be mixed with other forms of insulins

20. Insulin Icodec
 Newest ultra long acting analogue insulin with plasma half life
196 hrs (estimated)
 Designed to be able to cover full week basal insulin coverage
 Gradual, continuous release of Icodec from the albumin-bound
depots leads to prolonged action and it is expected that steady
state will occur after 3-4 weekly doses at which time the full
glucose lowering effect of the given Icodec dose will be
achieved
 Under phase-III clinical trail
 Novo Nordisk submitted a biologics license application
(BLA) in April 2023 to FDA

21. NPL and NPA
 “NPL” ( Neutral Protamine Lispro) and “NPA” ( Neutral
Protamine Aspart): Isophane complexes of Protamine with
insulin Lispro and insulin aspart.
 Intermediate acting insulin
 Determir vs NPL – Achieve similar glycaemic control, Weight
gain and nocturnal hypoglycemia rate were statistically higher
with NPL.
 NPL( 75/25) vs NPH (30/70) – Improved glycaemic profile ,
Hypoglycemia rat low.
 FDA has NPL/ Lispro (50/50, and 75/25) and NPA/aspart
(70/30) pre mixed formulations.

22. Oral Insulins
Hexyl-Insulin Monoconjugate 2 (HIM2)
 Modified regular insulin
 Single amphiphilic oligomer is covalently linked to the free
amino acid group on the Lys-B29 residue of recombinant human
insulin via amide bond.
 Under Phase II and III trials
Oral Insulin Spray Formulation ( oral-Lyn)
 Current status – approved by FDA for DM-I and II
 Contains human regular insulin
 Tasteless liquid aerosol mist formulation
 Absorbed through mucous membrane lining of the mouth and begins
lowering of glucose levels in 5 minutes – rapid action
 Advantages- higher patient compliance, rapid hepatic insulinization, and
avoidance of peripheral hyperinsulinemia.
 Efficacy; Dose related absorption, faster onset and short duration of action
 Safety: Well tolerated, transient mild dizziness during dosing

23. Inhalational Insulin
 Inhalable insulin is a powdered form of recombinant human insulins, deliver
with a nebulizer into the lungs where it is absorbed.
 PK
 Depend hugely on properties of device, breathing maneuver & local pathology
and physiology
 Tmax- 7-90 mins
Advantages Disadvantages
•Convenience: Inhaled insulin is easy
to use and requires no needles or
syringes.
•Faster Acting: it passes from your
lungs to your bloodstream in less than a
minute, and it can start reducing blood
sugar levels within about 12 minutes”.
Local Alveolar membrane
morphological changes : Insulin are
Growth Factors
Cant be Used In: Smokers, Severe lung
Diseases.
Cost : More expensive than inject able

24. Inhalational Insulin
 Exubera – 1st product (2006) discontinued – due to
unpredictable absorption and cost
 Afrezza – Only FDA approved inhaled insulin (2014)
 Contains rapid acting human insulin.
EXUBERA AFREZZA

25. Newer Insulin Delivery System
INSULIN PEN
INSULIN PUMPS

26. Continuous Subcutaneous Insulin Infusion
 Portable infusion devices with SC cannula
 Only rapid or regular insulins are used
 Programmed to deliver at low basal rates (1iu/hr) and premeal bolus (4-10
times of the basal rate
 No definite advantage over multidose SC inj
Indications Limitations
1. Cost
2. Pump failure
3. Scar
4. Allergic
reactions
1. Inadequate
glycaemic control
despite MDI
Therapy
2. Nocturnal
hypoglycemia
3. Dawn phenomenon
4. Pregnancy
5. Inconvenience of
MDI
6. Unpredictable
hypoglycemia

27. Potential Intervention
Pancreatic and Islets Cell Transplantation:
Whole organ Transplantation:
 In DM-I + End stage diabetic Nephropathy
 Risk of graft rejection
 Side effects of immunosuppressant
Artificial Pancreas : Artificial Pancreas also approved by
FDA in 2016
Islets Cell Transplantation- Promising
 Rx option for DM-I
 Donner β-cells injected into host portal vein

28. Potential Intervention
Stem Cells Technology
 Stem cells : totipotent  β cells
 Useful in DM-I
 Eg
 Mesenchymal Stem Cells
 Hematopoietic stem cells
 Embryonic stem cells
Limitation:
 absence of reliable methods
 Immunological rejection
 Uncontrolled proliferation

29. TYPE-II DM THERAPY

30. Conventional Oral Hypoglycemic
Drugs
 3 categories
1. Insulin Secretagogues – stimulate insulin secretion
2. Insulin sensitizers – sensitize tissues ( liver & adipose
tissues) to the action of insulin
3. Affect absorption of glucose

31. Insulin Secretagogues
Sulfonylureas
Primary stimulate insulin release by binding to sulfonyl receptor
1st gen- Tolbutamide, Chlorpromode,
2nd gen- Glyburide, Glipizide, Gliclazide
3rd gen- Glimperide
Meglitinide Analogues
Repaglinide, Mitiglinide
D-Phenylalanine Derivative
Nateglinide
`

32. Insulin Sensitizers
 Biguanides
Metformin, phenformin
 Thiazolidinediones (PPAR)
Pioglitazone, Rosiglitazone.
Drugs Affecting Glucose Absorption
Competitively inhibit the intestinal α-glucosidase enzymes
Acarbose, Voglibose, Miglitol

33. ``

34. Why We Need Newer Drugs ?
Limitations of Existing Drugs
Extensive Side Effects
 Weight gain, abdominal pain
 Hypoglycemia
 Bloating, Nausea, Vit def…
Contraindications
 Renal Disease, Hepatic Disease,
 Severe infections, CHF…

35. Newer Drugs In DM-II
 Newer Insulins
 Incretin-based therapy:
 GLP-1 Analogues : Exenatide, Liraglutide
 DPP-4 Inhibitors: Sitagliptin, Vidagliptin
 Amylin Analogue:
 Pramlintide
 SGLT-2 Inhibitors:
 Dapagliflozin, Empagliflozin
 Dual PPAR Agonists:
 Aleglitazar, Muraglitazar
 Others:
 Bromocriptine

36. Incretins
Incretins:
The Incretin effect
•GIT hormones produced
in response to incoming
nutrients that contribute to
glucose homeostasis
•Two Hormones
•Gastric Inhibitory
polypeptide (GIP)
•Glucagon-like peptide-1
(GLP-1)

37. GLP-1
30 amino acid peptide secreted by L cells in ileum & Colon.
GLP-1 receptors seen in islets and CNS
Effects
 Increase glucose dependent insulin secretion
 Inhibit glucagon secretion
 Increase satiety
 Slow gastric emptying
Problem with GLP-1
 GLP-1 metabolized by DPP-4 rapidly
 Very short plasma half life 1-2 mins
Solution
 Long acting GLP-1: Exenatide, semaglutide
 DPP-4-Inhibitors: Gliptins

38. GLP-1 Analogue – Exenatide Byetta &
Exenatide LAR
 Naturally occurring peptide from the saliva of the Gila monster
 PK:
 Pre filled 5-10mcg Pens (Exenatide Byetta)
 2mg powder (Exenatide LAR)
 Resistant to DPP-4 inactivation
 Plasma half life 2-2.4 hrs
 Duration of action 24-1 week
Therapeutic dose: 5-10 mcg twice daily before meals or 2mg weekly
 Adverse effects:
 nausea, vomiting, weight loss, hemorrhagic pancreatitis
 Contraindications:
 ESRD, Safety in pregnancy not studied
 Approved by FDA (Apr-2005)
as adjunctive therapy

39. GLP-1 Analogue – Liraglutide
 Approved by the FDA-2015, adjunctive therapy
 PK
 Longer plasma half life (12 hrs) SC once daily
 0.6 mg SC OD for 1 week initially then
increase 1.2 mcg OD and up to 1.8 mg OD
 Advantages
 Injection site and time of administration can be changed without dose
adjustment & independent of meals
 Good glycaemic control & wt loss
 Approved for OBESITY by the FDA-2014
 Side effects
 Nausea, Diarrhea, Vomiting , hypoglycemia with other drugs
 Thyroid cancer, MEN syndrome

40. GLP-1 Analogue – Semaglutide
 Oral and Injectable both forms available
 Approved by the FDA-Dec. 23-2022/Jan-23 as adjunct therapy.
 Synthetic analogue of GLP-1
 PK
 Longer plasma half life (1 week) SC once weekly
 Prefilled pens 0.25 mg weekly initially then
increase 0.5 mg, max 1mg
 Oral form 3mg PO OD for month initially then increase up to 7mg.
 Advantages
 Reducing the risk of heart disease, heart attack, and stoke.
 Improved mood.
 Improved sleep.
 Once weekly- more convenient
 Side effects
 Gastrointestinal issues, such as
diarrhea constipation and gassiness.
 Headache.
 Dizziness.

41. DPP-4 Inhibitors- Sitagliptin
Approved by FDA as monotherapy and
Combination with Metformin or TZD
PK
 Oral, plasma half life 8-14 hrs, hepatic
 Clearance, Dose- 100mg once daily
Advantages
 Better diabetes control
 Lower HbA1c by between 0.5 and 2%.
 Does not cause weight gain.
 No significant hypoglycemia
Side effects
 Headache, Nasopharigitis, peripheral odema,osteoarthritis
Contraindication
 ESRD, CHF , Sitagliptin hypersensitivity

42. Other DPP-4 Inhibitors
 Vildagliptin
 Less protein bound, less T ½ than sitagliptin
 25-100mg twice a day
 FDA approval pending
 Saxagliptin
 2.5 mg once a day
 Approved by FDA-2010 as monotherapy
 Discontinued in Marc -2022 due to cardiac
complication
 Alogliptin
 FDA approved 2013, risk of HF
 Linagliptin-
 FDA approved 2011, hypoglycemia with combination therapy


43. SGLT-2 inhibitors ( Sodium Glucose
Transporters-2 Inhibitors )
 80-90% of filtered renal glucose is reabsorbed by kidneys via SGLT1,2
 SGLT2 inhibitors inhibit the coupled reabsorption of sodium and glucose
from the proximal tubules, thereby increasing renal glucose and sodium
excretion
Normal conditions
Glucose reabsorbed by SGLT1-2
No glucose in urine
SGLT2i Mech of Action
Glucose reabsorption blocked
glucose excreted in urine
Canagliflozin
Empagliflozin
Dapagliflozin
Ertugliflozin

44. SGLT-2 Inhibitors
 PK of SGLT2 inhibitors
 Excellent oral bioavailability
 Long half-life (t ½) allowing once-daily administration
 Low accumulation index, no active metabolites and a limited renal excretion
 Current Status
 Canagliflozin, Dapagliflozin, Empagliflozin, and Ertugliflozin -2018 for DM-2
 April 30, 2021- FDA approved Dapagliflozin for kidney and CV reduce
outcomes
Advantages Disadvantages
•Weight loss
•No hypoglycemia
•Decrease heart failure
•Decrease renal dysfunction
•Decrease blood pressure
•Urinary tract infections
•Increased risk of DKA
•Osteoporosis
•Increased risk of amputation
(empa)
•Genital mycotic infections
•Postural hypotension

45. SGLT-2 Inhibitors

46. Amylin Mimetic
Amylin
 Glucoregulatory polypeptide
 Act centrally  Induce satiety
 suppress pancreatic glucagon secretion,
 slow gastric emptying
 Absent in DM-I and decrease in DM-II
 Analogues – approved for both type-1
and 2 DM as an adjunct to meal time insulin
i.e. Pramlintide
Cagrilintide- under trial Phase-III

47. Pramlintide
 Synthetic analogue of Amylin
 Act via amylin receptors in the brain
 FDA approved 2005
 PK
 SC inj,T ½ 50 min
 Metabolized in the kidney
 Therapeutic dose :
 DM-2  60-120 mcg
 DM-1  15-60 mcg
 Side effects  Nausea , hypoglycemia
 Pregnancy C category drug

48. Dual PPAR Agonists
 Dual PPAR agonists are new
Agents that increase insulin
Sensitivity and simultaneously
Lower bad-lipid hence prevent
Diabetic CV complications
Current status
Saroglitazar - approved in 2013 for
Diabetic dyslipidemia
Approved for NASH-2020
Muraglitazar - discontinued due to
MI,Stroke ,TIA and CHF incidence
Aleglitazar- phase –II

49. Bromocriptine
 Centrally acting D2 Receptor agonist
 FDA Approved -2009 for DM-II
 Improve insulin sensitivity & glycaemic control in DM-II
 Mono or Adjunct Therapy  dec HbA1c by 0.5 – 1.2%
 PK
 Oral, extensive first pass metabolism in the liver
 Plasma half life 2-8 hrs
 0.8mg daily max 4.8 mg taken with food

50. New Combinations
Sotagliflozin – SGLT-I/II Inhibtors.
 Added benefits in patients with DM+ HF
Retratutide - GIP/GLP-1/Glucagon Receptor Agonist
 Triple GGG agonist
 More Potent
 Once weekly injection
 CagriSema –Semaglutide + Cagrilintide
 Once weekly injection
 IcoSema – Icodec + Semaglutide
 Once weekly injection

51. New Potential Therapies
 Glucokinase Activators – Piragliain ( phase –II)

52. New Potential Therapies
PDEIs
 Beta-cells express several PDEs  degrade cAMP  dec insulin
release
 Transient inhibition of PDEs  Possible intervention.
 e.i Sildenafil, Vardenafil
β-3 Agonists
 Shown to stimulate insulin release & improve glycaemic control
in obese diabetic rodents
 e.i Solabegron
11B Hydroxysteroid Dehydrogenase Type-1 inhibitors
 Glucocorticoid antagonists
 Glucocorticoid  Truncal Obesity, Insulin Resistance,
hyperglycemia
 Potential Rx  Osteoporosis , Metabolic Syndrome

53. New Potential Therapies
Anti-CD3 Monoclonal Ab – Otelixizumab, Teplizumab
 a humanized anti- CD3 monoclonal ab
 Currently being evaluated in patient with DM-I
 Blocks function of effectors T cells mistakenly destroying
B-cells
 Phase –III trials

54. REFERENCES
1. The Pharmacological basis of therapeutics –Goodman &
Gilman
2. Rang & Dale’s pharmacology
3. Woldu MA, Lenjisa JL, Satessa GD (2014) Recent
advancements of in Diabetes Pharmacotherapy.Biochem
Pharmacol (Los Angel) 2014;143(3)
4. Muhammad AG,Kotwal S.Recent advances in Management of
Diabetes Mellitus. JIMSA.2012;23(30)171-175
5. Tiwari P.Recent Trends in the Therapeutic Approaches for
Diabetes Management : A Comprehensive Update . Journal of
Diabetes Research.2015
6. Aschner P.Recent advances in understanding /managing type2
diabetes mellitus.F1000 Research. 2017;6;F1000 Faculty Rev-
1922

55. THANK YOU