diabetes mellitus in detail

1. RECENT ADVANCES IN
MANAGEMENT OF
DIABETES MELLITUS
Dr.Shaila Banu
Final year Post Graduate
Dpt of Pharmacology
GMC , ATP

2. Learning Objectives
● Define Diabetes mellitus
● Enumerate Goals
● Outline Therapy available for Type 1 & Type 2
● Compare & contrast conventional insulins &
newer analogues
● Classify Oral antidiabetic drugs

3. DIABETES
MELLITUS
• Syndrome : metabolic, vascular and neuropathic components – interrelated
• Metabolic disorder: hyperglycemia (fasting plasma glucose >126 mg/dl and/or >200
mg/dl 2 hours after 75 g of oral glucose) due to defects in insulin secretion , insulin
action or both
• Coronary artery disease = diabetes
• Metabolic syndrome: Type 2 Diabetes Mellitus, Central obesity, Hypertension,
Hyperlipidemia [hypertriglyceridemia , reduced HDL]

4. History
●Diabetes : syphon (to pass through)
Appolonius of Memphis.
“Pissing evil”(17 th century)
●Mellitus: Honeyed
Thomas wills

8. TYPES
● TYPE I : Absolute insulin deficiency / Autoimmune disease
● TYPE 2 : Insulin resistance , inadequate insulin secretory response
● TYPE 3 : β cell, insulin action , exocrine pancreas, drugs, infection
● GESTA
TIONAL DIABETES

9. Therapy of diabetes : Comprehensive Diabetic care
● the symptoms related to hyperglycemia (fatigue, polyuria, weight loss)
● To prevent or reduce the acute metabolic decompensation and chronic end-organ complications.
Components of Comprehensive Diabetic Care
Management of diabetes
Glycemic control
Diet /life style exercise
/drugs
Treat associated conditions
Dyslipidemia
Hypertension
Obesity
Screen for / manage
complications
Retinopathy
Neuropathy
Nephropathy
CVS Disease
Others

10. Treatment Goals
INDEX GOAL
1. Hb A1C < 7.0 %
2. Pre-prandial plasma glucose 90–130 mg/dL
3. Peak post prandial plasma glucose <180 mg/dL
4. Blood pressure <130/80 mm of hg
5. LDL-C <100 mg/dL
6. HDL-C >40 mg/dL
7. Triglycerides <150 mg/dL
●
●
●
● To maintain normoglycemia
to normalize Hb A1c
To prevent complications
To improve QOL

11. Modalities of treatment

12. Insulin
No single event in the history of medicine has changed the lives of so
many people ,so suddenly – Stephen Hume

13. Insulin
● Evolution of insulin : Exogenous insulin available for more than 90 yrs
● Top medical breakthroughs
● Most powerful diabetic agent
● Limited only by hypoglycemia

14. Clinical use
• Meal time insulin: rapid
& short acting
•Basal insulin : IA& LA
Based on species of origin
Human
Porcine
Bovine
Classify ??

15. TIME COURSE OF ACTION
ONSET PEAK DOA
REGULAR 30-45 m 2 -4 h 5-8 h
LISPRO 15 m 1-1.5 h 2-5 h
ASPART 15 m 1 h 3-5 h
GLULISINE 15 m 1-1.5 h 1-2 h
NPH 1- 2 h 6-12 h 18-24 h
ULTRALENTE 4 -6 h 16-18 h 20-36 h
GLARGINE 2 -5 h FLAT 18- 24
DETEMIR 1- 2 h FLAT 6-24

16. Traditional Insulin preparations
● Short Acting : Insulin Regular
● Intermediate Acting : Isophane Insulin Suspension ( NPH) ,
Insulin Zinc Suspension ( Lente)
● Slow Acting : Extended Insulin Zinc Suspension ( Ultralente)

17. Ideal insulin
● Should match the physiological insulin secretion
● 50% in basal conditions
● Remainder in response to meals
● Secretion : Pulsatile
● Biphasic
• Acute insulin response : rapid 1st phase 5-10 mins / suppress HGO /

18. Traditional insulins
●Traditional insulins : Solutions of regular insulin, dissolved in a
buffer at neutral pH
●Forms a hexamer when stored in the
presence of Zn ions ( self aggregation )
● S/C Injection : dissociate into dimers
& then into monomers / time : 30 - 45 mins

19. Limitations of regular insulins
●Regular insulin : Delayed onset [1/2 hr -1 hr ] POST PRANDIAL
HYPERGLYCEMIA
● Peak : 2-3 hrs
● Duaration of action : 5-8 hrs
HYPOGLYCEMIA
LATE POST PRANDIAL
has to be administered 30-45 mins before meals : dose cannot be adjusted
according to size of meals
● Absorption varies with injection site and exercise

20. Insulin analogs
Rapid acting Lispro
Aspart
Glulisine
Long acting Glargine
Detemir
Ultra long acting Degludec
Inhaled insulin Afrezza
Insulin combinations Mixture : short acting (25%–50%) and long
acting (50%–75%)

21. Designer insulins
Modified recombinant insulins
●Regular insulin : altered through an amino
acid / substitution / addition / deletion
●Rearrangement impart a particular
physicochemical /PK property
●Proline and lysine at b 28 and b 29

23. Rapid acting analogues
●Rapid onset : 5 - 15 mins – better postprandial control
●PEAK : 1-2 hrs, DURATION : 4-5 hrs - decreased risk
of late postprandial hypoglycemia
●Mimics physiology : less propensity to cause hexamers ,
Dissociate rapidly / associate with less cohesive force
- Physical & chemical stability - faster absorption .

24. MODIFIED LONG ACTING
ANALOGUES
● Substitution of Glycine for Asparagine at A 21 / Provides Stability + 2 Arginines
at B Chain
● Addition of Fatty Acid to the Amino Group Of Lys B 29 / Myristoylated Insulin

25. DETEMIR
● New long-acting insulin analogue
threonine in B30 replaced by Myrsitic acid
● Addition of C-14 fatty acid chain to the amino group of LYS B 29
/ Myristoylated insulin
●Increase self aggregation in SC tissue & reversible binding to
albumin
● Detemir : has the Most reproducible effect of the IA& LA insulins

26. GLARGINE
pH 4.0 SC Tissue
pH 7.4
MICRO-PRECIPITATION
MAY CAUSE VARIABILITY IN ABSORPTION,
HENCE, IN ACTION
DETEMIR
PH 7.4
SC Tissue
pH 7.4
Binding to Albumin
No Precipitation
MORE PREDICTABLE IN ABSORPTION,
HENCE IN ACTION
MECHANISM

27. Insulin Degludec
Newest ULTRAlong acting basal insulin,
● Modified insulin with one amino acid deleted (threonine at position
B30) and is conjugated to hexadecanedioic acid via γ-l-glutamyl
spacer at the amino acid lysine at position B29.
● Active at a physiologic pH, forms multihexamers complexes that slow
absorption on subcutaneous injection ; Also binds well to albumin
● These two characteristics contribute to the prolonged effect of degludec
(>24 h at steady state). T 1 ⁄ 2- (25-40 hr) /100U & 200U/ML[PEN]
● Unlike Glargine it is effective at physiological pH
● less severe hypoglycemia than glargine.
● Unlike Glargine & Detemir, it can be mixed with other insulins

28. Glargine, Degludec, and Detemir have minimal peak activity at steady-
state
A major concern about all newer insulin analogues is their
altered mitogenic properties and resultant risk of carcinogenicity
on long term use.

29. Inhaled insulin
● Recently introduced Afrezza Meal time insulin
● FDA approval in both type 1 and type 2 diabetes [ Add on therapy for
uncontrolled type 2].
● Monomeric formulation
● Decreases the risk of hypoglycemia and weight gain
● Kinetics similar to ultra short acting insulins / Alternative to ultra SA insulins
[ More rapid onset and shorter duration than injected insulin analogues ] /
● Used in combination with a long-acting insulin in type 1 DM.
● It is not widely used / Expensive
● Adverse events include cough and throat irritation. Not to be used in individuals
who smokers, Asthma ,COPD .

30. INHALED INSULINS

31. New for Type 1 DM
● Faster acting aspart
[Fiasp] has added

32. • Oral insulin [Oramed’s] is currently in a pivotal clinical study going
through FDAregulatory channels and is considered a game-changer .
An orally ingestible insulin capsule (ORMD-0801). [Protein
oral delivery technology (POD) ].

33. New for Type 1 DM
Otelixizumab
Teplizumab
Intravenous humanised

35. ● Nasal spray
● Patches
● Artificial pancreas
● Transplant beta cells
●Personalised medicine [grouping of diseases, targeted therapy ,
developments in genetics and big data ]

36. INSULIN PATCH

38. TRANSPLAT BETA CELLS

39. Mixtures : 70 % NPH
50% NPH ,
, 30% REG
50% REG
Lispro
75% Lispro Protamine , 25%

40. Non-Insulin Antidiabetic Drugs

41. ORAL :
1. Insulin
secretagogues :

42. KATP Channel Modulators:
Sulfonylureas
1. Tolbutamide, Tolazamide, And
Chlorpropamide : Rarely Used Now
2.Glipenclamide,Glipizide,Gliclazide,Glimepiride are used
now

44. KATP Channel Modulators: Nonsulfonylureas
Repaglinide. Oral insulin secretagogue of the Meglitinide class, stimulates insulin release
by closing KATP channels
● Metabolized by the liver (CYP3A4) to inactive derivatives, ~10% is metabolized by the
kidney
● Hypoglycemia , weight gain
Nateglinide : orally effective insulin secretagogue, block KATP channels
● Rapid but less-sustained secretion of insulin
● Effective in reducing postprandial glycemic elevations in patients with type 2 diabetes.
● It is metabolized primarily by hepatic CYPs (2C9, 70%; 3A4, 30%) and should be used
cautiously in patients with hepatic insufficiency.
● Hypoglycaemia , weight gain

45. Thiazolidinediones
Ligands for the PPAR γ receptor : Rosiglitazone And Pioglitazone
MOA: Activate PPAR γ receptors- adipocyte differentiation, increased tissue
sensitivity to insulin [ liver, adipose tissue, and skeletal muscle]
● Pioglitazone reduces plasma triglycerides by 10%–15%, raises HDLcholesterol
levels, and increases LDL cholesterol.
ADR: Weight gain and Edema
● Increased incidence of heart failure of up to 2-fold [plasma volume expansion]
● Rosiglitazone increased the risk of cardiovascular events (myocardial
infarction, stroke). FDA has lifted the previous ban
● Increased risk of bone fracture in women
● Affect transaminases, liver function monitored

46. GLP-1–Based
Agents
●Incretins [GI hormones
released after meals and
stimulate insulin secretion

49. Liraglutide
●The liraglutide peptide is a long-acting, DPP-4-resistant form of
GLP-
1, but with a Lys34Arg substitution and addition of an α-glutamic
acid spacer coupled to a C16 fatty acyl group at Lys26. .
●The pharmacodynamic profile of liraglutide mimics GLP-1
and exenatide.
●Improvement in glycemic control and weight loss
●Adjunctive therapy in patients not achieving glycemic control with

50. Albiglutide : Fusion protein , two sequential GLP-1 moieties linked to human albumin;
The GLP-1 sequences are modified to prevent DPP-4 cleavage.
Dulaglutide : Fusion protein consisting of two linked molecules that have a modified
version of GLP-1 linked to the fc portion of a human immunoglobulin;
Lixisenatide : A slightly longer form of exenatide
GLP-1RA s : Pharmacodynamics are comparable to each other & can be used with
other oral antidiabetic agents and basal insulin.
● While all of the GLP-1RAS have demonstrated efficacy as monotherapy, none is
considered as a first- line agent.
● The differences in efficacy are small relative to the overall effect of the drugs, and
definitive differences await more comprehensive studies.

51. Adverse Effects : Nausea and vomiting [neural activation of specific CNS neurons].
● GI side effects.
● Hypoglycemia associated with GLP-1 agonist treatment is rare, but the combination of
GLP-1 agonist with sulfonylurea drugs causes an increased rate of hypoglycemia
compared to sulfonylurea treatment alone.
● Because of the reliance on renal clearance, exenatide, and probably lixisenatide, should not be
given to persons with
moderate-to-severe renal failure (creatinine clearance < 30 mL/min).
● possible association of exenatide treatment with pancreatitis;
● The GLP-1 receptor is expressed by thyroid C cells. Although there is not an established clinical
association with
medullary carcinoma of the thyroid, GLP-1 agonists should not be given to these patients.

52. DPP-4
Inhibitors
● Dipeptidyl peptidase IV : serine protease .
● inactivation of GLP-1 and GIP.
●Sitagliptin, Saxagliptin, Linagliptin,
alogliptin & Vildagliptin

54. • Mechanism of Action: Alogliptin, linagliptin, and sitagliptin are competitive
inhibitors of DPP-4; vildagliptin and saxagliptin bind the enzyme covalently.
• 2-fold elevation of active GIP and GLP-1 and is associated with increased
insulin secretion, reduced glucagon levels, and improvements in both fasting
and postprandial hyperglycemia.
• No direct effects on insulin sensitivity, gastric motility, or satiety& No
effect body weight.
• DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduce

55. ● SGLT2 is a Na+-glucose cotransporter : proximal
portion of the renal tubule.
●SGLT 2 is a high-affinity, low- capacity transporter that
moves glucose against a concentration gradient from the
tubular lumen using energy generated from Na+ flux
through the epithelial cells.
● Renal retention of glucose is nearly complete in nondiabetic persons,
Na+Glucose Transporter 2 Inhibitors

57. Pramlintide
● A Synthetic form of amylin with several amino acid modifications to improve
bioavailability
● acts through the amylin receptor in specific regions of the hindbrain. Activation of
the amylin receptor reduces glucagon secretion, delays gastric emptying, and fosters a
feeling of satiety.
● Subcutaneous injection prior to meals.
Adverse Effects: nausea and hypoglycemia.
● Prandial insulin doses be reduced 30%–50% at the time of pramlintide initiation and then
retitrated.
● Contraindicated in patients with gastroparesis or other disorders of motility.
Pramlintide is a pregnancy category C drug.
● Therapeutic Uses: Pramlintide is approved for treatment of Type 1 and 2 diabetes
as an adjunct in patients who take insulin with meals.

59. Bile Acid–Binding Resins
Colesevelam : Approved for the treatment of type 2 diabetes .
Mechanism of Action. Bile acid metabolism is abnormal in patients with type 2 diabetes
.Reduce intestinal glucose absorption, also act as signaling molecules through nuclear
receptors, some of which may act as glucose sensors.
● Colesevelam is provided as a powder for oral solution and as 625-mg tablets;
● dyspepsia, abdominal pain, and nausea affecting up to 10% of treated patients.
● increase plasma triglycerides
● Pregnancy category B drug & has no contraindications in patients with renal or liver
disease.
Therapeutic Uses. Treatment of hypercholesterolemia and may be used for treatment of
type 2 diabetes as an adjunct to diet and exercise. In clinical trials, colesevelam reduced
A1c by 0.5% when added to metformin, sulfonylurea, or insulin treatment in type 2
diabetic patients.

60. Bromocriptine
● Approved for the treatment of type 2 diabetes
●Bromocriptine is an established treatment of parkinson
disease and hyperprolactinemia
●Effects on blood glucose are modest and
may reflect an action in the CNS.
●The dose range for bromocriptine is 1.6 to 4.8 mg,
taken with food in the morning within 3 h of awakening.
● Side effects include nausea, fatigue, dizziness,

62. COMBINATION ANTIDIABETICS
1. Thiazolidinedione + Biguanide
DPP-4 inhibitors + Biguanide
SGLT2 inhibitor + Biguanide
DPP-4 inhibitor + SGLT2 inhibitor
GLP-1 agonist + Degludec insulin
GLP-1 agonist + Glargine insulin
2.
3.
4.
5.
6.

63. 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 [Non alcoholic steatohepatitis] in US ( june,2016)
●Diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by
statin therapy

64. OTHERS
● 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: Abandoned due to CAD
Tesaglitazar: no longer studied, discontinued: renal toxicity

65. Newer potential targets in DM

66. IRTK (Insulin receptor tyrosine kinase and insulin mimetics

69. New potential targets of carbohydrate metabolism

73. New potential targets of lipid metabolism

76. New drugs for complications & vaccines
● Arxxant (also known as ruboxistaurin) has been submitted to the FDA
(Food and Drug Administration) for approval in treating diabetic eye
disease . Failed
● Diabetes vaccines
Recombinant Human Glutamic Acid Decarboxylase-65 (rhGAD65)
Phase 3 , Antibodies against GAD - 80–90% type 1 DM
To slow or prevent autoimmune destruction of pancreatic islet cells
amongst recent-onset type 1 diabetes mellitus ,subcutaneously -
disappointing results.
In 2013, a new trial in combination with vitamin D and the anti-inflammatory
drug Ibuprofen

77. Emerging Therapies for Diabetes : what does our
Goodman.G say ?
● Immunomodulatory approaches : To prevent or block the autoimmune process central to type 1
diabetes,
● Activators of GK, glucagon antagonists, and inhibitors of 11β-hydroxysteroid dehydrogenase
[inactive cortisone to active cortisol]are being investigated as novel therapies for type 2 diabetes
● Advances in protein chemistry have allowed the development of peptides that activate more than
one receptor to improve glucose regulation.
● Most of these incorporate GLP-1 receptor agonism with the capacity to activate receptors for
glucagon, GIP, or gastrin. These compounds have been potent in pre-clinical models and are now
in human trials. Some drugs developed for type 2 diabetes are being tested as adjunctive therapy
for type 1 diabetes

78. ● Insulin Pumps: CSII
●Dexcom G5 Mobile Continuous Glucose Monitoring System, Approved
December 20, 2016 [Sensor, transmitter , compatible smart phone,or a
smart watch ]
●FreeStyle Libre Flash Glucose Monitoring System , Approved
September 27, 2017 [sensor plus mobile reader ]
● InPen system[ smart insulin pen] : FDAapproved in 2017 for apple iOS
and for android version in 2018 , is the first reusable insulin injector pen
Newer Insulin delivery systems & glucose monitors

80. Insulin & Pregnancy category [ Not used after 2015 ]
INSULIN PREGNANCY
CATEGORY
Regular B[U-100,500] LOW RISK
Aspart B LOW RISK
Lispro B [U- 100,200] LOW RISK
Glulisine C NO HUMAN DATA
NPH B LOW RISK
Glargine NO HUMAN DATA [Prev C] NO WELL
CONTROLLED
CLINICAL STUDIES
Detemir B LOW RISK
Degludec C [U-100 ,200] NO HUMAN DATA
Inhaled insulin C NO HUMAN DATA

83. To summarise
Diabetes is a metabolic disorder
Discovery of insulin : major breakthrough
Progressed from animal insulins to recombinant insulins - insulin analogs -
inhaled insulins
Not far off from oral insulins & regrowth of beta cells
In Type 2
Insulin secretagogues , sensitizers ,newer GLP 1 analogs ,DPP 4 INHIBITORS
, SGLT 1 inhibitors, pramlintide ,colesevelam, bromocriptine and the other

84. REFERENCES
1. The Pharmacological Basis of Therapeutics – Goodman &
Gilman
2. Rang & Dales Pharmacology
3. Essentials of Medical Pharmacology – KD tripathi
4. Internet - Journals

85. NOTHING LIKE DIET ,EXERCISE &
ADHERENCE TO
LIFE STYLE CHANGES
thank you