1) Diabetes is a chronic disease characterized by high blood glucose levels resulting from defects in insulin production, insulin action, or both. The main types are type 1 diabetes and type 2 diabetes. 2) Newer drug classes for diabetes treatment include GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, amylin mimetics, and newer insulin formulations. 3) Lifestyle modifications including diet, exercise, and weight control remain fundamental to diabetes management. Multiple drug classes are often combined to achieve optimal blood glucose control.

1. Newer Management in Diabetes
Dr. Ankit Gupta
PG-2
Dept. Of General Medicine
SRMSIMS

2. Introduction
Apollonius of Memphis coined the name "diabetes”
meaning "to go through" or siphon. He understood that the
disease drained more fluid than a person could consume.
Gradually the Latin word for honey, "mellitus," was added
to diabetes because it made the urine sweet.

3. Introduction
Diabetes mellitus is a chronic disorder characterized by
fasting and/or postprandial hyperglycemia with plasma
glucose levels that are above defined oral glucose
tolerance testing or random blood glucose measurements,
as defined by established criteria.

4. ADA Diagnostic criteria 2013
Indicator
American
(mg/dL)
SI
(mmo/L)
Glucose –
Fasting
Normal 65 - 99 3.6 – 5.5
DM > 126 > 7.0
Random (with
symptoms)
DM > 200 > 11.1
GTT (2 hr.) DM > 200 > 11.1
HbA1c DM > 6.5%

5. IDF Estimation
 366 million : 2011
 552 million : 2030
95 % T2DM
ICMR – INDIAB Study
61.3 million - 2011
9,83,000 - Deaths

6. Classification
1. T1DM
2. T2DM
3. Other specific
4. Gestational Diabetes
 Genetic defect in beta cell function : MODY
 Genetic defect in insulin action
 Pancreatic diseases
 Endocrinopathies
 Drug induced
 Infections
 Genetic syndromes

7. Pathogenesis
Beta-cell
workload
Beta-cell
response
DEMAND SUPPLY

8. Pathogenesis
Beta-cell
workload
Beta-cell
response
 Environmental Factors
 ↓ Physical activity
 chronic overnutrition
 Micronutrients imbalance
 fetal & neonatal programming
/epigenetics effects
 ↓ Insulin secretion in
response to elevated
glucose

9. Pathogenesis
Insulin
Resistance
Incretin
“Defect”
Relative Insulin
Deficiency
Hyperglycemia
Type 2 Diabetes
Incretin effect accounts for up to 70% of the insulin response to oral glucose intake

10. Classification of Hypoglycemics
Karela
Bel patti
Iso gel
Fanigreek seeds
Triphala powder
Agents ↓ Gastric emptyingDrugs ↓ Gastric emptying
Incretin mimmetics
Amylin agonist
Drugs improving Insulin secretions
Sulfonylureas 2nd generation
Maglitinides
DPP-4 Inhibitors
Incretin mimmetics
Drugs improving Insulin sensitivity
TZD
Dopamine-2 agonist
PPAR gamma activators
Drugs ↓ Hepatic Glucagon
Biguanides
PPAR gama agonist
Colesevelam
Amylin mimmetics
DPP-4 Inhibitors
GLP-1 receptor agonist

11. NEWER HEPATIC TARGETS FOR GLYCEMIC
CONTROL IN DIABETES
Glucagon Receptor Antagonist
Glucose 6-phosphatase Inhibitors (Peroxovanadium)
Fructose 1,6-bisphosphatase Inhibitors
Glycogen phosphorylase Inhibitors
Glucokinase Activators (Piragliatin)

12. Newer classes of Insulins
1996 2000 2004 2005 2006

13. Insulins

14. Insulin therapy regimens

15. Newer Classes of Antidiabetes Therapies
2005 2006 2007 20102008 2009 2012 2013

16. Incretins mimmetics
GLP-1 secreted upon
the ingestion of food

17. GLP 1 Analogues
 Exenatide-4
 Liraglutide
 Exenatide XR
 Taspoglutide
 Albiglutide
 Lixisenatide
TRIAL
Exenatide-4
 Dose : Min 10 mcg daily
Max 20 mcg daily
 Adverse effects : Diarrhea, hypoglycemia, nausea,
vomiting
 C/I : Gastroparesis, pancreatitis, severe renal diseases
Liraglutide
 Dose : 0.6 mg/day ↑ gradually in 1or 2 wks to 1.2 mg/day
 C/I : Thyroid nodule or thyroid malignancy AND
Pancreatitis
Exenatide XR
Dose : 2 mg once a week

18. Mechanism of action
DPP-4
DPP-4 inhibitors
Block the action of DPP-4DPP-4 rapidly breaks down GLP-1 and GIP
T1/2=1to2min
GLP-1 and GIP
DPP- 4 Inhibitors

19. DPP- 4 Inhibitors
 Sitagliptin
 Vildagliptin
 Saxagliptin
 Linagliptin

20. • Increases fasting and postprandial GLP-1 levels
• Reduces fasting and postprandial glycemia
• Improves ß-cell function
– Increases insulin secretion, reduces proinsulin/insulin ratio
– Increases beta-cell mass
• Inhibits glucagon secretion
– Reduces hepatic glucose production
• Increases insulin sensitivity
• Reduces postprandial lipidemia
• No effect on gastric emptying or body weight
• Reduces HbA1c by ~1%
• Is safe and tolerable in short term
DPP 4 Inhibitors

21. DPP 4 Inhibitors
Sitagliptin
 Prolong and Increase the action of Incretin hormones
 Indicated with diet and exercise
 can be used as :
- Monotherapy
- Initial combination with Metformin
- Combination as dual or triple therapy
Dose : 100mg once daily
If CR 30-50 mL/min/1.73m² : 50mg daily
If CR <30 mL/min/1.73m² : 25mg daily

22. DPP 4 Inhibitors
Vildagliptin
 Dosage : 50mg twice a day
 Not recommended in Renal failure
 It reduces postprandial lipidemia
 Favorable effect on BP
Saxagliptin
Dose : 2.5 or 5 mg once daily
Linagliptin
Dose : 5 mg once daily

23. SGLT2 inhibitors
 90% Glucose reabsorption at proximal tubule
Canagliflozin (approved Mar’13)
Dapagliflozin
Empagliflozin
Ipragliflozin
LX4211
PF-04971729

24. SGLT2 inhibitors
Benefits
• ↑ glucose control independent of insulin
• ↓ HbA1c
• Can be used in T1D and T2D
• Low risk of hypoglycaemia
• Weight loss
• Consistent fall in BP ~ 6/3 mmHg

25. INVOKANA™ (Canagliflozin)
 Indicated as an adjunct to diet and exercise
 Adverse effects : Genital mycotic (fungal) infections, UTI,
and ↑ed urination

26. Amylin mimetic
(Pramlinitide)
 Co-secreted with insulin
- Absent in type 1 DM, deficient in type 2 DM
 Slows gastric emptying and digestion
 Decreases post-prandial glucagon
 Satiety center effect
Injectable- insulin syringe
Starting dose Type 1 DM 15 mcg (2.5 units)
Starting dose Type 2 DM 60 mcg (10 units)
Titrate as tolerated every 3 days
Symlin® pens (60 and 120 mcg)
Use at the time of a meal
Separate injection from insulin
Decrease dose of prandial insulin by 50%
Potentially less nausea than with exenatide

27. NEWER PEROXISOME PROLIFERATOR
ACTIVATED RECEPTOR (PPAR) AGONISTS
Improved management of
dyslipidemia, associated with
PPAR α activation.
Improvements in insulin
sensitivity associated with
PPAR γ activation.
 Glitazar (alpha + gamma)
 Aleglitazar
 Tesaglitazar
 Muraglitazar

28. Bromocriptine mesylate
Decreased
lipolysis in
adipose tissue
Decreased
postprandial
hepatic glucose
output
Decreased
insulin
resistance
Diabetes patients may have low morning levels of
hypothalamic dopamine, which is thought to lead to
hyperglycemia and dyslipidemia
Dosage:
CYCLOSET®
Initial dose is one tablet (0.8 mg) daily increased weekly by
one tablet until maximal tolerated daily dose of 1.6 to 4.8
mg

29. Bile acid sequestrants
Contraindicated
A history of bowel obstruction
Serum TG’s >500 mg/dL
A history of hypertriglyceridemia-induced pancreatitis
Colesevelam
Dosage:
Oral suspension: one 3.75 gram packet once daily or one
1.875 gram packet twice daily (mixed with water),
Monotherapy or combination therapy with an HMG-CoA
reductase inhibitor

30. Immunotherapy for T1DM
Humanized anti CD3 Monoclonal Antibodies
Rituximab
Thymoglobulin
Otelixizumab & Teplizumab
Recombinant Human Glutamic Acid Decarboxylase
(rhGAD65)

31. STEM CELL THERAPY
Various Stem cells with potential role in T1D Therapy :
Cord blood stem cells (CB-SCs)
Mesenchymal stem cells (MSCs)
Hematopoietic stem cells (HSCs)
Embryonic stem cells (ESCs)
Induced pluripotent stem cells (iPS)

32. Bariatric surgery
Indications :
 Severe obesity ≥40 kg/m2
 Moderate obesity (≥35 kg/m2) with serious medical
condition
Procedures:
 Laparoscopic adjustable silicone gastric banding (LASBG)
 Roux-en-Y gastric bypass (RYGB)
 Biliopancreatic diversion (BPD)
 Biliopancreatic diversion with duodenal switch (BPDDS)

33. Diet, weight control, physical activity
Sulphonylurea TZD DPP-4
inhibitor
Insulin
(basal)
GLP-1
agonist
METFORMIN
TWO DRUG COMBINATION
ADA algorithm for Management of DM 2013
If needed to reach individualised HbA1c target after ~3months
SU
DPP-4 I
GLP-1 RA
INSULIN
Sulphonylurea TZD DPP-4
inhibitor
Insulin
(basal)
GLP-1
agonist
TZD
DPP-4 I
GLP-1 RA
INSULIN
SU
TZD
INSULIN
TZD
DPP-4 I
GLP-1 RA
SU
TZD
INSULIN
3 DRUG COMBINATION
If combination therapy that includes basal insulin has failed to
achieve HbA1c target after 3-6 months
INSULIN
Multiple daily doses

34. Insulin Delivery
• Pens, syringe or pump?
Types of Insulin Pens
• Rapid Acting Insulin
– Novolog FlexPen: Prefilled 300 units
– Humalog KwikPen: Prefilled 300 units
– Apidra SoloStar Pen: Prefilled 300 units (new April ’09)
– Humalog Memoir Pen: 300 unit cartridge
– Humalog Luxura Pen: 300 unit cartridge, can be dosed in ½
units
• Basal Insulin
– Lantus SoloStar Pen: prefilled 300 units
• Opticlick pen phasing out
– Levemir FlexPen : prefilled 300 units

35. Insulin Pumps
• Medtronic Minimed
Paradigm 522/722
• Animas One Touch Ping
• OmniPod