Modern Modalities for Management of Diabetes : An Overview for All Diabetic care Providers

1. Dr. Mahir Khalil Jallo
Associate Professor of Medicine Consultant Diabetes & Endocrinology
Gulf Medical University
Doctor MEET 2013
MODERN MODALITIES FOR MANAGEMENT
OF DIABETES
Mahir Jallo

2. WHAT IS DIABETES?
Type 1 diabetes (5-10%)
 Body’s own immune system attacks the cells in the
pancreas that produce insulin
Type 2 diabetes (90 - 95%)
 The pancreas does not produce enough insulin
and/or the bodies’ tissues do not respond properly
to the actions of insulin
 Caused by both genetic and environmental factors
Gestational diabetes
 Diabetes with first onset or recognition during
pregnancy
 Puts women at higher risk for type 2 DM later in life

3. WHAT DIABETES IS NOT
Diabetes is NOT “a touch of sugar”
 It is a serious chronic disease that can lead to
complications.
 Heart attack
 Stroke
 Blindness
 Amputation
 Kidney disease
 Sexual dysfunction
 Nerve damage


4. Diabetes Complications
Macrovascular
Stroke
Microvascular
Diabetic eye disease
(retinopathy and cataracts)
Heart disease
and hypertension
Renal disease (Kidney)
Peripheral
vascular disease
Neuropathy
Ulcers and
amputation
Foot problems

5. Diabetes = CVD
Up to 80% of adults with diabetes will
die of cardiovascular disease.
Adapted from Barrett-Connor 2001.

6. Diabetes Complications
Macrovascular
Stroke
Heart disease
and hypertension
Microvascular
Diabetic eye disease
(retinopathy and
cataracts)
Renal disease
(Kidney)
Peripheral
vascular disease
Neuropathy
Ulcers and
amputation
Foot problems

7. WHY THE EPIDEMIC?

Physical Inactivity
 60%
to 85% of adults are not active enough to
maintain their health

Diet
 Calorie
dense; high fat
Aging population
 Urbanization

 Shift
from an agricultural to an urban lifestyle
means a decrease in physical activity

9. PORTION SIZE: 1950S TO 2000

10. Millions of years
< 30 years

11. A GROWING DIVIDE
Evidence
Behaviour
How can we facilitate
translating science to better
outcomes?

12. POLYPHARMACY
A reality in modern diabetes management

13. DIABETES MEDICATIONS
In order to reach A1C, BP and lipid targets, people with diabetes
typically require many medications:
 To lower blood glucose: 1-3 pills and/or insulin
 To lower cholesterol: 1 or 2 pills
 To lower blood pressure: 2 or 3 pills
 For general vascular protection: aspirin
Adherence to complex drug regimens can be a
challenge for patients

14. A SOLUTION TO HELP IMPROVE
ADHERENCE…

15. THE PILL BURGER

16. GLYCEMIC MANAGEMENT IN TYPE 2
DIABETES
16

17. TYPE 2 DIABETES
High blood glucose
Impaired GI motility
1. Defective beta cell function
•
•
Diminished phase 1 insulin release
Delayed phase 2 insulin release
2. Overproduction of glucagon
1. Tissues less sensitive to insulin
2. Liver produces excess glucose
Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE
Type 2 Video from diabetes.com

18. PATHOPHYSIOLOGY OF T2DM
Organ System
Defect
Major Role
Pancreatic beta cells
Decreased insulin secretion
Muscle
Inefficient glucose uptake
Liver
Increased endogenous glucose secretion
Contributing Role
Adipose tissue
Increased FFA production
Digestive tract
Decreased incretin effect
Pancreatic alpha cells
Increased glucagon secretion
Kidney
Increased glucose reabsorption
Nervous system
Neurotransmitter dysfunction
18
DeFronzo RA. Diabetes. 2009;58:773-795

19. TYPE 2 DIABETES MEDICATIONS
Insulin
1922
SUs
1957
1960
Metformin
AGIs
1995
1995
Sitagliptin Saxagliptin
2006
2009
2000
Glinides
TZDs
1997
2005
2010
Exenatide
Pramlintide
2005
Liraglutide
2010
Philippe J. Int J Clin Pract 2009;63:321-332
Patlak M. Breakthroughs in Bioscience 2002. http://www.faseb.org/Portals/0/PDFs/opa/diabetes.pdf
19

20. NONINSULIN AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class
Primary Mechanism of Action
-Glucosidase
inhibitors

Delay carbohydrate absorption
from intenstine
Agent
Acarbose
Available as
Precose or generic
Miglitol
Glyset



Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Pramlintide
Symlin
Biguanide


Decrease HGP
Increase glucose uptake in
muscle
Metformin
Glucophage or generic
Bile acid
sequestrant


Decrease HGP?
Increase incretin levels?
Colesevelam
WelChol

Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Linagliptin
Saxagliptin
Trajenta
Onglyza
Sitagliptin
Vildagliptin
Januvia
Galvus
Bromocriptine
Cycloset
Amylin analog
DPP-4 inhibitors

Dopamine-2 agonist

Activates dopaminergic
receptors
20
Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]

21. NONINSULIN AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class
Primary Mechanism of Action
Glinides

Increase insulin secretion

Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Increase urinary excretion of
glucose
SGLT2 inhibitors
Sulfonylureas






Thiazolidinediones

Increase insulin secretion
Increase glucose uptake in
muscle and fat
Decrease HGP
Available as
Starlix or generic
Prandin
Exenatide
Byetta
Exenatide XR
Bydureon
Liraglutide
Victoza
Canagliflozin
Invokana
Glimepiride
Glipizide
Amaryl or generic
Glucotrol or generic
Glyburide
GLP-1 receptor
agonists
Agent
Nateglinide
Repaglinide
Diaeta, Glynase, Micronase,
or generic
Pioglitazone
Actos
Rosiglitazone*
Avandia
*Use restricted due to increased risk of myocardial infarction (MI)
21
Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]

22. INSULINS AVAILABLE FOR THE TREATMENT
OF TYPE 2 DIABETES (2012)
Class
Primary Mechanism of Action
Insulin


Basal
Prandial
Premixed
Agent
Available as
Detemir
Glargine
Levemir
Lantus
Neutral protamine
Hagedorn (NPH)
Generic
Aspart
Glulisine
Lispro
Regular human
Biphasic aspart
Biphasic lispro
NovoLog
Apidra
Humalog
Humulin
NovoLog Mix
Humalog Mix
Increase glucose uptake
Decrease HGP
22
Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]

23. COMBINATION AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class
Metformin + sulfonylurea
Metformin + thiazolidinedione
Thiazolidinedione + sulfonylurea
Jentadueto
Saxagliptin
Kombiglyze XR
Sitagliptin
Metformin + glinide
Available as
Linagliptin
Metformin + DPP-4 inhibitor
Added Agent
Janumet
Repaglinide
Prandimet
Glipizide
Metaglip and generic
Glyburide
Glucovance and generic
Pioglitazone
ACTOplus Met
Rosiglitazone*
Avandamet
Pioglitazone
Duetact
Rosiglitazone*
Avandaryl
*Use restricted due to increased risk of myocardial infarction (MI)
23

24. TREATMENT ORAL OPTIONS FOR TYPE 2 DIABETES

Sulfonylureas






Non-sulfonylureic e.g. repaglinide
Amino acid derivatives e.g. nateglinide
Biguanides



e.g. Metformin. Metformin XR
Thiazolidinediones

e.g. Pioglitazone
-glucosidase inhibitors
 e.g. Acarbose
DPP4 Inhibitors
–
–
–
–
Glinides/meglitinides


1st generation e.g. chlorpropamide,
tolbutamide
2nd generation e.g. glyburide,
gliclazide, glipizide, gliquidone
3rd generation e.g. glimepiride
Modified release


Sitagliptin.
Vildagliptin.
Saxagliptin.
Linagliptin.
Fixed-dose oral antidiabetic
drug combinations
 e.g. Glyburide/Metformin,
Glimepride/Metformin,
Pioglitazone/Metformin
Sitagliptin/Metformin,
Sitagliptin/Simvastatin
Vildagliptin/Metformin,
Saxagliptin/Metformin XR

25. DPP-4 INHIBITORS & COMBINATIONS
DRUGS IN THE CLASS
Strengths
FDA Approval
Date
Patent
Expiration
Date
Januvia (Merck)
25mg, 50mg,
100mg
10/16/2006
04/24/2017
Sitagliptin/
Metformin
Janumet
(Merck)
50mg/500mg,
50mg/1000mg
03/30/2007
04/24/2017
Saxagliptin
Onglyza (BMS)
2.5mg, 5mg
07/31/2009
02/16/2021
Saxagliptin/
Metformin XR
Kombiglyze XR
(BMS)
2.5mg/1000mg
5mg/500mg
5mg/1000mg
11/05/2010
02/16/2021
5mg
5/2/2011
-
50mg
EUROPE
September 2007
-
Active
Ingredient
Brand
Sitagliptin
Linagliptin
Vildagliptin
Vildagliptin/
Metformin
Trajenta
(Lilly/BI)
Galvus
(Novartis)
Galvusmet
(Novartis)
50mg/850mg
50mg/1000mg
-

26. AACE COMPREHENSIVE DIABETES
MANAGEMENT 2013

31. FIRST PRINCIPLES OF THE AACE/ACE
ALGORITHM
Avoidance of hypoglycemia is a priority
 Avoidance of weight gain is a priority
 All medication options need to be considered
 Acquisition cost is not the total cost of a drug
 Therapy selection must be stratified by A1C
 Post-prandial glucose is an important target

Rodbard HW, et al. Endocr Pract. 2009;15:540-559

32. SECONDARY PRINCIPLES OF THE
AACE/ACE ALGORITHM
Ease of use improves adherence
 Minimal side effects improves adherence
 Improved -cell performance over a longer
period of time is possible
 Multiple combinations are required

Rodbard HW, et al. Endocr Pract. 2009;15:540-559

33. NINE TO KNOW
THE MINIMUM THAT MUST BE KNOWN ABOUT DRUGS!









Brand & Generic Name
Mechanism of action
Therapeutic effect
Relevant pharmacokinetics and pharmacodynamics
Dosing by route
Adverse reactions and contraindications
Monitoring parameters
Drug-drug and drug food interactions
Comparisons between agents w/in the same class of
drugs

34. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
INDICATIONS
Diabetes Mellitus Type II
MOA
Inhibits the breakdown of GLP-1 by DPP-4
therefore increasing GLP-1 levels resulting in
increased glucose-dependent insulin release
and decreased level of circulating glucagon
and hepatic glucose production

35. ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS
Ingestion of food
Pancreas2,3
Glucose-dependent
 Insulin from beta cells
(GLP-1 and GIP)
Release of gut
hormones :
Incretins
Glucose
uptake by
muscles
Blood
glucose
Beta cells
Alpha cells
Active
GLP-1 & GIP
DPP-4
enzyme
Glucose dependent
 Glucagon from
alpha cells
(GLP-1)
Glucose
production
by liver
Inactive Inactive
GLP-1
GIP
DPP-4 = dipeptidyl-peptidase 4
Sources :1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
35

36. SITAGLIPTIN

37. SITAGLIPTIN / SIMVASTATIN

38. VILDAGLIPTIN

39. SAXAGLIPTIN

40. LINAGLIPTIN

41. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
SPECIAL POPULATION CONSIDERATIONS:
Renal Impairment: avoid combo drugs w/ metformin
 For Sitagliptin:
 CrCl 30-50 mL/min : 50 mg daily
 CrCl < 30 mL/min: 25 mg daily
 End Stage Renal Disease Requiring dialysis: 25 mg
daily
 Geriatric: caution due to age related renal function
decreases
Cautions/Severe Adverse Reactions
 Acute pancreatitis
 Rash (Stevens-Johnson syndrome)


42. SODIUM GLUCOSE CO-TRANSPORTER 2
INHIBITORS
 Canagliflozin



Invokana not only helped patients improve blood sugar
control, but also lose weight and control their BP.
Losing weight help people control their diabetes.
In one 26-week study, those on Invokana lost about 6 to 8
pounds.
 Dapagliflozin
42

43. SGLT-2 INHIBITORS
Drugs 2010;70(4):377-385
43

44. GLP1
Exenatide BYETTA®
•
Approved by FDA in April 2005
•
Indication and usage :
Type 2 Diabetes :
Combination therapy with metformin and/or a sulfonylurea and/or thiazolidinedione
when the single agent does not provide adequate glycemic control.
•
Important limitations of use : BYETTA® should not be used in patients with T1D or
for the treatment of diabetic ketoacidosis.
44

45. LIRAGLUTIDE VICTOZA




An extended half-life (~12 hours)‫ ‏‬long-acting analog of
GLP1
Single daily injection 0.6 -1.8
↓ Weight and ↓ HbA1c
Nausea is the most common adverse effect
Liraglutide, NN2211 (NovoNordisk)‫‏‬
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly
Glu
Albumin
C-16 fatty acid (noncovalent binding to albumin)
45

46. EXENATIDE LAR
BYDUREON
 First once-weekly injection for type 2 diabetes
52 doses a year vs. 730

Based on Alkermes’ proprietary technology for long-acting
medications
Better efficacy and
tolerability
than BYETTA
Improves
Patient compliance
and outcomes
46

47. EXENATIDE LAR BYDUREON

48. INCRETIN MIMETICS AND DPP-4 INHIBITORS:
MAJOR DIFFERENCES
Properties/effect
Restitution of insulin secretion
Incretin mimetics DPP-4 inhibitors
Yes (exenatide)
Yes
Hypoglycaemia
No
No
Maintained counter-regulation by
glucagon in hypoglycaemia
Yes
Not tested
Inhibition of gastric emptying
Yes
Marginal
Reduces food intake
None
Weight loss
Weight neutral
Nausea
None observed
Subcutaneous
Oral
Twice daily
Once daily
Effects on satiety
Effect on body weight
Side effects
Administration
Dosage
48

49. INSULIN DEGUDEC

50. INVESTIGATIONAL GLP-1 AGONISTS

Albiglutide (GlaxoSmithKline)
 Recruitment

complete in 8 Phase III studies
Lixisenatide (Sanofi-Aventis)
 Phase
III results presented at EASD 2010
 Decreased A1C significantly vs placebo
 Additional Phase III results expected Q2 2011

Taspoglutide (Roche)
 Returned
rights to Ipsen after hypersensitivity, GI
reactions led to halt of Phase III trials in 9/2010
50

51. PIPELINE CLASSES AND AGENTS (2013)
Class
Phase of Development
Dual peroxisome proliferator activated
receptor - (PPAR-) agonist
Phase 3
Short-acting GLP-1 receptor agonist
Agents
Description
Lixisenatide
Improve insulin sensitivity in the periphery as well as lipid profiles
Approved agents may reduce both cardiovascular risks and potential for
diabetes complications
Human-derived molecule with effects similar to exenatide
Long-acting GLP-1 receptor agonists
Phase 3
Albiglutide
Taspoglutide
Effects probably similar to currently available GLP-1 receptor agonists
Longer duration of action will permit longer intervals between injections
Insulin
Phase 3
Degludec
Aleglitazar
DegludecPlus
Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject
variability and potential for reduced incidence of hypoglycemia
Premixed insulin containing degludec plus aspart, providing both fasting and
postprandial glucose control
Generically available anti-inflammatory medication currently approved for
treatment of arthritis; inhibits activity of NF-B, an inflammatory factor
Salicylates
Phase 3
Salsalate
Sodium-dependent glucose
cotransporter 2 (SGLT-2) inhibitors
Phase 3
Dapagliflozin
Empagliflozin
Tofogliflozin
Act in the kidney
Reduce hyperglycemia by inhibiting glucose reabsorption into the
bloodstream from the renal filtrate, increasing urinary excretion of glucose
INCB13739
RG4929
Inhibit 11HSD-1 mediated conversion of low-activity cortisone to cortisol,
which is primarily produced in the liver and adipose tissue
May lessen stress-induced obesity, improve insulin sensitivity, enhance
insulin-secretory responsiveness, and improve glucose tolerance in patients
with metabolic syndrome and/or type 2 diabetes
11-Hydroxysteroid dehydrogenase type
1 (11HSD-1) inhibitors
Phase 2
Bakris GL, et al. Kidney Int. 2009;75:1272-1277; Calado J, et al. Kidney Int Suppl. 2011:S7-S13;
Garber AJ. Expert Opin Investig Drugs. 2012;21:45-57; Goldfine AB, et al. Ann Intern Med. 2010;152:346-357;
King A. J Fam Pract. 2012;61:S28-S31; Tahrani AA, et al. Lancet. 2011;378:182-197;
51
Tahrani AA, et al. Lancet. 2012;379:1465-1467.

52. SMBG IN TYPE 2 DIABETES

53. SMBG IN TYPE 2 DIABETES: AACE/ACE
RECOMMENDATIONS



Noninsulin Users
Introduce at diagnosis
Personalize frequency of
testing
Use SMBG results to
inform decisions about
whether to target FPG or
PPG for any individual
patient
Testing positively affects glycemia in
T2DM when the results are used to:
• Modify behavior
• Modify pharmacologic treatment

Insulin Users
All patients using insulin
should test glucose



≥2 times daily
Before any injection of
insulin
More frequent SMBG (after
meals or in the middle of
the night) may be required


Frequent hypoglycemia
Not at A1C target
SMBG, self-monitoring of blood glucose.
53
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

54. CSII IN TYPE 2 DIABETES

55. CSII IN TYPE 2 DIABETES: PATIENT CANDIDATES




Absolutely insulindeficient
Take 4 or more insulin
injections a day
Assess blood glucose
levels 4 or more times
daily
Motivated to achieve
tighter glucose control




Mastery of carbohydrate
counting, insulin correction,
and adjustment formulas
Ability to troubleshoot
problems related to pump
operation and plasma
glucose levels
Stable life situation
Frequent contact with
members of their healthcare
team, in particular their
pump-supervising physician
CSII, continuous subcutaneous insulin infusion.
55
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

56. SURGICAL INTERVENTION IN
TYPE 2 DIABETES
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Baseline
P<0.001
P<0.001
3
6
9
12
 FPG (mg/dL)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Baseline
Sleeve gastrectomy
Roux-en-Y gastric bypass
20
0
-20
-40
-60
-80
-100
-120
-140
-160
Baseline
P=0.02
P<0.001
3
6
9
12
0
P<0.001
P<0.001
3
6
Months
9
12
 BMI (kg/m2)
Average no. diabetes
medications
 A1C (%)
Intensive medical therapy
-2
-4
-6
P<0.001
-8
-10
-12
Baseline
P<0.001
3
6
9
12
Months
56
Schauer PR, et al. N Engl J Med. 2012;366:1567-1576.

57. TECHNOSPHERE® INHALED INSULIN
http://www.mannkindcorp.com/Technology.aspx
57

58. 
Afrezza® (MannKind)
 Excipient:
fumaryl diketopiperazine (FKDP)
 FKDP self-assembles into microspheres 2 - 5 µm
diameter
 Insulin microencapsulated within microspheres
 Freeze dried to form powder for inhalation
 Rapid acting mealtime insulin (tmax = 15 min)
 Bioavailability = 37% of SQ regular insulin
Ann Pharmacother 2010;44:1231-1239
58

59. TECHNOSPHERE® INHALED INSULIN
Randomized, open-label, 52 week trial
 Prandial inhaled insulin + basal insulin glargine
OR
 Twice daily premixed biaspart insulin (Novolog
Mix 70/30)
 A1C: -0.68% vs -0.76% (noninferior)
 Hypoglycemia: 48% vs 69%
 Cough (33%), URI (12%)

Lancet 2010;375:2244-2253
59

60. AACE COMPREHENSIVE CARE PLAN
60
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

61. Mahir Jallo