modern modalities for management of diabetes dr mahir jallo gulf medical university 2013 signed
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MODERN MODALITIES FOR MANAGEMENT
OF DIABETES
Dr. Mahir Khalil Jallo Associate Professor of Medicine Consultant Diabetes & Endocrinology
Gulf Medical University
Doctor MEET 2013
Mahir Jallo
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
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
Macrovascular Microvascular
Stroke
Heart disease and hypertension
Ulcers and
amputation
Diabetic eye disease (retinopathy and cataracts)
Renal disease (Kidney)
Neuropathy
Foot problems
Peripheral vascular disease
Diabetes Complications
Diabetes = CVD
Up to 80% of adults with diabetes will
die of cardiovascular disease.
Adapted from Barrett-Connor 2001.
Macrovascular Microvascular
Stroke
Heart disease and hypertension
Ulcers and
amputation
Diabetic eye disease (retinopathy and cataracts)
Renal disease
(Kidney)
Neuropathy
Foot problems
Peripheral vascular disease
Diabetes Complications
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
PORTION SIZE: 1950S TO 2000
Millions of years < 30 years
A GROWING DIVIDE
Evidence Behaviour
How can we facilitate
translating science to better
outcomes?
POLYPHARMACY
A reality in modern diabetes management
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
A SOLUTION TO HELP IMPROVE
ADHERENCE…
THE PILL BURGER
GLYCEMIC MANAGEMENT IN TYPE 2
DIABETES
16
TYPE 2 DIABETES
High blood glucose
1. Defective beta cell function • Diminished phase 1 insulin release
• Delayed phase 2 insulin release
2. Overproduction of glucagon
Impaired GI motility
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
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
DeFronzo RA. Diabetes. 2009;58:773-795
18
TYPE 2 DIABETES MEDICATIONS
19
1960 1995 2000 2005 2010
Insulin 1922 SUs
1957
Metformin AGIs 1995
Glinides TZDs 1997
Exenatide Pramlintide
2005
Sitagliptin 2006
Liraglutide 2010
Patlak M. Breakthroughs in Bioscience 2002. http://www.faseb.org/Portals/0/PDFs/opa/diabetes.pdf
Philippe J. Int J Clin Pract 2009;63:321-332
Saxagliptin 2009
NONINSULIN AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class Primary Mechanism of Action Agent Available as
-Glucosidase
inhibitors
Delay carbohydrate absorption
from intenstine
Acarbose Precose or generic
Miglitol Glyset
Amylin analog
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
DPP-4 inhibitors
Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Linagliptin Trajenta
Saxagliptin Onglyza
Sitagliptin
Vildagliptin
Januvia
Galvus
Dopamine-2 agonist Activates dopaminergic
receptors Bromocriptine Cycloset
20 Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
NONINSULIN AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class Primary Mechanism of Action Agent Available as
Glinides Increase insulin secretion Nateglinide Starlix or generic
Repaglinide Prandin
GLP-1 receptor
agonists
Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Exenatide Byetta
Exenatide XR Bydureon
Liraglutide Victoza
SGLT2 inhibitors Increase urinary excretion of
glucose Canagliflozin Invokana
Sulfonylureas Increase insulin secretion
Glimepiride Amaryl or generic
Glipizide Glucotrol or generic
Glyburide Diaeta, Glynase, Micronase,
or generic
Thiazolidinediones
Increase glucose uptake in
muscle and fat
Decrease HGP
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]
INSULINS AVAILABLE FOR THE TREATMENT
OF TYPE 2 DIABETES (2012)
Class Primary Mechanism of Action Agent Available as
Insulin Increase glucose uptake
Decrease HGP
Basal
Detemir Levemir
Glargine Lantus
Neutral protamine
Hagedorn (NPH) Generic
Prandial
Aspart NovoLog
Glulisine Apidra
Lispro Humalog
Regular human Humulin
Premixed Biphasic aspart NovoLog Mix
Biphasic lispro Humalog Mix
22 Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
COMBINATION AGENTS AVAILABLE FOR THE
TREATMENT OF TYPE 2 DIABETES (2012)
Class Added Agent Available as
Metformin + DPP-4 inhibitor
Linagliptin Jentadueto
Saxagliptin Kombiglyze XR
Sitagliptin Janumet
Metformin + glinide Repaglinide Prandimet
Metformin + sulfonylurea Glipizide Metaglip and generic
Glyburide Glucovance and generic
Metformin + thiazolidinedione Pioglitazone ACTOplus Met
Rosiglitazone* Avandamet
Thiazolidinedione + sulfonylurea Pioglitazone Duetact
Rosiglitazone* Avandaryl
*Use restricted due to increased risk of myocardial infarction (MI)
23
TREATMENT ORAL OPTIONS FOR TYPE 2 DIABETES
Sulfonylureas
1st generation e.g. chlorpropamide, tolbutamide
2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone
3rd generation e.g. glimepiride Modified release
Glinides/meglitinides
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
– 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
DPP-4 INHIBITORS & COMBINATIONS
DRUGS IN THE CLASS
Active
Ingredient Brand Strengths
FDA Approval
Date
Patent
Expiration
Date
Sitagliptin 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
Linagliptin Trajenta
(Lilly/BI) 5mg 5/2/2011 -
Vildagliptin Galvus
(Novartis) 50mg
EUROPE
September 2007 -
Vildagliptin/
Metformin
Galvusmet
(Novartis)
50mg/850mg
50mg/1000mg -
AACE COMPREHENSIVE DIABETES
MANAGEMENT 2013
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
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
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
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
ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS
35
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.
Ingestion of food
Beta cells Alpha cells
Release of gut
hormones :
Incretins
Pancreas2,3
Glucose-dependent
Insulin from beta cells
(GLP-1 and GIP) Glucose
uptake by
muscles
Glucose
production
by liver
Blood
glucose
Glucose dependent
Glucagon from
alpha cells
(GLP-1)
Active
GLP-1 & GIP
DPP-4
enzyme
Inactive
GIP
Inactive
GLP-1
SITAGLIPTIN
SITAGLIPTIN / SIMVASTATIN
VILDAGLIPTIN
SAXAGLIPTIN
LINAGLIPTIN
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)
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
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
SGLT-2 INHIBITORS
43 Drugs 2010;70(4):377-385
44
• 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.
GLP1
Exenatide BYETTA®
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
45
Thr Glu Gly Phe Thr Ser Asp Val Ser Ser Ala His Tyr Leu Glu Gly Gln Ala Ala Arg Gly Phe Ile Trp Ala Leu Val Arg Gly Glu Lys
Glu
Albumin
Liraglutide, NN2211 (NovoNordisk)
C-16 fatty acid (noncovalent binding to albumin)
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
46
Better efficacy and tolerability
than BYETTA Improves
Patient compliance and outcomes
EXENATIDE LAR BYDUREON
INCRETIN MIMETICS AND DPP-4 INHIBITORS:
MAJOR DIFFERENCES
48
Properties/effect Incretin mimetics DPP-4 inhibitors
Restitution of insulin secretion Yes (exenatide) Yes
Hypoglycaemia No No
Maintained counter-regulation by
glucagon in hypoglycaemia
Yes Not tested
Inhibition of gastric emptying Yes Marginal
Effects on satiety Reduces food intake None
Effect on body weight Weight loss Weight neutral
Side effects Nausea None observed
Administration Subcutaneous Oral
Dosage Twice daily Once daily
INSULIN DEGUDEC
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
PIPELINE CLASSES AND AGENTS (2013)
Class
Phase of Development Agents Description
Dual peroxisome proliferator activated
receptor - (PPAR-) agonist
Phase 3
Aleglitazar
Improve insulin sensitivity in the periphery as well as lipid profiles
Approved agents may reduce both cardiovascular risks and potential for
diabetes complications
Short-acting GLP-1 receptor agonist Lixisenatide 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 Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject
variability and potential for reduced incidence of hypoglycemia
DegludecPlus Premixed insulin containing degludec plus aspart, providing both fasting and
postprandial glucose control Salicylates
Phase 3 Salsalate
Generically available anti-inflammatory medication currently approved for
treatment of arthritis; inhibits activity of NF-B, an inflammatory factor
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
11-Hydroxysteroid dehydrogenase type
1 (11HSD-1) inhibitors
Phase 2
INCB13739
RG4929
Inhibit 11HSD-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
51
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;
Tahrani AA, et al. Lancet. 2012;379:1465-1467.
SMBG IN TYPE 2 DIABETES
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
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
53
Testing positively affects glycemia in
T2DM when the results are used to:
• Modify behavior
• Modify pharmacologic treatment SMBG, self-monitoring of blood glucose.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
CSII IN TYPE 2 DIABETES
CSII IN TYPE 2 DIABETES: PATIENT CANDIDATES
Absolutely insulin-
deficient
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
55 CSII, continuous subcutaneous insulin infusion.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
SURGICAL INTERVENTION IN
TYPE 2 DIABETES
56
Schauer PR, et al. N Engl J Med. 2012;366:1567-1576.
Months Months
3.5
2.5
1.5
0.5
0.0
1.0
2.0
3.0
Baseline 3 6 9 12
Ave
rag
e n
o. d
iab
ete
s
me
dic
ati
on
s
P<0.001
P<0.001
-2
-6
-10
-12
-8
-4
0
Baseline 3 6 9 12
B
MI (k
g/m
2)
P<0.001
P<0.001
20
-40
-100
-140 -160
-120
-60
-20
-80
0
Baseline 3 6 9 12
F
PG
(m
g/d
L)
P=0.02
P<0.001
0.0
1.0
2.0
3.0
3.5
2.5
1.5
0.5
Baseline 3 6 9 12
A
1C
(%
)
P<0.001
P<0.001
Intensive medical therapy Sleeve gastrectomy Roux-en-Y gastric bypass
TECHNOSPHERE® INHALED INSULIN
57 http://www.mannkindcorp.com/Technology.aspx
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
58
Ann Pharmacother 2010;44:1231-1239
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%)
59 Lancet 2010;375:2244-2253
AACE COMPREHENSIVE CARE PLAN
60 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Mahir Jallo
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