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