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Dr Cleo Cheng
Midwest Health
Beverley
22.11.2011
1.
Refresh pathophysiology of DM
2.
↑awareness of at risk groups to screen
3.
Competence in conducting brilliant GPMP–DM
4.
↑Awareness of latest combination therapies
(Gliptins)






Diabetes overview – 10 min
Screening at risk groups – 10min
GPMP
– 30min
DM foot assessment– 10min
Medications
– 20min
Q&A
– 10min
Diabetes in Australia – BIG problem & getting bigger
Around 275 Australians develop DM/day
For every person diagnosed, there is another not yet diagnosed = 1.7
million DM
Total no of Australians with DM & and pre-DM = around 3.2 million
Means:
4.0% - Diagnosed (4% missed)
8.0% - DM
15% - Pre DM & DM
↟300% in past 20 years –Obesogenic environment
Diabetes Atlas, third edition, International Diabetes Federation, 2007
Diabetes and Cardiovascular Disease: Time to Act, International Diabetes Federation, 2001
AusDiab Report, 2006
The Economic Costs of Obesity, 2006
World Health Organisation Diabetes Uni
TOO MUCH SUGAR IN THE BLOOD!!...
but starving in the face of plenty!!
◦ Insulin :  let glucose into cells
 - insufficient
 - inefficient
◦ Glucagon :  let glucose out of liver cells
 - lost of negative feedback  too much
β-cells of Islet of Langerhans in pancreas  insulin
α-cells of Islet of Langerhans in pancreas  glucagon
+
Insulin#
(plasma concentration)
#Insulin
–
Glucose
(plasma concentration)
–
Glucagon*
(plasma concentration)
+
secretion is also stimulated by other nutrients, such as amino acids and free fatty acids, and neural input
*Glucagon secretion is also influenced by other nutrients, hormones, and neural input.
Impaired insulin
secretion
Type 2 Diabetes Pathophysiology
-Cells
produce
excess
glucagon
-Cells
Hyperglycaemia
produce
less insulin
Increased HGP
DeFronzo RA. Diabetes 2009; 58:773–95.
Decreased glucose
uptake
Islet-Cell Dysfunction
Glucagon
(α cell)
Pancreas
Hepatic
glucose
output
Insulin
(β cell)
Insulin
resistance
Glucose uptake
Hyperglycaemia
Liver
Muscle
Adipose
tissue
Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
But there are other forces at work to BSL
 Glucocorticoid
 Catecholamine
 Thyroid hormones
 Growth Hormones
 Adipose/Fat cells
EXERCISE -  BSL
Insulin Resistance and -cell Dysfunction
in T2DM
Normal
IGT
Type 2 diabetes
Insulin
resistance
Increased insulin
resistance
Insulin
secretion
Hyperinsulinemia,
then -cell failure
Postprandial
glucose
Abnormal
glucose tolerance
Fasting
glucose
Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.
Hyperglycemia

Type I –
Autoimmune mediated/IDDM
 Childhood onset - preschool
 Adolescent – puberty
 LADA – young adults

Type II –
Insulin resistance and relative insufficiency/NIDDM
 Adult onset
 Most common 85-90%

Gestational –
Insulin resistance due to placental hormones
 Transient but  NIDDM risk later on

Others –
rare <5%
 Congenital/CF related/Cushing/Hyperthyroidism/
 Pancreatitis/haemochromatosis/pancreatectomy

Family history

Obesity/Overweight - BMI >25 (85%)

Over 40+

Ethnicity:
◦
◦
◦
◦
Aboriginal/TSI/Maori
Indian
Chinese
Vietnamese/Cambodian/Laos/Thai
(>18)
(>30)
(>30)
(>30)
AUSDRISK
 10 questions to assess risk of developing NIDDM over next 5 years
 Completed by patient +/- help of a doctor/nurse or practice staff
 40–49 +“high score”  eligible: NIDDM risk evaluation (MBS 713) /GP
Tool available in 3formats:
Interactive diabetes risk assessment tool - online risk level calculator
Non-interactive diabetes risk assessment tool
Australian type 2 diabetes risk assessment tool (AUSDRISK)
http://www.diabetesaustralia.com.au/en/For-HealthProfessionals/Resources/
http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di17-diabetes-detection-diagnosis.pdf

Fasting BSL
◦ >5.4  ? - do GTT
◦ >7.0 


- NIDDM 
Random BSL
o
>11.1 
 - NIDDM 
____________________________________________

HbA1c
o
>6.4% 
 - NIDDM 

1. Disease Specific Care
 HbA1c/BSL/BP/Lipids/Aspirin

2. Complications
 – Foot care/Eye/Kidney/Sexual Dysfunction

3. Lifestyle Changes
 –Weight/SNAP/Immunisation/Mental Health/Sleep

4. Medication Review
 – Compliance/understanding/ability/?HMR

5. IDDM
 – Driving/Medic alert bracelet/Glucagon Kit

1. HbA1c %

2. BSL

3. BP

4. Lipids

5. Aspirin
- <6.4/<7.0 / elderly
- Fast 4-6/Post -8
(+2 = Fair
;
+4 = Poor)
-130/80
(avoid thiazide diuretics/ B – blockers)
-Annual ECG
- TC <4.0; TG<1.5; HDL>1.0; LDL<2.5 (1.8)
- CVS risk calculator >15%  (75-100mg/day)

1. Nerve Damage/Foot care
- Neuropathy
- ABCS Foot Assessment**

2. Eye Damage
-Biannual retinal assessment -ophthalmologist/ optometrist

3. Kidney Damage
-Microalbuminuria (<20nmol/L- spot)
-Urine Albumin/creatinine ratio (<3.5 –W; <2.5 –M)

4. Sexual Dysfunction
- ED – earliest indicator for microvascular complication

1. Weight Management

2. Smoking – Quit/CXR/Spirometry

3. Nutrition - Understanding of GI/GL- ? Dietician input

4. Alcohol - M <2 SD; W<1 SD

5. Physical Activity 30 min/d ; 5/7 - ? Exercise physio

6. Immunisation - Influenza/pneumococcal/Tetanus

7. Mental Health - Sleep/depression–DASS/K10- ?psychologist
- <90cm –M; <84cm- W
- BMI :20-25

1. Compliance –

2. Understanding of how medication works

3. Does medication needs changing?
metformin/ exenetide
- Correlating this with BSL readings/HbA1c%
- Time for insulin?

4. Patient’s ability to manage medication
- ? HMR

5. Adverse reaction/Side effects?
- infections? Osteoporosis? Hypo? acidosis? renal
/liver function?

Driving
◦
◦
◦
◦
Check BSL prior to driving & 1-2 hourly on long trips.
If BGL < 5 do not drive.
Always carry jelly beans & graze on low GI food on long trips
All IDDM needs to notify Registrar of Motor Vehicles of their
insulin use

Medic Alert Bracelet

Glucagon Kit
- Know how to use as well as educate a close friend or family
member
AB–
CS-
Anaesthesia
Blood supply
Care
Structure
5 A’s:
Ask
Assess
Advise
Assist
Arrange
- Symptoms
- Signs
- Foot care; foot wear; action plans
- Involving other carers
- Regular reviews +/- referrals
Traffic Lights:
- General foot care advice
- Regular podiatry care and assessment
- Refer promptly to a podiatrist
Insulin
Oral + Insulin
Oral Combination
+
+
+
Oral Monotherapy
Diet and Exercise
Adapted from Riddle MC. Endocrinol Metab Clin North Am. 2005;34:77-98.
GLP-1 analogues
glucagon secretion; insulin secretion;
gastric emptying; improve satiety
Biguanides
↑ glucose uptake; ↓hepatic
glucose production
DPP-4 inhibitors
Prolong GLP-1 action leading to
improved pancreatic islet glucose
sensing, ↑ glucose uptake
Thiazolidinediones
↓lipolysis in adipose tis,
↑glucose uptake in
skeletal mm &↓glucose
production in liver
Sulfonylureas/Glinides
↑insulin secretion from
pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption
•
•
•
•
•
Metformin1
Alpha-glucosidase inhibitors2
Thiazolidinediones1,3
GLP-1 agonists4
DPP-4 inhibitors5–7
• Insulin
• Sulfonylurea
• Glinides








1. Kahn SE, et al. N Engl J Med. 2006;355:2427–2443;
2. Cefalu WT. Nature. 2007;81:636–649;
3. Bolen S, et al. Ann Intern Med. 2007;147:386–399;
4. DeFronzo RA, et al. Diabetes Care. 2005;28:1092–1100;
5. Stonehouse A. Curr Diabetes Rev. 2008;4:101–109;
6. Aschner P, et al. Diabetes Care. 2006;29:2632–2637;
7. Rosenstock J, et al. Diabetes Obes Metab 2008;10:376–386
OAD Agents
Weight Change (kg)
-3.8–0.5
Metformin1–3
-0.4–1.7
SUs1–4
0.9–4.6
TZDs4–6
0.3–3.0
Meglitinides4,7,8
Metformin +
-0.3–1.9
SU1–3
0.8–2.1
Metformin + TZD5,6,9
−5 −4 −3 −2 −1
Weight
Loss (kg)
0
1
Weight
Neutral
2
3
4
5
Weight
gain (kg)
OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione.
1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004.
3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert].
Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ:
Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC:
GlaxoSmithKline, 2005.
•
Metformin
GLP-1 agonists
DPP-4 inhibitors
•
•
•
•
Insulin
Sulfonylurea
Glinides
Thiazolidinediones
•
•







Exenetide
DPP4-I
200
400
150
300
Insulin (pmol/L)
Glucose (mg/dL)
OGTT and Matched IV Infusion
100
200
50
100
0
0
-30
0
30
60 90 120 150 180 210
Time (min)
Oral
-30
0
30
60 90 120 150 180 210
Time (min)
IV
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
Ingestion of
food
Release of gut
hormones —
incretins*
Active
GLP-1 & GIP
Glucose-dependent
 Insulin from β cells
(GLP-1 and GIP)
Pancreas
Blood glucose in
fasting and
postprandial states
β cells
α cells
GI tract
DPP-4
enzyme
Inactive
GLP-1
Glucose
uptake
by muscles
Glucose-dependent
 Glucagon from
α cells
(GLP-1)
Glucose
production
by liver
Inactive
GIP
*Incretin GLP-1 & GIP are released by the intestine
throughout the day; their levels ↑in response to a meal.
Meal
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
Active
GLP-1
DPP-4
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.
DPP-4
inhibitor
GLP-1
inactive
(>80% of pool)
44
Exenatide (Exendin-4)
◦ Synthetic
version
of
salivary
protein found in the Gila monster
◦ Approximately 50% identity with
human GLP-1
 Binds to known human GLP-1
receptors on  cells in vitro
 Resistant to DPP-4 inactivation
◦ Injectable S/C – like insulin
 BD before meals (10-30min
prior)
 Cold storage


In combination (double therapy) with Met or
SU where A1c>7%
In combination with Met and SU and A1c>7%
(triple therapy) where both Met and SU doses
have reached maximum
1.
2.
3.
Sitagliptin – Januvia
Vildagliptin – Galvus
Saxagliptin – Onglyza
Combination Therapy:
◦ Galvumet
– 50/500; 50/850; 50/1000
◦ Janumet - 50/500; 50/850; 50/1000
Insulin Resistance
(Impaired insulin action)
Pancreatic Islet Dysfunction
Inadequate
glucagon
suppression
(-cell
dysfunction)
Metformin
TZDs
Insufficient
Insulin
secretion
(β-cell
dysfunction)
Progressive
decline of βcell function
Sulfonylureas
Glinides
DPP-4
Weight of red arrows reflects the degree to which DPP-4 inhibitors influence the disease
mechanisms.
DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus.
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24–S40.

Safety & efficacy have not been compared to Insulin

Weight neutral or small loss

Risk of hypos vs SU significantly less

Weight gain and hypos can still occur with SU, may
need to reduce SU dose

Long term risk:benefit not known

Not in pregnancy or breast feeding

Not for T1DM




PBS listed Authority Required (STREAMLINED) item (code:
3540)
PBS-subsidised treatment is for dual oral combination
therapy with Met or SU
The listing also allows switching from another Gliptin,
GLP-1 or Glitazone
Gliptins are not PBS-subsided for monotherapy, triple
therapy or in combination with a Glitazone


Usual dose 100mg daily; BD in combination
with Metformin
Reduce dose in moderate-severe CRF
◦ CrCl 30-50 = 50mg daily
◦ CrCl <30 = 25mg daily


URTI, Nasopharyngitis
Rare anaphylaxis, angioedema, rash,
urticaria, exfoliative skin conditions,
pancreatitis

50mg bd with Metformin, 50mg daily with SU

Single pill combination to improve compliance

Use only if GFR>60

Not for patients with hepatic impairment, ALT/AST >2x

Incidence of skin reactions and pancreatitis rare

No Cyp450 interactions



Dose 5mg daily
Not in renal failure, has to have CrCl>50
No combination with Metformin available yet
Dosing
Januvia1
(sitagliptin)
100 mg
once daily
Galvus2
(vildagliptin)
50 mg
once or
twice daily
Onglyza3
(saxagliptin)
HbA1c (%)
Difference from placebo +
metformin adjusted mean
-0.65 *
Mean baseline 7.96%
- 0.7** (once daily dosing)
-1.1** (twice daily dosing)
5 mg once
daily
*p < 0.001 vs placebo + metformin
**p < 0.05 vs placebo + metformin
***p < 0.0001 vs placebo + metformin
CV safety data
-
-
Mean baseline 8.4%
-0.8***
Mean baseline 8.1%
Not associated with an
increased risk of CV events in
a pooled retrospective
analysis of the Phase 2b/3
clinical program4
1. Januvia Approved Product Information. 2. Galvus Approved Product
Information.
3. Onglyza Approved Product Information 4. Frederich R et al. Postgrad Med.
2010122:16–27.

Januvia (Sitagliptin)
◦ URTI**
◦ Nasopharyngitis**
◦ Headache

(uncommon)
Galvus (Vildagliptin)
◦ Dizziness
◦ Tremor
◦ Headache
(uncommon)
(uncommon)
(uncommon)






DPP-4 and GLP-1 based therapies offer a
novel new way to manage T2DM
Actions are beneficial physiologically
S/E are relatively minor
They are effective, but long term safety and
benefits not yet available
Used early in T2DM most useful
Single pill combo with Metformin useful
Ok, you can go home now!!!....