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Role of Combination Therapy in Type II Diabetes
Dr Cleo ChengMidwest HealthBeverley
22.11.2011
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1. Refresh pathophysiology of DM2. ↑awareness of at risk groups to screen3. Competence in conducting brilliant
GPMP–DM4. ↑Awareness of latest combination
therapies (Gliptins)
Objectives :
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Diabetes overview – 10 min
Screening at risk groups – 10min GPMP – 30min DM foot assessment– 10min Medications – 20min Q & A – 10min
Presentation Plan:
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Diabetes in Australia – BIG problem & getting biggerAround 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% - DM15% - Pre DM & DM
↟300% in past 20 years –Obesogenic environment
Diabetes Atlas, third edition, International Diabetes Federation, 2007Diabetes and Cardiovascular Disease: Time to Act, International Diabetes Federation, 2001AusDiab Report, 2006The Economic Costs of Obesity, 2006World Health Organisation Diabetes Uni
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What is Diabetes?
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◦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 insulinα-cells of Islet of Langerhans in pancreas glucagon
DiabetesTOO MUCH SUGAR IN THE BLOOD!!... but starving in the face of plenty!!
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Roles of Glucagon and Insulin in Normal Glucose Homeostasis
#Insulin 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.
+Glucagon*
(plasma concentration)
–
–Insulin#
(plasma concentration)
+Glucose(plasma
concentration)
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Type 2 Diabetes Pathophysiology
Impaired insulin secretion
Hyperglycaemia
Increased HGP Decreased glucose uptake
DeFronzo RA. Diabetes 2009; 58:773–95.
-Cellsproduce
less insulin
-Cellsproduce excess
glucagon
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Physiology in Type 2 Diabetes
Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Hepatic glucoseoutput
Insulin resistance
Glucose uptake
Glucagon(α cell)
Insulin(β cell)
Liver
Hyperglycaemia
Islet-Cell Dysfunction
MuscleAdipose
tissue
Pancreas
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But there are other forces at work to BSL Glucocorticoid Catecholamine Thyroid hormones Growth Hormones Adipose/Fat cells
EXERCISE - BSL
Diabetes
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Normal IGT Type 2 diabetes
Post-prandial glucose
Abnormalglucose tolerance
Insulin resistance
Increased insulinresistance
Fasting glucose Hyperglycemia
Insulinsecretion
Hyperinsulinemia,then -cell failure
Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.
Insulin Resistance and -cell Dysfunction in T2DM
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Types of Diabetes
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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
Types of Diabetes
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Who is susceptible?
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Family history Obesity/Overweight - BMI >25 (85%) Over 40+ Ethnicity:
◦ Aboriginal/TSI/Maori (>18)◦ Indian (>30)◦ Chinese (>30)◦ Vietnamese/Cambodian/Laos/Thai (>30)
At Risk groups - NIDDM
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How to screen?
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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-Health-Professionals/Resources/
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http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di17-diabetes-detection-diagnosis.pdf
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Diagnosing NIDDM Fasting BSL
◦ >5.4 ? - do GTT◦ >7.0 - NIDDM
Random BSLo >11.1 - NIDDM
____________________________________________ HbA1c
o >6.4% - NIDDM
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GPMP -Diabetes
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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
GPMP/TCA : NIDDM
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1. Disease Specific Care 1. HbA1c %
- <6.4/<7.0 / elderly
2. BSL- Fast 4-6/Post -8 (+2 = Fair ; +4 = Poor)
3. BP-130/80 (avoid thiazide diuretics/ B – blockers)-Annual ECG
4. Lipids TC <4.0; TG<1.5; HDL>1.0; LDL<2.5 (1.8)
5. Aspirin- CVS risk calculator >15% (75-100mg/day)
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2. Complications 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
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3. Lifestyle 1. Weight Management
- <90cm –M; <84cm- W - BMI :20-25
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
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4. Medication Review 1. Compliance – metformin/ exenetide 2. Understanding of how medication
works 3. Does medication needs changing?
- 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?
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5. IDDM 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
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DM Foot Assessment
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Traffic Lights: - General foot care advice
- Regular podiatry care and assessment
- Refer promptly to a podiatrist
ABCS Diabetes Foot AssessmentA - Anaesthesia
B – Blood supplyC - CareS - Structure
5 A’s:Ask - SymptomsAssess - SignsAdvise - Foot care; foot wear; action plansAssist - Involving other carersArrange - Regular reviews +/- referrals
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NIDDM Medication
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Lifestyle Changes
Adapted from Riddle MC. Endocrinol Metab Clin North Am. 2005;34:77-98.
Diet and Exercise
Oral Monotherapy
Standard Approach to Management of T2DM: Treatment Intensification
Oral Combination +
Oral + Insulin + +
Insulin
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Current Drugs Used in T2DM
-glucosidase inhibitorsDelay intestinal carbohydrate absorption
Thiazolidinediones↓lipolysis in adipose tis, ↑glucose uptake in skeletal mm &↓glucose production in liver
Sulfonylureas/Glinides↑insulin secretion from pancreatic -cells
GLP-1 analoguesglucagon secretion; insulin secretion; gastric emptying; improve satiety
Biguanides↑ glucose uptake; ↓hepatic glucose production
DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, ↑ glucose uptake
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Agents : Lower hypoglycaemic risks• 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
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TZDs4–6
Metformin + TZD5,6,9
Metformin + SU1–3
Meglitinides4,7,8
SUs1–4
Metformin1–3
Weight Change (kg)OAD Agents
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.
Weight Gain - Common SE of NIDDM Treatments
−5 −4 −3 −2 −1 0 1 2 3 4 5
-3.8–0.5
-0.4–1.7
0.9–4.6
0.3–3.0
-0.3–1.9
0.8–2.1
Weight Neutral
Weight Loss (kg)
Weight gain (kg)
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Agents :neutral to positive weight loss
• Metformin • GLP-1 agonists • DPP-4 inhibitors
• Insulin
• Sulfonylurea
• Glinides
• Thiazolidinediones
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Exenetide DPP4-I
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Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
OGTT and Matched IV Infusion
Glu
cose
(m
g/dL
)
0
50
100
150
200
-30 0 30 60 90 120 150 180 210Time (min)
Insu
lin (
pmol
/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210Time (min)
Proof of a GI ‘Incretin Effect’: ΔResponses to Oral vs IV Glucose
Oral IV
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Incretins modulate Insulin & Glucagon to ↓BSL during Hyperglycaemia
Ingestion of food
β cells
Release of gut hormones — incretins*
Pancreas
Glucose-dependent Insulin from β cells
(GLP-1 and GIP)Glucose uptake
by muscles
Glucose-dependent Glucagon from
α cells(GLP-1)
GI tract
ActiveGLP-1 & GIP
DPP-4 enzym
e
InactiveGIP
InactiveGLP-1
*Incretin GLP-1 & GIP are released by the intestine throughout the day; their levels ↑in response to a
meal.
Glucose productio
n by liver
Blood glucose in fasting and postprandial
statesα cells
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Inhibition of DPP-4 Increases Active GLP-1
GLP-1inactive
(>80% of pool)
ActiveGLP-1
Meal
DPP-4
IntestinalGLP-1 release
GLP-1 t½=1–2 min
DPP-4inhibitor
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.
44
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Exenatide (Byetta)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
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Exenatide – Authority PBS 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
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DPP-4 inhibitors 1. Sitagliptin – Januvia2. Vildagliptin – Galvus3. Saxagliptin – Onglyza
Combination Therapy: ◦Galvumet – 50/500; 50/850; 50/1000◦Janumet - 50/500; 50/850; 50/1000
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Mechanisms of Action of Currently Available Treatments
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.
Sulfonylureas
Glinides
TZDsMetformin
DPP-4
Pancreatic Islet Dysfunction
Inadequate glucagonsuppression(-cell dysfunction)
Progressivedecline of β-cell function
Insufficient Insulin secretion (β-celldysfunction)
Insulin Resistance (Impaired insulin action)
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Gliptins: DPP4-I 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
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PBS listing information for Gliptins
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
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Sitagliptin (Januvia) 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
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Vildagliptin (Galvus) 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
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Saxagliptin (Onglyza) Dose 5mg daily Not in renal failure, has to have CrCl>50 No combination with Metformin available
yet
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DPP-4 inhibitors: Efficacy
Dosing HbA1c (%)Difference from placebo + metformin adjusted mean
CV safety data
Januvia1
(sitagliptin) 100 mg
once daily-0.65 *
Mean baseline 7.96% -
Galvus2 (vildagliptin)
50 mg once or
twice daily
- 0.7** (once daily dosing)-1.1** (twice daily dosing)
Mean baseline 8.4%-
Onglyza3 (saxagliptin)
5 mg once daily
-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
*p < 0.001 vs placebo + metformin **p < 0.05 vs placebo + metformin***p < 0.0001 vs placebo + metformin
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.
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Januvia (Sitagliptin)◦ URTI**◦ Nasopharyngitis**◦ Headache (uncommon)
Galvus (Vildagliptin)◦ Dizziness (uncommon)◦ Tremor (uncommon)◦ Headache (uncommon)
SE profile:
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Summary 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
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Questions?
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The End! Ok, you can go home now!!!....