Role of Combination Therapy in Type II Diabetes

Dr Cleo ChengMidwest HealthBeverley

22.11.2011

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 :

Diabetes overview – 10 min

Screening at risk groups – 10min GPMP – 30min DM foot assessment– 10min Medications – 20min Q & A – 10min

Presentation Plan:

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

What is Diabetes?

◦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!!

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)

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

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

But there are other forces at work to BSL Glucocorticoid Catecholamine Thyroid hormones Growth Hormones Adipose/Fat cells

EXERCISE - BSL

Diabetes

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

Types of Diabetes

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

Who is susceptible?

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

How to screen?

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/

http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di17-diabetes-detection-diagnosis.pdf

Diagnosing NIDDM Fasting BSL

◦ >5.4 ? - do GTT◦ >7.0 - NIDDM

Random BSLo >11.1 - NIDDM

____________________________________________ HbA1c

o >6.4% - NIDDM

GPMP -Diabetes

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

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)

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

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

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?

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

DM Foot Assessment

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

NIDDM Medication

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

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

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

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)

Agents :neutral to positive weight loss

• Metformin • GLP-1 agonists • DPP-4 inhibitors

• Insulin

• Sulfonylurea

• Glinides

• Thiazolidinediones

Exenetide DPP4-I

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

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

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

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

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

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

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)

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

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

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

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

Saxagliptin (Onglyza) Dose 5mg daily Not in renal failure, has to have CrCl>50 No combination with Metformin available

yet

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.

Januvia (Sitagliptin)◦ URTI**◦ Nasopharyngitis**◦ Headache (uncommon)

Galvus (Vildagliptin)◦ Dizziness (uncommon)◦ Tremor (uncommon)◦ Headache (uncommon)

SE profile:

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

Questions?

The End! Ok, you can go home now!!!....