When to Start InsulinWhen to Start Insulin Doctors and Nurses Working Doctors and Nurses Working

TogetherTogether

Dr Ketan DhatariyaDr Ketan DhatariyaConsultant in Diabetes and EndocrinologyConsultant in Diabetes and Endocrinology

Norfolk and Norwich University Hospital NHS TrustNorfolk and Norwich University Hospital NHS Trust

Good Timing!Good Timing!

Why is it the 14Why is it the 14thth of of November?November?

Fred Banting – one Fred Banting – one of the co-of the co-discoverers of discoverers of insulin insulin

Born on 14Born on 14thth November 1891November 1891

We’re All Trying to Achieve The We’re All Trying to Achieve The Same Thing – But Using Different Same Thing – But Using Different

ApproachesApproaches

Some DefinitionsSome Definitions

Type 1Type 1

Type 2Type 2

Others (not mentioned any more)Others (not mentioned any more)

Two Main TypesTwo Main Types

Type 1Type 1 Autoimmune destruction of the Autoimmune destruction of the ββ cells of cells of

the Islets of Langerhans in the pancreas. the Islets of Langerhans in the pancreas. This leads to an absolute insulin This leads to an absolute insulin deficiency. Insulin treatment is therefore deficiency. Insulin treatment is therefore mandatorymandatory

Previously known as IDDM or juvenile Previously known as IDDM or juvenile onset diabetesonset diabetes

Two Main TypesTwo Main Types Type 2Type 2

Impaired insulin action (insulin Impaired insulin action (insulin resistance) and eventually, impaired resistance) and eventually, impaired insulin secretion as wellinsulin secretion as well

Usually treated with oral medication Usually treated with oral medication initially, then may move onto insulininitially, then may move onto insulin

Formerly known as NIDDM or maturity Formerly known as NIDDM or maturity onset diabetesonset diabetes

EpidemiologyEpidemiology

Diabetes currently affects approximately 3 Diabetes currently affects approximately 3 to 4% of the populationto 4% of the population

90% of whom have type 2 diabetes90% of whom have type 2 diabetes

Lifetime risk of developing diabetes is Lifetime risk of developing diabetes is about 10%about 10%

Why is it Important?Why is it Important?

Poorly controlled diabetes leads to Poorly controlled diabetes leads to accelerated cardiovascular morbidity and accelerated cardiovascular morbidity and mortalitymortality

A combination of microvascular and A combination of microvascular and macrovascular diseasemacrovascular disease

Thom T et al Circulation 2006;113(6):e85-151

Some Good NewsSome Good News

Health Consumer Power House Euro Consumer Diabetes Index Sept 2008

UKPDS HbA1c Median Values

06

7

8

9

0 3 6 9 12 15

Hb

A 1c (%

)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

Data From 3.3M DanesData From 3.3M Danes

Schramm TK et al Circulation 2008;117:1945-1954

An (?Uncontroversial) An (?Uncontroversial) Starting PointStarting Point

People with type 1 diabetes need to be People with type 1 diabetes need to be referred to the specialist hospital team at referred to the specialist hospital team at the time of suspected diagnosisthe time of suspected diagnosis

Many people continue to be followed up in Many people continue to be followed up in secondary care. secondary care. This depends heavily on the competence and This depends heavily on the competence and

confidence of the primary care team – and the confidence of the primary care team – and the support offered by secondary caresupport offered by secondary care

Non-Insulin Hypoglycaemic Non-Insulin Hypoglycaemic AgentsAgents

αα glucosidase inhibitors glucosidase inhibitors

MetaglinidesMetaglinides

MetforminMetformin

SulphonylureasSulphonylureas

ThiazolidindionesThiazolidindiones

GLP – 1 analoguesGLP – 1 analogues

DPP IV inhibitorsDPP IV inhibitors

αα Glucosidase Inhibitors Glucosidase Inhibitors

There is only 1 – acarbose There is only 1 – acarbose

Intestinal disaccharidase inhibitor Intestinal disaccharidase inhibitor

Taken one with each mealTaken one with each meal

If they don’t eat, no need to take the If they don’t eat, no need to take the tablettablet

HbA1c reduction of 0.5 - 0.8%HbA1c reduction of 0.5 - 0.8%

MetaglinidesMetaglinides

There are 2 – repaglinide and nateglinideThere are 2 – repaglinide and nateglinide

Work by binding to the sulphonylurea Work by binding to the sulphonylurea receptor and ‘squeezing’ the receptor and ‘squeezing’ the ββ cell to release cell to release insulininsulin

They stimulate first-phase insulin release in a They stimulate first-phase insulin release in a glucose-sensitive mannerglucose-sensitive manner

HbA1c reduction of 0.5 - 1.5%HbA1c reduction of 0.5 - 1.5%

MetforminMetformin

Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis)

MetforminMetformin First choice oral hypoglycaemic agent for First choice oral hypoglycaemic agent for

people with type 2 diabetes, regardless of BMIpeople with type 2 diabetes, regardless of BMI

Works by decreasing hepatic Works by decreasing hepatic gluconeogenesis, decreasing gut glucose gluconeogenesis, decreasing gut glucose uptake and increasing peripheral insulin uptake and increasing peripheral insulin sensitivitysensitivity

Metformin does not (or very rarely) give Metformin does not (or very rarely) give people hypos, because it works by preventing people hypos, because it works by preventing blood glucose levels rising rather than by blood glucose levels rising rather than by lowering glucose levels lowering glucose levels

HbA1c reduction of 1.0 – 2.0%HbA1c reduction of 1.0 – 2.0%

SulphonylureasSulphonylureas

• Have been around since the 1950’sHave been around since the 1950’s

• Act by binding to the SU receptor causing Act by binding to the SU receptor causing an influx of Caan influx of Ca2+2+ and an exocytosis of and an exocytosis of insulin containing vesiclesinsulin containing vesicles

• Use limited to individuals with a BMI < 25 Use limited to individuals with a BMI < 25 or in whom metformin is contraindicatedor in whom metformin is contraindicated

HbA1c reduction of 1.0 – 2.0%HbA1c reduction of 1.0 – 2.0%

ThiazolidinedionesThiazolidinediones Work by increasing peripheral insulin Work by increasing peripheral insulin

sensitivity at a nuclear level on peroxisome sensitivity at a nuclear level on peroxisome proliferator-activated receptor proliferator-activated receptor γγ (PPAR(PPAR γγ))

HbA1c reduction of 0.5 - 1.4%HbA1c reduction of 0.5 - 1.4%

Several controversies thus use is decliningSeveral controversies thus use is declining Increased CV death ratesIncreased CV death rates Increased fracture ratesIncreased fracture rates Increased rates of macular oedemaIncreased rates of macular oedema

Nissen SE NEJM 2007;356(24):2457-2471Loke Y et al In press

Ryan EH et al Retina 2006; 26(5):562-70

GLP-1 and DPP-IVGLP-1 and DPP-IV

Nauck MA et al. Diabetologia 1993;36:741–744; Larsson H et al. Acta Physiol Scand 1997;160:413–422; Nauck MA et al. Diabetologia 1996;39:1546–1553; Flint A et al. J Clin Invest 1998;101:515–520; Zander et al. Lancet

2002;359:824–830.

GLP-1 secreted upon the ingestion of food

1.-cell:cell:Enhances glucose-Enhances glucose-

dependent insulin secretion dependent insulin secretion in the pancreasin the pancreas

3.Liver:3.Liver: reduces hepatic glucose reduces hepatic glucose

outputoutput

2.2.αα--cell:cell:Suppresses postprandialSuppresses postprandial

glucagon secretionglucagon secretion

4.Stomach:4.Stomach: slows the rate of slows the rate of gastric emptyinggastric emptying

5.Brain:5.Brain:Promotes satiety and Promotes satiety and

reduces appetitereduces appetite

Their Effects Are AdditiveTheir Effects Are Additive

HbA1C

Time

The Goalposts Are ChangingThe Goalposts Are Changing

HbAHbA11C targets are coming downC targets are coming down

The tighter the control, the likelihood of The tighter the control, the likelihood of developing complications reduces – to a developing complications reduces – to a pointpoint

EVERY 1%

reduction in HbA1c

REDUCED RISK*

1%

Deaths from diabetes –21%

Heart attacks –14%

Microvascular complications–37%

Peripheral vascular disorders

UKPDS 35. BMJ 2000;321:405–12

Lessons from UKPDS:Lessons from UKPDS:Better Control Means Fewer Better Control Means Fewer

ComplicationsComplications

–43%

*p<0.0001

How Many Guidelines?How Many Guidelines?

EASD / ADAEASD / ADA Nathan et al Diabetes care 22/10/08 epub Nathan et al Diabetes care 22/10/08 epub

ahead of publication ahead of publication http://care.diabetesjournals.org/misc/dv08-http://care.diabetesjournals.org/misc/dv08-9025.pdf9025.pdf

NICENICE http://www.nice.org.uk/nicemedia/pdf/http://www.nice.org.uk/nicemedia/pdf/

CG66diabetesfullguideline.pdfCG66diabetesfullguideline.pdf

Royal College of PhysiciansRoyal College of Physicians http://www.rcplondon.ac.uk/pubs/contents/http://www.rcplondon.ac.uk/pubs/contents/

14f051f1-8fa4-4d0b-9385-9f2e77edc2ca.pdf14f051f1-8fa4-4d0b-9385-9f2e77edc2ca.pdf

Recent ADA / EASD Recent ADA / EASD GuidelinesGuidelines

Nathan DM et al Diabetes Care 22/10/08 epub online

NICE AdviceNICE Advice

http://www.nice.org.uk/nicemedia/pdf/CG66diabetesfullguideline.pdf Accessed 9th November 2008

RCP Management of Type 2 diabetes – May 2008 Accessed 9.11.08

http://www.rcplondon.ac.uk/pubs/contents/14f051f1-8fa4-4d0b-9385-9f2e77edc2ca.pdf

Tighter ControlTighter Control

This means that oral agents alone may not This means that oral agents alone may not be sufficient and that insulin needs to be be sufficient and that insulin needs to be addedadded

Consider the Following Consider the Following ScenariosScenarios

60 year old, CVA, blind, dense hemiplegia, 60 year old, CVA, blind, dense hemiplegia, lives in a nursing home, fully dependent lives in a nursing home, fully dependent

80 year old, plays golf daily, travels the 80 year old, plays golf daily, travels the world extensively with their 60 year old world extensively with their 60 year old partner looking for ‘excitement’partner looking for ‘excitement’

QOF is not ‘situation specific’QOF is not ‘situation specific’

InsulinInsulin

Should be started when the HbAShould be started when the HbA11C is C is ≥ ≥ 7.5% on maximal oral hypoglycaemics7.5% on maximal oral hypoglycaemics

PregnancyPregnancy

SteroidsSteroids

Intercurrent illnessIntercurrent illness

Now You’ve made Your Now You’ve made Your DecisionDecision

A few questionsA few questions Which insulin?Which insulin?

What dose?What dose?

What regime?What regime?

What do I do with the tablets?What do I do with the tablets?

Should I address their weight first??Should I address their weight first??

InsulinsInsulins

Soluble (short acting)Soluble (short acting)

NPH (intermediate)NPH (intermediate)

Once dailyOnce daily

MixturesMixtures

Insulin analogues – ultra short, long and Insulin analogues – ultra short, long and

mixturesmixtures

EASD / ADA EASD / ADA RecommendationsRecommendations

Start with once daily basal insulin Start with once daily basal insulin Which type of insulin depends on when BG levels are highestWhich type of insulin depends on when BG levels are highest

If there are no contraindications – stay on night If there are no contraindications – stay on night time insulin, with day time metformin or SU’stime insulin, with day time metformin or SU’s

Keep regularly increasing the dose until the Keep regularly increasing the dose until the fasting blood glucose is less than 7.0 mmol/Lfasting blood glucose is less than 7.0 mmol/L

Holman RR et al N Engl J Med 2007;357:1716-1730

Bretzel RG et al Lancet 2008;371:1073-1084; Nathan DM et al Diabetes Care 22/10/2008; epub

Riddle MC Endocrine and Metabolic Clinics of North America 2005;34:77-98; Pala L et al Diabetes Res Clin Pract 2007;78:132-135

Other OptionsOther Options

Twice daily mixtures are commonly used Twice daily mixtures are commonly used but may be associated with greater weight but may be associated with greater weight gain than once daily injectionsgain than once daily injections

Three times daily mixtures are also Three times daily mixtures are also common on the continentcommon on the continent

In people who have unpredictable In people who have unpredictable lifestyles, a basal bolus regime may be lifestyles, a basal bolus regime may be appropriateappropriate

ADA/EASD ADA/EASD Insulin Insulin

Initiation Initiation GuidelineGuideline

ss

Nathan DM et al Diabetes Care 22/10/08

epub online

There are Other Algorithms There are Other Algorithms

At:Lantus – starting at 10 IU / dayAt:Lantus – starting at 10 IU / day

Davies M et al Diabetes Care 2005;28:1282-1288

Potential ImplicationsPotential Implications

DrivingDriving

InsuranceInsurance

Recent DataRecent Data

ACCORD ACCORD (Action to Control Cardiovascular Risk in (Action to Control Cardiovascular Risk in Diabetes)Diabetes)

ADVANCE ADVANCE (Action in Diabetes and Vascular Disease: (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Preterax and Diamicron Modified Release Controlled Evaluation)Evaluation)

VADT VADT (Veteran’s Administration Diabetes Trial)(Veteran’s Administration Diabetes Trial)

NEJM 2008;358(24):2545-2559NEJM 2008;358(24):2560-2572

Duckworth WC et al Diabetes Care 2001;24:942-945

Tighter Glycaemic Control Tighter Glycaemic Control Does Does NOTNOT Influence Influence

OutcomesOutcomes Getting HbA1C to less that 7.0% added no Getting HbA1C to less that 7.0% added no

benefitbenefit

In ACCORD it lead to a higher mortality In ACCORD it lead to a higher mortality raterate

Lots of reasons – including better risk Lots of reasons – including better risk factor managementfactor management

Increased Use of Adjunctive Increased Use of Adjunctive AgentsAgents

Charlton J et al Diabetes Care 2008;31(8):1761-1766

Things That Make the Most Things That Make the Most DifferenceDifference

Smoking Smoking OR 2.87OR 2.87 Raised ApoB/ApoA1 ratioRaised ApoB/ApoA1 ratio OR 3.25OR 3.25 History of hypertensionHistory of hypertension OR 1.91OR 1.91 DiabetesDiabetes OR 2.37OR 2.37 Abdominal obesityAbdominal obesity OR 1.12OR 1.12 Psychosocial factorsPsychosocial factors OR 2.67OR 2.67 Daily fruit and veg intakeDaily fruit and veg intake OR 0.7OR 0.7 Regular alcohol consumptionRegular alcohol consumption OR 0.9OR 0.9 Regular physical activityRegular physical activity OR 0.86OR 0.86

Yusuf et al Lancet 2004 364:937-952

In SummaryIn Summary There are a lot of medications to try firstThere are a lot of medications to try first

Weight loss is a cornerstone to delaying Weight loss is a cornerstone to delaying insulininsulin

To ensure the best outcomes for your To ensure the best outcomes for your patients with diabetes patients with diabetes Be Aggressive! Be Aggressive! Treat Early!Treat Early!

Being on insulin is not ‘failure’Being on insulin is not ‘failure’

Thank you for your attention