Therapeutics in Therapeutics in DiabetesDiabetes

Kate SpittleKate Spittle

Prescribing AdvisorPrescribing Advisor

Cwm Taf LHBCwm Taf LHB

SummarySummary

Issues around diabetesIssues around diabetes Drugs used for control of Drugs used for control of

hyperglycaemiahyperglycaemia Monitoring of glucose controlMonitoring of glucose control NICE guidanceNICE guidance

Hypertension in diabetesHypertension in diabetes Lipids Lipids AspirinAspirin

QuestionsQuestions

DiabetesDiabetes Around 7% in Wales are being treated Around 7% in Wales are being treated

for diabetesfor diabetes 16% of these are > 65yrs16% of these are > 65yrs Incidence is increasing -predicted to Incidence is increasing -predicted to

rise to 10.3% in 2020, 11.5& in 2030rise to 10.3% in 2020, 11.5& in 2030 Poor diet, lack of physical activity and a Poor diet, lack of physical activity and a

sedentary lifestyle are major sedentary lifestyle are major contributorscontributors

½ adult population and around a 1/3 of ½ adult population and around a 1/3 of children in Wales are classified as children in Wales are classified as overweight or obeseoverweight or obese

DiabetesDiabetes

Lifestyle interventions promoting Lifestyle interventions promoting moderate weight loss together with moderate weight loss together with an increase in physical activity have an increase in physical activity have been shown to result in a more than been shown to result in a more than 50% reduction in the risk of type 2 50% reduction in the risk of type 2 diabetes amongst at risk individuals diabetes amongst at risk individuals

( Knowler et al 2002 )( Knowler et al 2002 )

!!!!

Realistic Plans?Realistic Plans?

Aims of ManagementAims of Management

Prevent diabetesPrevent diabetes Lifestyle choices, minimise riskLifestyle choices, minimise risk

Early detectionEarly detection Fast, effective treatmentFast, effective treatment

Live longer and healthier livesLive longer and healthier lives Support living with diabetesSupport living with diabetes

Patients are supported and informed to Patients are supported and informed to manage their diabetesmanage their diabetes

Type 2 DiabetesType 2 Diabetes

90% of cases of diabetes90% of cases of diabetes Often associated with obesityOften associated with obesity Characterised by;Characterised by;

Insulin resistance ( a greater than Insulin resistance ( a greater than normal amount of insulin is required to normal amount of insulin is required to produce a biological response )produce a biological response )

Relative insulin deficiencyRelative insulin deficiency SymptomsSymptoms

Financial CostsFinancial Costs

In Cwm Taf we spend per year;In Cwm Taf we spend per year; £4.78million on drugs for diabetes£4.78million on drugs for diabetes

£2million on insulins£2million on insulins £1million on blood glucose testing £1million on blood glucose testing

reagentsreagents £0.5million on metformin£0.5million on metformin £0.5million on exenatide and liraglutide£0.5million on exenatide and liraglutide

Treatment AimsTreatment Aims

Optimal glycaemic controlOptimal glycaemic control ‘‘target’ HbA1c of <6.5 – 7.5% ( 48-target’ HbA1c of <6.5 – 7.5% ( 48-

59mmol )59mmol ) Cardiovascular risk reductionCardiovascular risk reduction Minimise the risk of long term Minimise the risk of long term

complicationscomplications

PolypharmacyPolypharmacy

Therapeutic OptionsTherapeutic Options Lifestyle ( diet, exercise, weight loss, Lifestyle ( diet, exercise, weight loss,

smoking )smoking ) Structured education ( not covered )Structured education ( not covered ) TreatmentTreatment

BiguanidesBiguanides SulfonylureasSulfonylureas ThiazolidinedionsThiazolidinedions Repaglinide / NateglinideRepaglinide / Nateglinide Incretins – DPP4 inhibitors and GLP-1 Incretins – DPP4 inhibitors and GLP-1

analoguesanalogues AcarboseAcarbose Insulin ( not covered )Insulin ( not covered )

Biguanides - MetforminBiguanides - Metformin

Decreases hepatic gluconeogenesisDecreases hepatic gluconeogenesis Increases peripheral utilisation of Increases peripheral utilisation of

glucoseglucose Only acts in the presence of Only acts in the presence of

endogenous insulin, so only effective endogenous insulin, so only effective if there are some functioning if there are some functioning pancreatic islet cellspancreatic islet cells

No risk of hypoglycaemiaNo risk of hypoglycaemia

MetforminMetformin

Drug of first choice in overweight patientsDrug of first choice in overweight patients (May be considered if patient is not (May be considered if patient is not

overweight)overweight) Dosage – start low and go slowDosage – start low and go slow BNF – initially 500mg once daily with BNF – initially 500mg once daily with

breakfast for at least a week, then 500mg breakfast for at least a week, then 500mg twice daily for 1 week, then 500mg three twice daily for 1 week, then 500mg three times a daytimes a day

Max dose ( BNF ) 2g daily ( 3g daily )Max dose ( BNF ) 2g daily ( 3g daily )

MetforminMetformin Side effectsSide effects

NauseaNausea VomitingVomiting DiarrhoeaDiarrhoea AnorexiaAnorexia Bloating and Bloating and

discomfortdiscomfort Metallic tasteMetallic taste B12 malabsorptionB12 malabsorption Lactic acidosis Lactic acidosis

( rare )( rare )

Contra-indicationsContra-indications eGFR <30 ml/mineGFR <30 ml/min ( care if <45ml/min)( care if <45ml/min) Liver failureLiver failure Moderate / severe Moderate / severe

cardiac failurecardiac failure General anaesthesia General anaesthesia

(stop on morning of (stop on morning of surgery and restart surgery and restart when renal function when renal function returns to baseline )returns to baseline )

MetforminMetformin

If GI problems occur, slow down If GI problems occur, slow down titrationtitration

50% will tolerate the MR 50% will tolerate the MR preparation if they experience GI preparation if they experience GI side effectsside effects

If swallowing difficulties, use sachets If swallowing difficulties, use sachets or check with LHB prescribing teamor check with LHB prescribing team

How much do you How much do you think we spend on think we spend on Metformin in Cwm Metformin in Cwm

Taf?Taf?..

Usage of Metformin in Cwm Usage of Metformin in Cwm TafTaf

SulfonylureasSulfonylureas

Gliclazide, Glipizide, Glimepiride, Gliclazide, Glipizide, Glimepiride, Glibenclamide, TolbutamideGlibenclamide, Tolbutamide

Enhance insulin secretion – independent of Enhance insulin secretion – independent of glucoseglucose

Only effective when residual pancreatic Only effective when residual pancreatic beta-cell activity is presentbeta-cell activity is present

Lower HbA1c by 1.5%Lower HbA1c by 1.5% Weight gain typically 2kgWeight gain typically 2kg Hypoglycaemia risk especially in elderly / Hypoglycaemia risk especially in elderly /

renal impairmentrenal impairment

SulfonylureasSulfonylureas

Side effectsSide effects HypoglycaemiaHypoglycaemia Weight gainWeight gain GI disturbanceGI disturbance HeadacheHeadache FeverFever JaundiceJaundice Blood dyscrasiasBlood dyscrasias

Contra-indicationsContra-indications PregnancyPregnancy breast feedingbreast feeding Renal impairmentRenal impairment Hepatic impairmentHepatic impairment

DisadvantageDisadvantage Accelerates decline Accelerates decline

in beta cell functionin beta cell function

SulfonylureasSulfonylureas

Choice of preparation is determined Choice of preparation is determined by side effects and the duration of by side effects and the duration of actionaction

Gliclazide – short acting Gliclazide – short acting Glibenclamide – long acting so Glibenclamide – long acting so

should be avoided in the elderlyshould be avoided in the elderly

GliclazideGliclazide

Initially 40-80mg dailyInitially 40-80mg daily Adjust dose according to response Adjust dose according to response

( review in one week?)( review in one week?) Up to 160mg as a single daily dose Up to 160mg as a single daily dose

with breakfastwith breakfast Max dose 320mg daily in divided Max dose 320mg daily in divided

dosesdoses

Usage ofUsage of Sulfonylureas in Sulfonylureas in Cwm TafCwm Taf

ThiazolidinedionesThiazolidinedionesPioglitazonePioglitazone

Reduce peripheral insulin resistance Reduce peripheral insulin resistance leading to a reduction in blood leading to a reduction in blood glucoseglucose

Sensitizes fat, muscle and liver to Sensitizes fat, muscle and liver to endogenous and exogenous insulinendogenous and exogenous insulin

Rosiglitazone – withdrawn due to CV Rosiglitazone – withdrawn due to CV riskrisk

Pioglitazone – concerns over bladder Pioglitazone – concerns over bladder cancer riskcancer risk

PioglitazonePioglitazone

Side effectsSide effects GI disturbanceGI disturbance Weight gainWeight gain Fluid retentionFluid retention DizzinessDizziness HeadacheHeadache anaemiaanaemia

Contra-indicationsContra-indications PregnancyPregnancy BreastfeedingBreastfeeding Hepatic impairmentHepatic impairment Cardiac failureCardiac failure

PioglitazonePioglitazone

DosageDosage Adult, initially 15-30mg daily , increased Adult, initially 15-30mg daily , increased

to 45mg daily according to responseto 45mg daily according to response Elderly, initiate with lowest possible dose Elderly, initiate with lowest possible dose

and increase graduallyand increase gradually Review treatment after 3-6 monthsReview treatment after 3-6 months Dose of sulfonylurea or insulin may need Dose of sulfonylurea or insulin may need

to be reduced if used concomitantlyto be reduced if used concomitantly

PioglitazonePioglitazone

Cardiovascular safety (Dec 07,Jan 11)Cardiovascular safety (Dec 07,Jan 11) Incidence of heart failure is increased if Incidence of heart failure is increased if

pioglitazone is combined with insulin especially in pioglitazone is combined with insulin especially in patient with predisposing factors. Patients should patient with predisposing factors. Patients should be closely monitored for signs of heart failurebe closely monitored for signs of heart failure

Bladder cancer ( July 11 )Bladder cancer ( July 11 ) Small increased risk. Should not be used in Small increased risk. Should not be used in

patients with active bladder cancer or past history patients with active bladder cancer or past history of bladder cancer or in those with uninvestigated of bladder cancer or in those with uninvestigated macroscopic haematuria. Pioglitazone should be macroscopic haematuria. Pioglitazone should be used with caution in the elderly as the risk of used with caution in the elderly as the risk of bladder cancer increases with agebladder cancer increases with age

PioglitazonePioglitazone

Review at 3-6 monthsReview at 3-6 months Stop if inadequate response to Stop if inadequate response to

treatmenttreatment NICE – continue only if HbA1c is NICE – continue only if HbA1c is

reduced by 0.5% within 6 months of reduced by 0.5% within 6 months of starting treatmentstarting treatment

MetiglinidesMetiglinidesPrandial Glucose Prandial Glucose

RegulatorsRegulators Nateglinide / repaglinideNateglinide / repaglinide Stimluate release of insulinStimluate release of insulin Early phase of insulin release in response Early phase of insulin release in response

to food lost in type 2 diabetes to food lost in type 2 diabetes Rapid onset of action Rapid onset of action Short duration of action – so do not Short duration of action – so do not

stimulate beta cells constantlystimulate beta cells constantly Take just before each main meal. Gives Take just before each main meal. Gives

flexibility with meal timesflexibility with meal times HbA1c reduction ~1%HbA1c reduction ~1%

MetiglinidesMetiglinides

Side effectsSide effects HypoglycaemiaHypoglycaemia NauseaNausea VomitingVomiting ConstipationConstipation DiarrhoeaDiarrhoea RashRash prurituspruritus

Contra-indicationsContra-indications Severe hepatic Severe hepatic

impairmentimpairment PregnancyPregnancy Breast feedingBreast feeding

Surgery – omit on Surgery – omit on morning of surgery morning of surgery and recommence and recommence when eating and when eating and drinking normallydrinking normally

MetiglinidesMetiglinides NateglinideNateglinide

Adult, initially 60mg Adult, initially 60mg three times a day three times a day within 30mins of main within 30mins of main meal. meal.

Adjust according to Adjust according to responseresponse

Max 180mg three times Max 180mg three times a daya day

RepaglinideRepaglinide Adult, initially 500mcg Adult, initially 500mcg

within 30mins of main within 30mins of main meal ( 1mg if meal ( 1mg if transferring from other transferring from other oral hypoglycaemic )oral hypoglycaemic )

Adjust according to Adjust according to response at intervals of response at intervals of 1-2 weeks1-2 weeks

Up to 4mg may be Up to 4mg may be given as single dosegiven as single dose

Max 16mg dailyMax 16mg daily Over 75years not recOver 75years not rec

AcarboseAcarbose Slows rate of carbohydrate absorptionSlows rate of carbohydrate absorption Reduces post prandial hyperglycaemiaReduces post prandial hyperglycaemia Reduces HbA1c ~0.8%Reduces HbA1c ~0.8% Rarely used in UK due to GI side effectsRarely used in UK due to GI side effects

Flatulence, soft stools, diarrhoea, Flatulence, soft stools, diarrhoea, abdominal distension and painabdominal distension and pain

Dose – Adult, 50mg daily increased to Dose – Adult, 50mg daily increased to 50mg three times a day, then 100mg 50mg three times a day, then 100mg three times a day after 6-8 weeks. Max three times a day after 6-8 weeks. Max 200mg three times a day200mg three times a day

The Sugar Coated Pill?The Sugar Coated Pill?

Progressive Defects in Type Progressive Defects in Type 2 Diabetes2 Diabetes

Progressive decline in beta cell Progressive decline in beta cell functionfunction

Inadequate insulin secretionInadequate insulin secretion Unsuppressed post prandial Unsuppressed post prandial

glucagon secretionglucagon secretion

GLP – 1 EnzymeGLP – 1 Enzyme GLP -1 secretion is impaired in type GLP -1 secretion is impaired in type

2 diabetes2 diabetes Activation of the GLP-1 receptorActivation of the GLP-1 receptor

increases insulin secretionincreases insulin secretion Suppresses glucagon secretionSuppresses glucagon secretion Slow gastric emptyingSlow gastric emptying

Exenatide and Liraglutide both bind Exenatide and Liraglutide both bind to and activate the GLP-1 receptorto and activate the GLP-1 receptor

The gliptins block DPP-4, the The gliptins block DPP-4, the enzyme that degrades GLP-1enzyme that degrades GLP-1

ExenatideExenatide Treatment is associated with the Treatment is associated with the

prevention of weight gain and prevention of weight gain and possible weight losspossible weight loss

Subcutaneous injectionSubcutaneous injection NICE – treatment continued only if NICE – treatment continued only if

HbA1c is reduced by at least 1% and HbA1c is reduced by at least 1% and a weight loss of at least 3% within 6 a weight loss of at least 3% within 6 monthsmonths

How often are patients reviewed and How often are patients reviewed and treatment stopped?treatment stopped?

ExenatideExenatide Dose – s/c injectionDose – s/c injection Initially 5mcg twice daily,1 hour Initially 5mcg twice daily,1 hour

before 2 main mealsbefore 2 main meals Increased if necessary after at least Increased if necessary after at least

1 month to 10mcg twice daily1 month to 10mcg twice daily If dose is missed, do not administer If dose is missed, do not administer

after a meal, continue with next after a meal, continue with next scheduled dosescheduled dose

Dose of sulfonylurea may need to be Dose of sulfonylurea may need to be reduced if used togetherreduced if used together

Exenatide Usage in Cwm Exenatide Usage in Cwm TafTaf

LiraglutideLiraglutide

Dose – by s/c injectionDose – by s/c injection Adult 0.6mg once dailyAdult 0.6mg once daily Increased after at least 1 week to Increased after at least 1 week to

1.2mg daily1.2mg daily Further increased if nec. after at Further increased if nec. after at

least 1 week to max 1.8mg dailyleast 1 week to max 1.8mg daily Dose of sulfonylurea may need to be Dose of sulfonylurea may need to be

reducedreduced

Liraglutide Usage in Liraglutide Usage in Cwm TafCwm Taf

Exenatide / LiraglutideExenatide / Liraglutide

Side effectsSide effects GI effectsGI effects Decreased appetiteDecreased appetite Weight lossWeight loss HeadacheHeadache dizzinessdizziness

Contra – Contra – indicationsindications Severe GI diseaseSevere GI disease PregnancyPregnancy PancreatitisPancreatitis Severe renal Severe renal

impairmentimpairment

IssuesIssues

Long term safety dataLong term safety data InjectionInjection Cost - expensiveCost - expensive

DPP-4 Inhibitors DPP-4 Inhibitors ( Gliptins )( Gliptins )

Sitagliptin, Vildagliptin, Saxagliptin, Sitagliptin, Vildagliptin, Saxagliptin, LinagliptinLinagliptin

Increase insulin sectrion Increase insulin sectrion Lower glucagon secretionLower glucagon secretion Have theoretical advantages of SU’s Have theoretical advantages of SU’s

but no long term safety databut no long term safety data ExpensiveExpensive

DPP-4 InhibitorsDPP-4 Inhibitors

Side effectsSide effects GI disturbanceGI disturbance OedemaOedema URTI’sURTI’s AnorexiaAnorexia HeadacheHeadache hypoglycaemiahypoglycaemia

Contra-indicationsContra-indications Renal impairment Renal impairment

( check gliptin used ( check gliptin used ))

PregnancyPregnancy Breast feedingBreast feeding

GLP-1 vs DPP-4GLP-1 vs DPP-4

DPP-4DPP-4 GLP-1GLP-1

RouteRoute OralOral Sub cutSub cut

CostCost ~£30~£30 ~£70~£70

WeightWeight Weight Weight neutralneutral

Weight lossWeight loss

HbA1cHbA1c ~0.6 – 0.8%~0.6 – 0.8% ~0.8 – 1.1%~0.8 – 1.1%

GI side GI side effectseffects

Less nauseaLess nausea More nauseaMore nausea

Therapeutic OptionsTherapeutic Options

Lots of choicesLots of choices NICE guidance – see flow chartNICE guidance – see flow chart

MetforminMetformin Dual therapyDual therapy Triple therapyTriple therapy Check licensing for combinationsCheck licensing for combinations

CostCost MonitoringMonitoring

Monitoring ResponseMonitoring Response

Minimum – annual reviewMinimum – annual review HbA1cHbA1c

<6.5-7.5%<6.5-7.5% BPBP

<130/80<130/80 Lipid profileLipid profile

Chol <4, LDL <2Chol <4, LDL <2 Lifestyle interventionsLifestyle interventions

Self MonitoringSelf Monitoring Self care – vitally important in diabetesSelf care – vitally important in diabetes Should be available ( NICE )Should be available ( NICE )

to those on insulinto those on insulin To those on oral glucose lowering medications To those on oral glucose lowering medications

to provide info on hypglycaemiato provide info on hypglycaemia To assess changes resulting from medication To assess changes resulting from medication

or lifestyle changesor lifestyle changes To ensure safety during activities including To ensure safety during activities including

drivingdriving To monitor changes during illnessTo monitor changes during illness

Must be clear purpose of testing and Must be clear purpose of testing and information obtainedinformation obtained

Frequency of monitoring?Frequency of monitoring?

Self MonitoringSelf Monitoring Diet alone – testing?Diet alone – testing? Diet + metformin – once / twice a week?Diet + metformin – once / twice a week? ( 1 -2 pot per year )( 1 -2 pot per year ) Diet + tablets stimulating insulin Diet + tablets stimulating insulin

secretion ( SU’s, metaglinides, gliptins )– secretion ( SU’s, metaglinides, gliptins )– twice a week and at one other time pre twice a week and at one other time pre meals ( 3 pots of strips per year )meals ( 3 pots of strips per year )

Diet + injectable stimulators of insulin Diet + injectable stimulators of insulin secretion ( exenatide / liraglutide ) – secretion ( exenatide / liraglutide ) – twice a week and at one other time twice a week and at one other time before meals ( 3 pots of strips per year )before meals ( 3 pots of strips per year )

Blood Glucose Testing in Blood Glucose Testing in Cwm TafCwm TafCwm Taf - Glucose Blood Testing Reagents

210000

215000

220000

225000

230000

235000

240000

245000

250000

255000

Mar-11 Jun-11 Sep-11 Dec-11 Mar-12 Jun-12 Sep-12 Dec-12

Period

Pre

scri

berB

asic

Pri

ce

Glucose Blood Testing Reagents

NICE GuidanceNICE Guidance

Clinical guideline 87Clinical guideline 87 Management of hypertensionManagement of hypertension Management of lipidsManagement of lipids AspirinAspirin

Management of Management of Hypertension in DiabetesHypertension in Diabetes

TargetsTargets If kidney, eye or cerebrovascular If kidney, eye or cerebrovascular

damage <130/80damage <130/80 Others 140<80Others 140<80

If hypertensive and BP target is If hypertensive and BP target is reached, monitor every 4-6 monthsreached, monitor every 4-6 months

Measure BP annually if not Measure BP annually if not hypertensive or with renal diseasehypertensive or with renal disease

Hypertension in DiabetesHypertension in Diabetes Lifestyle measuresLifestyle measures Treatment;Treatment;

Offer ACE inhibitor ( titrate dose ) Offer ACE inhibitor ( titrate dose ) (ramipril) 1(ramipril) 1StSt dose effect dose effect

For African-Caribbean descent offer ACE For African-Caribbean descent offer ACE plus diuretic or CCBplus diuretic or CCB

Add diuretic ( bendrofluazide 2.5mg in Add diuretic ( bendrofluazide 2.5mg in the morning) or CCB ( amlodipine 5mg the morning) or CCB ( amlodipine 5mg daily )daily )

Add other drug ( diuretic or CCB )Add other drug ( diuretic or CCB ) Add alpha-blocker, beta blocker of Add alpha-blocker, beta blocker of

potassium sparing diuretic (with caution)potassium sparing diuretic (with caution)

Lipid Management in Lipid Management in DiabetesDiabetes

Review CV risk annuallyReview CV risk annually Full lipid profile annuallyFull lipid profile annually If history of elevated serum TG, If history of elevated serum TG,

perform full fasting lipid profile perform full fasting lipid profile TargetTarget

Total cholesterol <4.0mmol/LTotal cholesterol <4.0mmol/L LDL <2.0mmol/LLDL <2.0mmol/L

Assess lipid profile and modifiable risk Assess lipid profile and modifiable risk factors 1-3 months after starting factors 1-3 months after starting therapytherapy

Lipid Management in Lipid Management in DiabetesDiabetes

Age <40yrs, poor CV risk – consider Age <40yrs, poor CV risk – consider statinstatin

Age 40yrs+, CV risk >20% /10yrs – Age 40yrs+, CV risk >20% /10yrs – offer statinoffer statin

Age 40yrs +, high CV risk – offer statinAge 40yrs +, high CV risk – offer statin High serum TG ( >4.5mmol/l ) – offer High serum TG ( >4.5mmol/l ) – offer

fibrate. If lifestyle and fibrate fibrate. If lifestyle and fibrate ineffective, consider trial of omega 3ineffective, consider trial of omega 3

Simvastatin is first line statinSimvastatin is first line statin

NICE GuidanceNICE Guidance Aspirin is not licensed for the Aspirin is not licensed for the

primary prevention of vascular primary prevention of vascular events. If aspirin is used in primary events. If aspirin is used in primary prevention, the balance of benefits prevention, the balance of benefits and risks should be considered for and risks should be considered for each individual, particularly the each individual, particularly the presence of risk factors for vascular presence of risk factors for vascular disease (including conditions such as disease (including conditions such as diabetes) and the risk of diabetes) and the risk of gastrointestinal bleeding.gastrointestinal bleeding.

Secondary prevention?Secondary prevention?

NICE Guidance 87NICE Guidance 87

Age 50+ and BP <145/90Age 50+ and BP <145/90 Offer low dose aspirin or if clear Offer low dose aspirin or if clear

intolerance, clopidogrelintolerance, clopidogrel Age <50yrs and significant other CV Age <50yrs and significant other CV

risk factorsrisk factors Offer low dose aspirin or if clear Offer low dose aspirin or if clear

intolerance, clopidogrelintolerance, clopidogrel

SummarySummary

Lifestlye issues are keyLifestlye issues are key Patient must be at centre of carePatient must be at centre of care Many options for treatmentMany options for treatment Optimise treatment before adding in Optimise treatment before adding in

other medicationsother medications Always check complianceAlways check compliance Clear planClear plan

Prescribing TeamsPrescribing Teams

Merthyr and CynonMerthyr and Cynon Kate Spittle ( based at PCH )Kate Spittle ( based at PCH )

Rhondda and Taf ElyRhondda and Taf Ely Bev Woods ( based at RGH )Bev Woods ( based at RGH )

Please ask us for information / Please ask us for information / supportsupport