update on type 2 diabetes - psnc main...

Update on Type 2 Diabetes

North Staffs and Stoke LPC Keele Hall

17th June 2015

Karon Gilkes Senior Medical Liaison Manager

Boehringer Ingelheim

Content * Key facts and figures around Type 2 Diabetes

* Treatment Guidelines for T2D * Pros and Cons of different treatment classes

UK/EMP/00073 July 2014

References 1. Diabetes UK. Diabetes in the UK 2012. Available at: http://www.diabetes.org.uk/Documents/Reports/Diabetes-in-the-UK-2012.pdf (Accessed April 2014) 2. Diabetes UK. Diabetes: Facts and Stats (Version 3. Revised: March 2014). Available at: http://www.diabetes.org.uk/Documents/About%20Us/Statistics/Diabetes-key-stats-guidelines-April2014.pdf (Accessed June 2014) 3. Prevention and early diagnosis of type 2 diabetes. The NHS health check programme: let’s get it right. September 2012.

Available at: http://www.diabetes.org.uk/Documents/Reports/nhs-health-check-lets-get-it-right-0912.pdf (Accessed April 2014)

Diabetes is one of the biggest health challenges facing the UK1

● Currently 3.2 million people are living with the condition2

● About 630,000 people with diabetes remain undiagnosed2

● At diagnosis, half of the people with type 2 diabetes show signs of complications2

– Diabetes costs the NHS over £10 billion a year2

– This is approximately 10% of the NHS budget2

– 80% of these costs are spent on complications3

http://www.diabetes.org.uk/Documents/Reports/Diabetes-in-the-UK-2012.pdf









http://www.diabetes.org.uk/Documents/About Us/Statistics/Diabetes-key-stats-guidelines-April2014.pdf









http://www.diabetes.org.uk/Documents/Reports/nhs-health-check-lets-get-it-right-0912.pdf. Accessed April 2014
















Reference Diabetes UK. Diabetes: Facts and Stats (Version 3. Revised: March 2014). Available at: http://www.diabetes.org.uk/Documents/About%20Us/Statistics/Diabetes-key-stats-guidelines-April2014.pdf (Accessed June 2014)











By 2025, it is estimated that five million people will have diabetes in the UK

UK/EMP/00073 June 2014

Reference Diabetes UK. Diabetes: Facts and Stats (Version 3. Revised: March 2014). Available at: http://www.diabetes.org.uk/Documents/About%20Us/Statistics/Diabetes-key-stats-guidelines-April2014.pdf (Accessed June 2014)












Reference Preventing type 2 diabetes: population and community-level interventions. NICE public health guideline 35. Available at: www.guidance.nice.org.uk/ph35 (Accessed June 2014)

Individual risk factors for type 2 diabetes

● Weight - a body mass index of 25 kg/m2 or more

● A large waist circumference

– more than 80 cm (31.5 in) in women

– more than 94 cm (37 in) in men

● Low physical activity levels

● A family history of type 2 diabetes

● A history of gestational diabetes

● Age

– being older than 40, or

– older than 25 for some black and minority ethnic groups


References 1. Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2000;321:405–12; 2. Jeerakathil T et al. Stroke 2007;38(6):1739–1743. 3. World Heart Federation. Cardiovascular Risk Factors – Diabetes. Available at: www.worldheart.org/cardiovascular-health/cardiovascular-disease-risk-factors/diabetes/ (Accessed May 2010) 4. Hovind P et al. Kidney Int 2001;59(2):702–709; 5. Fong DS et al., Diabetes Care. 2004;27(10):2540–2553; 6. Deshpande AD et al. Phys Ther 2008;88:1254–1264. 7. Adler AI et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2000;321:412-9. 8. Peripheral artery disease. Available at: www.diabetes.co.uk/diabetes-complications/peripheral-artery-disease.html (Accessed June 2014) 9. Dang CN et al., Int J Low Extrem Wounds 2003;2(1):4-12.

Type 2 diabetes is a chronic, lifelong condition that can damage our bodies dramatically ● Hyperglycaemia is a major and independent risk factor for both microvascular and macrovascular

complications of diabetes1

Macrovascular complications Microvascular complications

The risk of stroke in newly treated type 2 diabetes is more than double that of the general population2

Peripheral vascular disease affects 1 in 3 people with diabetes and increases the risk of heart attack and stroke8

Damage to the kidney filtering systems from diabetes (diabetic nephropathy) is a leading cause of kidney failure4

Microvascular damage to the retina from diabetes (diabetic retinopathy) is a leading cause of blindness5

Damage to the nerves from diabetes (diabetic neuropathy) is a leading cause of foot wounds and ulcers which frequently lead to foot and leg amputation9

People with diabetes are twice more likely to have cardiovascular disease than someone without diabetes3

There is almost a 10% increase in the risk of myocardial infarction6

Hypertension is a significant risk factor for the complications of type 2 diabetes 7

http://www.diabetes.co.uk/diabetes-complications/peripheral-artery-disease.html








Reference National Health and Nutrition Examination Surveys (NHANES), USA 1999-2004 Adapted from Deshpande AD et al. Phys Ther 2008;88:1254–1264.

Prevalence of diabetes-related complications among people with type 2 diabetes

Pe

rce

nta

ge w

ith

co

mp

licat

ion

s (%

)


Microvascular and macrovascular complications associated with type 2 diabetes

Observational analysis

Updated mean HbA1c

Aggregate endpoints

No. of events

Decrease in risk

Any endpoint related to diabetes 1255 21%

Deaths related to diabetes 346 21%

All cause mortality 597 14%

Myocardial infarction 496 14%

Stroke 162 12%

Peripheral vascular disease* 41 43%

Microvascular disease 323 37%

Single endpoints

Heart failure 104 16%

Cataract extraction 195 19%

*Lower extremity amputation or fatal peripheral vascular disease

The importance of controlling HbA1c: the impact of a 1% fall in HbA1c

Observational analysis of relation between glycaemic exposure and complications of diabetes as estimated by decrease in risk for 1% reduction in haemoglobin A1c (HbA1c) concentration, measured at baseline and as updated mean, controlled for age at diagnosis of diabetes, sex, ethnic group, smoking, albuminuria, systolic blood pressure, high and low density lipoprotein cholesterol, and triglycerides (n=3642) compared with results of clinical trial of intensive v conventional glucose control policy (n=3867)

Reference Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group BMJ. 2000;321:405–12.


NICE goals for effective management of type 2 diabetes and current treatment options


Reference TYPE 2 DIABETES: National clinical guideline for management in primary and secondary care (update). Available at: http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf (Accessed June 2014)

NICE goals of treatment

To manage type 2 diabetes through the effective control of:

● Blood glucose

– Initial HbA1c target: <6.5%

● Hypertension

– Target: <140/80 mmHg <130/80 mmHg if kidney, eye or cerebrovascular damage

● Blood lipids

– Target: <4.0 mmol/L TC <2.0 mmol/L LDL

● Antithrombotic therapy

– Offer low-dose aspirin (75 mg) to patients >50yrs if BP<145/90 mmHg or <50yrs with significant other CV risk

http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf

HbA1c target for people with type 2 diabetes recommended by NICE

• Individualised HbA1c target – may be above the general target of 48 mmol/mol (6.5%)

• HbA1c monitored every 2–6 months until stable on unchanging therapy

• HbA1c monitored every 6 months once blood glucose level and therapy are stable

NICE guideline on type 2 diabetes

• Personalised HbA1c target – usually between 48 mmol/mol and 58 mmol/mol (6.5% and 7.5%)

• Ongoing treatment review to minimise hypoglycaemia

NICE quality standard for diabetes

NICE (2009) Type 2 diabetes: The Management of Type 2 Diabetes. NICE Clinical Guidance 87. Available at: http://nice.org.uk/cg87 (accessed: 12.05.2015); NICE (2011) Diabetes in adults quality standard. Available at: http://bit.ly/1bbFunM (accessed 12.05.2015)

Job code: UK/DIA/00242i. Date of preparation: May 2015.

Case study: Mr IS

BP=blood pressure; CVD=cardiovascular disease; DRSSW=Diabetic Retinopathy Screening Service for Wales; eGFR=estimated glomerular filtration rate. Mr IS is a fictional case for illustrative purposes.

Presenting features

•Age

•52 years old

•BMI

•36 kg/m2

•Smoker

•6–8 cigarettes/day

•Family history

•CVD

Medical history

•Type 2 diabetes

•4 years duration

•Hypertension

•Dyslipidaemia

•Background retinopathy at recent DRSSW screen

Latest test results

•HbA1c

•75 mmol/mol (9.0%)

•Cholesterol

•5.1 mmol/L

•BP

•148/68 mmHg

•eGFR

•>90 mL/min/ 1.73 m2

Current medications

•Metformin 1 g twice daily

•Gliclazide 80 mg twice daily

•Simvastatin 40 mg at night

•Aspirin 75 mg morning


Achievement of therapeutic targets

• 2012/13 National Diabetes Audit

– 62.4% HbA1c <7.5%

– 76.2% Cholesterol <5mmol/l

– 69.0% BP <140/80

• What percentage of patients met all 3 of the above targets ?

Interventional relationships between cholesterol,

blood pressure and HbA1c with CVD events

119

44

34

0 50 100 150

0.9% reduction in HbA1c

1 mmol/L reduction in cholesterol

10/5 mmHg reduction in BP

NNT for 5 years in order to prevent 1 CVD event

For each variable, data shown are for a change corresponding to the mean change of the variable in intervention studies.

BP=blood pressure; CVD=cardiovascular disease; NNT=number needed to treat.

Adapted from Yudkin JS et al (2010) Diabetologia 53: 2079–85

Dat

e o

f p

rep

arat

ion

: May

20

15

UK

/DIA

/00

25

2h

Biosimilars

Exenatide

Repaglinide

▼Dapagliflozin

▼Liraglutide

▼Canagliflozin

▼Degludec

Insulin

Protamine Zn Insulin

Sulphonvlureas

Metformin

Biguanides Human Insulin

Metformin

Acarbose

Rosiglitazone Lantus (insulin glargine)

Insulin detemir

Exenatide

Pramlintide

Sitagliptin

Saxagliptin

Nu

mb

er o

f n

ew t

her

apie

s

1921 1932 1957 1952 1970 1983 1995 1999 2000 2002 2005 2006 2009 2010 2012 2014

▼Empagliflozin

▼Linagliptin

Limitations of older therapies

• Weight gain (SU1, TZD2, insulin3)

• Hypoglycaemia (SU1, insulin3)

• Concerns over CV safety (TZD2)

• Concerns over cancer risks (TZD2, some insulins3)

• Limited options in patients with renal disease4

• Natural history of disease not altered

1. Smith CJ, et al. Br J Cardiol 2010;17:279-82.; 2. McGrane D, et al. Br J Cardiol 2011;18:24–7.; 3. Barwell N, et al. Br J Cardiol 2010;18:224-8.-82;

4. Marshall SM. B J Renal Med 2011;16:28–31.


References 1. Nathan DM et al. Diabetes Care 2009; 32:193–203. 2. Wulffele MG et al. J Intern Med 2004; 256: 1–14; 3. 3. Victoza (liraglutide) Summary of Product Characteristics. Available at: www.medicines.org.uk/emc (Accessed June 2014) 4. JARDIANCE (empagliflozin) Summary of Product Characteristics 5. Valentine V. Clinical Diabetes 2012 30:151–155. 6. Phillips P et al. Diabetes Care 2003;26:269–273. 7. Acarbose Summary of Product Characteristics. Available at: www.medicines.org.uk/emc (Accessed June 2014) 8. Kurukulasuriya LR, Sowers JR. Cardiovasc Diabetol 2010; 9:45. 9. The Cochrane Colloboration. Meglitinide analogues for type 2 diabetes mellitus (Review) 10. Prandin (replaginide) Summary of Product Characteristics. Available at: www.medicines.org.uk/emc (Accessed June 2014) 11. Inzucchi SE, McGuire DK. Circulation 2008; 117:574-84.

Treatment options in the management of type 2 diabetes

Class HbA1c

reduction

Increased risk of hypo-

glycaemia

Weight change

Systolic blood pressure change

Metformin 1.0 – 2.01 X1 Neutral1 Neutral2

Sulphonylurea 1.0 – 2.01

1 Gain1 Not reported

TZDs 0.5 – 1.41 X1 Gain1 Not reported

DPP-4 inhibitors 0.5 – 0.81 X1 Neutral1 Not reported

GLP-1 agonists 0.5 – 1.01 X1 Loss1 Reduction3

Long acting insulin 1.5 – 3.51


Rapid acting insulin 1.5 – 3.51 1 Gain1 Not reported

SGLT2 inhibitors 0.5 – 1.14 X4 Loss5 Reduction5

Acarbose 16 X7 Loss8 Not reported

Meglitinides 0.1 – 2.19


Adapted from: Nathan DM et al. Diabetes Care 2009 32:193–203

http://www.medicines.org.uk/EMC/medicine/21986



UK/EMP/00073a July 2014

Drug treatments for type 2 diabetes and their sites of action

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose co-transporter 2

Reference Tahrani AA, et al. Lancet. 2011;378:182–197.

Hyperglycaemia

Increased glucose

production

Glucose absorption

Impaired insulin

secretion

Decreased glucose uptake

Increased glucose reabsorption

Acarbose

Metformin Pioglitazone Insulin

SGLT2 inhibitors Insulin Sulphonylureas

Meglitinides GLP-1 receptor agonists

DPP-4 inhibitors

Metformin GLP-1 receptor agonists

DPP-4 inhibitors Insulin

National Institute for Health and Clinical Excellence (NICE):

T2D treatment algorithm1

Consider substituting

DPP-4 or TZD for SU if:

• Risk of hypoglycaemia

or SU is

contraindicated or not

tolerated

Consider SU if:

• Not overweight

• MET not tolerated

• Rapid response

needed because of

hypoglycaemic

symptoms

1. Adapted from: National Institute for Health and Clinical Excellence. Clinical Guideline 87. Type 2 diabetes - newer

agents (a partial update of CG66): quick reference guide.

MET = metformin, SU = sulphonylureas, TZD = thiazolidinedione, DPP-4= dipeptidyl peptidase-4 inhibitor

Insulin + MET + SU

MET + SU + sitagliptin, or

MET + SU + TZD, or

MET + SU + exenatide

HbA1c

≥7.5%

HbA1c

≥7.5%

Consider adding sitagliptin

or TZD:

• Instead of insulin if insulin is

unacceptable

Consider adding exenatide

to MET and SU if

• BMI ≥35kg/m2 or BMI <35

kg/m2 and insulin

unacceptable

Start insulin

MET +

DPP-4 or TZD

MET

MET + SU

HbA1c

≥7.5%

HbA1c

≥6.5%

HbA1c ≥6.5% after

lifestyle intervention

SU

SU + DPP-4

or TZD

Consider adding

DPP-4 or TZD if: • MET not tolerated

or contraindicated

HbA1c

≥6.5%

HbA1c

≥7.5%

HbA1c

≥7.5%

Increase insulin dose and intensify regimen.

Consider adding pioglitazone if:

• A TZD has previously had marked effect or blood

glucose control is inadequate with high-dose insulin HbA1c

≥7.5%

20

2012: Updated joint 2012 position statement

from the ADA and EASD

• “…an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes, the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care.”

• “…individualization of treatment is the cornerstone of success.”

• “Our recommendations are less prescriptive than and not as algorithmic as prior guidelines. This follows from the general lack of comparative effectiveness research in this area.”

ADA=American Diabetes Association; EASD=European Association for the study of Diabetes.

Inzucchi SE et al (2012) Diabetes Care 35: 1364–79

ADA/EASD: Approach to the management

of hyperglycaemia

ADA=American Diabetes Association; EASD=European Association for the study of Diabetes.

Adapted from: Inzucchi SE et al (2012) Diabetes Care 35: 1364–79

More stringent Less stringent

Patient attitude and

expected treatment efforts

Risks potentially associated

with hypoglycaemia, other

adverse events

Disease duration

Life expectancy

Important comorbidities

Established vascular

complications

Resources, support system Readily available Limited

Severe

Severe

Short

Long-standing

High

Less motivated, non-adherent,

poor self-care capacities

Absent

Absent

Long

Newly diagnosed

Low

Highly motivated, adherent,

excellent self-care capacities

ADA/EASD: Antihyperglycaemic therapy in

type 2 diabetes – general recommendations

ADA=American Diabetes Association; DPP-4=dipeptidyl peptidase-4; EASD=European Association for the study of Diabetes; GLP-1=glucagon-

like peptide-1; SU=sulphonylurea; TZD=thiazolidinedione.


Weight gain with sulphonylureas, meglitinides, thiazolidinediones and insulin

● An increase in body weight was observed all second-line therapies except DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues

CrI=credible interval; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Mixed-treatment comparison (MTC) results showing the effect of adding second-line agents versus placebo in adults taking metformin on change from baseline in bodyweight (kg). MTC analysis based on 30 randomised controlled trials (n=15,265). Most trials were 6–12 months long. Overall, meta-regression and sensitivity analyses yielded minimal differences from the reference case. Adapted from: McIntosh B et al (2011) Open Medicine 5: E35–48

Sulphonylureas 2.01 (1.09, 2.94)

Meglitinides 1.80 (0.35, 3.29)

Thiazolidinediones 2.59 (1.66, 3.51)

DPP-4 inhibitors 0.57 (–0.45, 1.60)

Alpha-glucosidase inhibitors –0.92 (–2.35, 0.51)

GLP-1 analogues –1.79 (–3.43, –0.14)

Basal insulin 1.56 (–0.46, 3.63)

Biphasic insulin 2.96 (0.96, 5.00)

–5.0 –2.5 0 2.5 5.0

Treatment MTC estimate (95% CrI) Favours placebo Favours treatment

Difference in change from baseline in body weight kg (95% CI)


Hypoglycaemia: Sulphonylureas, meglitinides and insulin

● As add on to metformin, sulphonylureas, meglitinides and insulin significantly increase the risk of hypoglycaemia versus placebo

Mixed-treatment comparison (MTC) results showing the effect of adding second-line agents versus placebo in adults taking metformin on odds of at least 1 event of overall hypoglycaemia. MTC analysis based on 34 randomised controlled trials (n=16,704). Most trials were 6–12 months long. Overall, meta-regression and sensitivity analyses yielded minimal differences from the reference case. CrI=credible interval; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Adapted from: McIntosh B et al (2011) Open Medicine 5: E35–48

Sulphonylureas 8.22 (4.5, 16.63)

Meglitinides 8.59 (3.34, 25.20)

Thiazolidinediones 1.10 (0.54, 2.27)

DPP-4 inhibitors 1.05 (0.56, 2.21)

Alpha-glucosidase inhibitors 0.39 (0.01, 6.67)

GLP-1 analogues 1.12 (0.33, 3.90)

Basal insulin 5.20 (1.48, 21.46)

Biphasic insulin 11.02 (3.48, 40.43)

0.001 0.01 0.1 1 10 100

Treatment MTC estimate (95% CrI) Favours placebo Favours treatment

Log median odds ratio (95% CI)

Odds ratio of at least 1 event of overall hypoglycaemia


ADA/EASD: Recommendations for antihyperglycaemic therapy

ADA=American Diabetes Association; DPP-4=dipeptidyl peptidase-4; EASD=European Association for the Study of Diabetes; GLP-1 RA=glucagon-like peptide-1 receptor agonist; SGLT2=sodium-glucose co-transporter-2; SU=sulphonylurea; TZD=thiazolidinedione. Adapted from: Inzucchi SE et al (2015) Diabetes Care 38: 140–9


Factors to be taken into consideration when

selecting an appropriate drug

Person with type 2

diabetes

Age

Occupation

Hobbies

Sex

Past medical history (e.g. haematuria/

cancer)

Renal function

Fasting

Live alone/nutritio

n

Driving

Liver function

BMI / body weight

Fracture risk

The series of considerations above was

generated by the programme committee.

Aims of treatment of

hyperglycaemia in

Type 2 Diabetes

Symptom control

Prognosis

Side effects

Adherence

The ideal diabetes drug?

• blood glucose • βcell function • insulin resistance • Without hypoglycaemia • Give durable control • Well tolerated • Convenient to take • Weight loss/no weight gain • Able to be used in

challenging patient populations eg elderly, renal and hepatic impairment, other co-morbidities

• blood pressure

• LDL cholesterol

• HDL and trigs

• Cheap

• Trialed and licensed for use with all other combinations of diabetes drugs

• Long term data showing improvements in clinical outcomes

Metformin: Advantages and disadvantages

Advantages

•Extensive clinical experience

•No weight gain

•Low inherent risk of hypoglycaemia

•Likely ↓ CVD events (UKPDS)

•Low unit cost

Disadvantages

•Gastrointestinal side-effects (diarrhoea, abdominal cramping)

•Lactic acidosis risk (rare)

•Vitamin B12 deficiency

•Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc.

CKD=chronic kidney disease; CVD=cardiovascular disease; UKPDS=UK Prospective Diabetes Study.

Adapted from Inzucchi SE et al (2012) Diabetes Care 35: 1364–79

Primary physiological action: ↓ Hepatic glucose production

SUs: Advantages and disadvantages

Advantages

• Extensive clinical experience

• ↓ Microvascular risk (UKPDS)

• Low unit cost

Disadvantages

• Hypoglycaemia

• Weight gain

• Blunts myocardial ischaemic preconditioning

• Low durability

SUs=sulphonylureas; UKPDS=United Kingdom Prospective Diabetes Study.


1. British National Formulary (2012) 6.1.2.1 Sulfonylureas. Available at: www.bnf.org (accessed 19.09.2012)

Primary physiological action: ↑ Insulin secretion

Available agents1: glibenclamide, gliclazide, glimepiride, glipizide, tolbutamide

http://www.bnf.org

UK Hypoglycaemia Study: Prevalence of

self-reported hypoglycaemia with SU use

SU=sulphonylurea; T1D=type 1 diabetes; T2D=type 2 diabetes.

Adapted from: UK Hypoglycaemia Study Group (2007) Diabetologia 50: 1140–7

SU <2 yr >5 yr <5 yr >15 yr

T1D T2D

SU <2 yr >5 yr <5 yr >15 yr

T1D T2D

Severe hypoglycaemia Mild hypoglycaemia

Pro

po

rtio

n r

ep

ort

ing

at le

ast o

ne

hyp

og

lyca

em

ic e

pis

od

e

39% of patients

receiving an SU

reported mild

hypoglycaemia

7% of patients

receiving an SU

reported severe

hypoglycaemia

Driving and hypoglycaemia with SUs and

meglitinides: Updated DVLA medical rules

• Group 1 drivers:

– Must not have had more than one episode of

hypoglycaemia requiring the assistance of another

person within the preceding 12 months.

– It may be appropriate to monitor blood glucose

regularly and at times relevant to driving to enable

the detection of hypoglycaemia.

– Must be under regular medical review.

• Group 2 drivers: must satisfy the following criteria:

– No episode of hypoglycaemia requiring the

assistance of another person has occurred in the

preceding 12 months.

– Has full awareness of hypoglycaemia.

– Regularly monitors blood glucose at least twice daily

and at times relevant to driving.

– Must demonstrate an understanding of the risks of

hypoglycaemia.

– There are no other debarring complications of

diabetes such as a visual field defect.

The applicant or licence holder must notify DVLA unless stated otherwise in the text

0

DVLA=Driver and Vehicle Licensing Agency; SUs=sulphonylureas.

Drivers Medical Group (2012) At a Glance Guide to the Current Medical Standards of Fitness to Drive. Available at: http://bit.ly/lPWwxf

(accessed 08.08.2012)

http://bit.ly/lPWwxf

This presentation has been developed by Boehringer Ingelheim Ltd. and Eli Lilly Company Ltd. UK/TRJ/00296c. October 2013.

Certain factors are associated with an

increased risk of hypoglycaemia

• Use of insulin secretagogues and insulin therapy

• Behavioural, physiological and therapeutic factors including:

– Missed or irregular meals

– Older age

– Longer duration of diabetes

– Presence of comorbidities

– Loss of residual insulin secretion

– Loss of awareness of hypoglycaemia

– Time of day (lowest plasma glucose of the day is just before the evening

meal and unsuspected hypoglycaemia can occur at this time once drug

therapy is started)

Amiel SA, et al. Diabet Med. 2008; 25(3):245–254.

Acarbose

Advantages1 - Not associated with hypoglycaemia - ↓Postprandial glucose excursions

- Possible cardiovascular benefit - Non-systemic

Adverse effects of note*2 - Flatulence - Diarrhoea

- Gastrointestinal and abdominal pains

Cautions2 - Hypoglycaemia (may potentiate effects

of other antihyperglycaemic agents; episodes may be treated with glucose,

not sucrose) - Liver enzyme monitoring

Contraindications2 - Inflammatory bowel disease, colonic

ulceration, partial intestinal obstruction or in patients predisposed to intestinal

obstruction - Severe hepatic impairment

- Severe renal impairment

Acarbose Slows intestinal carbohydrate digestion and absorption (should be chewed with the first

mouthful of food, or swallowed directly before the meal2)

*Common or very common in summary of product characteristics 1. Inzucchi S et al (2015) Diabetes Care 38: 140–9; 2. Acarbose Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc (accessed 07.05.2015)


Meglitinides

Advantages1 - ↓Postprandial glucose excursions

- Dosing flexibility

Adverse effects of note*2

- Hypoglycaemia - Gastrointestinal disturbances

Cautions3 - Substitute insulin during intercurrent

illness and surgery - Debilitated and malnourished patients

- Renal and hepatic impairment

Contraindications3 - Ketoacidosis

- Severe hepatic impairment2

Repaglinide, nateglinide3 ↑Insulin secretion (rapid onset and short duration of action; taken with meals)1,3

*Listed as common in summaries of product characteristics 1. Inzucchi S et al (2015) Diabetes Care 38: 140–9; 2. Summaries of product characteristics for repaglinide and nateglinide, available from http://www.medicines.org.uk/emc (accessed 07.05.2015); 3. British National Formulary (2015) 6.1.2.3 Other antidiabetic drugs. Available at: http://bit.ly/1P3jlMM (accessed 07.05.2015)


Pioglitazone: Advantages and

disadvantages

Advantages

• Low inherent risk of hypoglycaemia

• Durable glucose lowering

• ↑ HDL-cholesterol

• ↓ Triglycerides

• ↓ CVD events (PROactive)

Disadvantages

• Weight gain

• Oedema/heart failure

• Bone fractures

• ? ↑ Bladder cancer

CVD=cardiovascular disease.


Primary physiological action: ↑ Insulin sensitivity

DPP-4 inhibitors: Advantages and

disadvantages

Advantages

•Low inherent risk of hypoglycaemia

•Weight neutrality

•Well tolerated

•CVOT – SAVOR-TIMI, EXAMINE, TECOS

Disadvantages

•High unit cost

•Lack of long-term efficacy and tolerability data

•Concern regarding possible risk of pancreatitis, increased hospitalisations for heart failure

DPP-4=dipeptidyl peptidase-4.


1. British National Formulary (2012) 6.1.2.3 Other antidiabetic drugs. Available at: www.bnf.org (accessed 19.09.2012)

Primary physiological actions: ↑ Insulin secretion (glucose-dependent); ↓ glucagon

secretion (glucose-dependent)

Available agents1: linagliptin, saxagliptin, sitagliptin, vildagliptin

http://www.bnf.org

Are all DPP-4 inhibitors the same?

Drug Features Prescribing considerations

Sitagliptin1 Once daily, renal

excretion

Dose reduction in CKD

Vildagliptin2 Twice daily, renal

excretion, liver upset

described

Dose reduction in CKD, LFT

monitoring recommended

Saxagliptin3 Once daily, renal

excretion


Linagliptin4 Once daily, biliary

excretion

No dose reduction in CKD

Alogliptin5 Once daily, renal

excretion


References 1-5: Summary of Product Characteristics for sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin.

Available at www.medicines.org.uk/emc (accessed October 2014)

http://www.medicines.org.uk/emc

DPP-4 inhibitors: Differences in extent of urinary elimination

DPP-4=dipeptidyl peptidase-4. All information taken from relevant summaries of product characteristics, available from http://www.medicines.org.uk/emc (last accessed 08.05.2015)


Effect of renal impairment on DPP-4 inhibitor pharmacokinetics

*Estimated creatinine clearance values were calculated using the Cockcroft–Gault formula. ESRD=end-stage renal disease; DPP-4=dipeptidyl peptidase-4; HD=haemodialysis. Adapted from Graefe-Mody U et al (2011) Diab Obes Metab 13: 939–46. Alogliptin became available after this analysis was published and was therefore not included.

Two-fold increase in exposure

Normal n=6

Mild n=8

Moderate n=6

Severe n=6

ESRD n=6

1

2

3

4

5

6

7

Fold

incr

eas

e in

e

xpo

sure

re

lati

ve t

o

no

rmal

re

nal

fu

nct

ion

Linagliptin Sitagliptin

Normal n=6

Mild n=6

Moderate n=6

Severe n=6

ESRD n=6

1

2

3

4

5

6

7

Fold

incr

eas

e in

e

xpo

sure

re

lati

ve t

o

no

rmal

re

nal

fu

nct

ion

Normal n=8

Mild n=8

Moderate n=8

Severe n=7

ESRD n=8

1

2

3

4

5

6

7

Fold

incr

ease

in

exp

osu

re r

ela

tive

to

n

orm

al r

enal

fu

nct

ion

Saxagliptin (5-hydroxy saxagliptin metabolite)

Vildagliptin (LAY151 metabolite)

Normal Mild Moderate Severe ESRD

1

2

3

4

5

6

7

Fold

incr

ease

in

exp

osu

re r

elat

ive

to

no

rmal

re

nal

fu

nct

ion

Creatinine clearance >80 >50 to ≤80 >30 to ≤50 ≤30 ≤30 on HD (mL/min)

Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 ≤30 on HD (mL/min)

Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 ≤30 on HD (mL/min)


Dosing considerations with DPP-4 inhibitors in renal impairment

DPP-4 inhibitor

Degree of renal impairment

Mild (CrCl 50 to 80 mL/min)

Moderate (CrCl 30 to 50 mL/min)

Severe or ESRD (CrCl <30 mL/min)

Sitagliptin† 100 mg od

50 mg od 25 mg od

Vildagliptin 50 mg bd (50 mg od with SU) 50 mg od

50 mg od (with caution in ESRD on dialysis)

Saxagliptin† 5 mg od 2.5 mg od

2.5 mg od (with caution; ESRD only if no dialysis)

Linagliptin 5 mg od 5 mg od 5 mg od

Alogliptin† 25 mg od

12.5 mg od 6.25 mg od (use with caution)

†Assessment of renal function is recommended prior to initiation and periodically thereafter. bd=twice daily; CrCl=creatinine clearance; DPP-4=dipeptidyl peptidase-4; ESRD=end-stage renal disease; od=once daily; SU=sulphonylurea. All information taken from relevant summaries of product characteristics, available at: http://www.medicines.org.uk/emc (accessed 08.05.2015)


SGLT2 inhibitors: Advantages and

disadvantages

Advantages

•Low risk of hypos

•Weight reduction

•Blood pressure lowering

•Effect independent of insulin

Disadvantages

•Bacterial urinary tract infections

•Fungal genital tract infections

•Dehydration/nocturia

•Renal function

•Cost

UKPDS=UK Prospective Diabetes Study.

1. British National Formulary (2012) 6.1.1 Insulins. Available at: www.bnf.org (accessed 19.09.2012)


Primary physiological actions: decreased renal reuptake of glucose

Available agents1: Dapagliflozin, Canagliflozin, Empagliflozin

http://www.bnf.org

Date of preparation: September 2014. UK/EMP/xxxxxx

SGLT2 inhibitors: therapeutic indications

Empagliflozin1 Canagliflozin2 Dapagliflozin3

Monotherapy*

In combination with other

glucose-lowering products

including insulin

(except pioglitazone)

Available doses 10 mg od

25 mg od

100 mg od

300 mg od 10 mg od

References

1. Jardiance® (empagliflozin) Summary of product characteristics.

2. Invokana® (canagliflozin) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/28400 (accessed August 2014).

3. Forxiga® (dapagliflozin) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/27188 (accessed August 2014).

*When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of

metformin is considered inappropriate due to intolerance.

http://www.medicines.org.uk/emc/medicine/28400



SGLT2 inhibitors in patients with renal

impairment

Empagliflozin1 Canagliflozin2 Dapagliflozin3

eGFR ≥60 ml/min/1.73 m2 No dose adjustment required

eGFR ≥45ml <60 ml/min/1.73 m2 Not to be initiated

In existing patients whose eGFR

persistently <60ml then use lower

dose

Not to be initiated

Discontinue

treatment in

existing patients

eGFR <45 ml/min/1.73 m2 Discontinue treatment

References

1. Jardiance® (empagliflozin) Summary of product characteristics.






HbA1c reduction: SGLT2 inhibitor add on to metformin

indirect SPC comparison There are no head-to-head studies comparing SGLT2 inhibitors

Empagliflozin

+ MET

10 mg 25 mg

Canagliflozin

+ MET

100 mg 300 mg

Dapagliflozin

+ MET

5 mg* 10 mg

Patients, n 217 213 368 367 n/a 135

Baseline HbA1c, % 7.94 7.86 7.94 7.95 n/a 7.92

All values are placebo correct, all trials are 24-26 weeks’ duration.

*Clinical studies for dapagliflozin only report outcomes for 10 mg. As per the SPC, it is recommended that 5 mg is the recommended dose for certain populations.

MET, metformin; SE, standard error

References

1. Jardiance® (empagliflozin) Summary of Product Characteristics.





GLP-1 receptor agonists: Advantages and

disadvantages

Advantages • Low inherent risk of hypoglycaemia

• Potential for weight reduction

• Potential for blood pressure reduction

Disadvantages • Gastrointestinal side effects (nausea/vomiting)

• Injectable

• Training requirements

• High unit cost

• Concerns regarding possible risk of pancreatitis


1. British National Formulary (2012) 6.1.2.3 Other antidiabetic drugs. Available at: www.bnf.org (accessed 19.09.2012)

Primary physiological actions: ↑ insulin secretion (glucose-dependent); ↓ glucagon

secretion (glucose-dependent); slows gastric emptying; ↑ satiety

Available agents1: exenatide once weekly, exenatide twice daily, liraglutide

http://www.bnf.org

Insulin: Advantages and disadvantages

Advantages

• Universally effective

• Theoretically unlimited efficacy

• ↓ Microvascular risk (UKPDS)

Disadvantages

• Hypoglycaemia

• Weight gain

• Injectable

• Training requirements

• “Stigma” (for patients)

UKPDS=UK Prospective Diabetes Study.

1. British National Formulary (2012) 6.1.1 Insulins. Available at: www.bnf.org (accessed 19.09.2012)


Primary physiological actions: ↑ Glucose disposal; ↓ hepatic glucose production

Available agents1: various short-acting, long-acting and premixed preparations, of human, animal or

analogue origin.

http://www.bnf.org

This presentation has been developed by Boehringer Ingelheim Ltd. and Eli Lilly Company Ltd. UK/TRJ/00125a. May 2012

Pre

va

len

ce

in

T2

D

po

pu

latio

n (

%)

0

20

30

40

27.5

2.7

6.3

24.8

2.5

0.2

Adapted from: Middleton RJ et al. Nephrol Dial Transplant 2006;21:88-92.

Prevalence of CKD in T2D

GFR

ml/min/1.73m2

≥90

≥90

60-89

30-59 15-29

<15

Stage 0 1 2 3 4 5

Kidney

Function

Kidney normal

Kidney

damage

with

normal

GFR

Kidney

damage

with mild

↓GFR

Moderate

↓GFR

Severe

↓GFR

Kidney

failure

• Over a third of people with T2D have impaired kidney function (CKD stage 2-5)

Impaired kidney function (33.8%)

Note: 36% of subjects with GFR ≥ 60 ml/min/1.73m2 without albuminuria data may have no kidney disease or stage 1–2 CKD

49

Renal impairment and glucose-lowering drugs for type 2 diabetes

● Many of the glucose-lowering agents for type 2 diabetes require dose adjustment or additional monitoring as renal function declines

● The level of intervention required as renal function declines is dependent on the specific drug chosen


Prescribing considerations in

renal disease1

• Stop metformin when eGFR <45ml/min/1.73m2

• Caution with SUs as increased risk hypoglycemia1

• Pioglitazone can be used1

• Dose reduction required for gliptins except linagliptin1

• SGLT-2s become less effective in developing CKD1

1. Marshall SM. B J Renal Med 2011;16:28–31. 2. Medicines.org.uk accessed 21st January 2015

Cautions related to renal impairment for oral glucose-lowering therapies

Contraindicated/not recommended Dose adjustment/caution required No dose adjustment required

No SPC available for glibenclamide. *CrCl cut-offs differ from those stated for some agents. †Periodic monitoring of renal function required. Further information on dual “traffic light” symbols can be found in the speaker notes section. CrCl=creatinine clearance; DPP-4=dipeptidyl peptidase-4; SGLT2=sodium–glucose co-transporter 2; SPC=summary of product characteristics. All information taken from relevant SPCs, available at http://www.medicines.org.uk/emc (accessed 08.05.2015)

Renal impairment*

Metformin† Sulphonylureas Acarbose Meglitinides Pioglitazone DPP-4 inhibitors SGLT2 inhibitors†

Mild (CrCl 50– 80 mL/min)

Gliclazide Glipizide Glimepiride

Nateglinide Sitagliptin† Vildagliptin Saxagliptin† Linagliptin Alogliptin† Tolbutamide Repaglinide

Moderate (CrCl 30– 50 mL/min)

Gliclazide Glipizide Glimepiride

Nateglinide Linagliptin Canagliflozin†

Empagliflozin† Sitagliptin†

Vildagliptin Saxagliptin† Alogliptin

Tolbutamide Repaglinide Dapagliflozin†

Severe (CrCl <30 mL/min)

Linagliptin

Sitagliptin† Vildagliptin Saxagliptin† Alogliptin†

End-stage

Linagliptin

Saxagliptin†

Sitagliptin† Vildagliptin Alogliptin†


Cautions related to renal impairment for injectable glucose-lowering therapies

Renal impairment* Insulin Glucagon-like peptide-1 receptor agonists

Mild (CrCl 50–80 mL/min)

Liraglutide

Dulaglutide

Lixisenatide

Exenatide twice daily

Exenatide once weekly

Moderate (CrCl 30–50 mL/min)

Liraglutide

Dulaglutide

Lixisenatide



Severe (<30 mL/min)

Liraglutide

Dulaglutide

Lixisenatide



End-stage

Liraglutide

Dulaglutide

Lixisenatide



*CrCl cut-offs differ from those stated for some agents. CrCl=creatinine clearance. All information taken from relevant summaries of product characteristics, available at http://www.medicines.org.uk/emc (accessed 08.05.2015)

Contraindicated/not recommended Dose adjustment/caution required No dose adjustment required



heart failure

• May use metformin in chronic

heart failure, withhold during

acute episodes of failure1

• Avoid pioglitazone1

• DPP-4 inhibitors may increase

hospitalization for heart failure1

• Caution with SGLT2 inhibitors

in volume depleted patients1

1. White A, et al. Br J Cardiol 2012;19:85-9.


liver disease

• Most drugs not tested in

advanced liver disease

• Pioglitazone may reduce

steatosis1

• LFT monitoring recommended

for vildagliptin2

• Lower starting dose for

dapaglifozin in severe hepatic

impairment3

1. Musso G, et al. Diabetologia 2012;55:885-904.; 2. Vildaglitin Summary of Product Characteristics.

Available at www.medicines.org.uk/emc (accessed Oct 2014) 3. 3. Dapaglifozin Summary of Product Characteristics.

Available at www.medicines.org.uk/emc (accessed Oct 2014)



Prescribing considerations in the elderly1

• Co-morbidities -

polypharmacy with risk of

drug interactions1,2

• Increased likelihood of AEs

to drugs1,2

• Decrease in eGFR1,2

• Increased likelihood of

hypoglycaemia1,2

• Individualise therapy

balancing likely benefit with

potential risks1,2

Benefits

Risks

1. McLaren LA, et al. BMJ 2013;346:f2625.; 2. Kirkman MS, et al. Diabetes care 2012;35;2650-64

Cardiovascular outcomes trials within diabetes

2013 2014 2015 2016 2017 2018 2019 2020

Pre-approval Pre+post-approval Post-approval Other Terminated

TECOS (Sitagliptin, DPP-4i)

n=14,724; duration ~5 yrs completion Q1 2015

CARMELINA (Linagliptin, DPP-4i)

n= 8,300; duration ~4 yrs completion Q1 2018

CAROLINA (Linagliptin, DPP-4i vs SU) n= 6,000; duration ~8 yrs

completion Q3 2018

SAVOR TIMI-532,3 (Saxagliptin, DPP-4i)

n=16,492 (randomised); follow-up ~2 yrs Q2 2013 - RESULTS

EXAMINE1

(Alogliptin, DPP-4i) n=5,380; follow-up ~1.5 yrs

Q2 2013 - RESULTS

ALECARDIO (Aleglitazar*, PPAR-αγ) n=7,226;

follow-up 2.5 yrs Termin. Q4 2013 RESULTS

LEADER (Liraglutide, GLP-1)

n=9,340; duration 3.5–5 yrs completion Q4 2015

ELIXA (Lixisenatide, GLP-1)


EMPA-REG OUTCOME† (Empagliflozin, SGLT2i)

n=7,000; duration up to 5yrs completion Q2 2015

EXSCEL (Exenatide, QW GLP-1)

n=14,000; duration ~7.5 yrs completion Q2 2018

NCT01703208 (Omarigliptin*, QW DPP-4i)


CANVAS (Canagliflozin, SGLT2i)

n=4,365; duration 4+yrs completion Q2 2017

CANVAS-R (Canagliflozin, SGLT2i)


DEVOTE (Insulin degludec)

n=7,638; duration up to 3yrs completion Q4 2016

FREEDOM-CVO (ITCA 650*, GLP-1 in DUROS)


CREDENCE (cardio-renal) (Canagliflozin, SGLT2i)

n= 3,700; duration ~5.5 yrs completion Q1 2019

REWIND (Dulaglutide, QW GLP-1)

n=9,622; duration ~6.5yrs completion Q2 2019

DECLARE-TIMI58 (Dapagliflozin, SGLT2i)

n=17,150; duration~6 yrs completion Q2 2019

NCT01986881 (Ertugliflozin*, SGLT2i)

n=3,900; duration~6.3 yrs completion Q4 2020

*These agents are not licenced in the UK for the management of type 2 diabetes. †Also known as C-SCADE-8. “Completion date” is the estimated completion date for the primary outcomes measure. CVOT=cardiovascular outcomes trial; DPP-4i=dipeptidyl peptidase 4 inhibitor; GLP-1=glucagon-like peptide 1; PPAR-αγ=peroxisome proliferator-activated receptor agonist; Q=quarter; QW=once-weekly; SGLT2i=sodium glucose co-transporter inhibitor; SU=sulphonylurea; yrs=years. Source: Clinicaltrials.gov (accessed 08.05.2015); 1. White et al (2013) N Engl J Med 369: 1327–35; 2. McMurray JJ et al (2014) Lancet Diabetes Endocrinol 2: 843–51; 3. Scirica BM et al (2013) N Engl J Med 369: 1317–26

SUSTAIN 6 (Semaglutide*, GLP-1)

n=3,297; duration ~2.8 yrs completion Q1 2016


Conclusions

• Many different types of

patients with type 2

diabetes at different stages

of the disease

• Many different oral agents

available to choose from

• Guidelines may help

• Individualise therapy choice

• Regular follow up to monitor

therapeutic effectiveness is

essential.

Symptom control

Prognostic benefit

Side effects

Adherence