Dr Roselle Herring

Centre for Endocrinology,

Diabetes and Research

(CEDAR)

University of Surrey

Diabetes Mellitus: Advances in Treatment

New Advances in Diabetes

• Type 2 diabetes mellitus

• Type 2 diabetes management considerations

• Steroids and hyperglycaemia

• Monitoring guidelines

• End of life and hyperglycaemia

Diabetes is a huge problem

IDF. IDF Diabetes Atlas, 6th edition revision, 2014. www.idf.org/diabetesatlas

IDF. IDF Diabetes Atlas, 6th edition, 2013

Top 10 countries by prevalence: 2013

• 387 million people have diabetes

• By 2035, this number will rise to 592 million

Diabetes is a huge and growing problem

2014 2035

WORLD

387million

WORLD

592millionpeople living with diabetes

Middle East and North Africa 85%

Southeast Asia 64%

South and Central America 55%

Western Pacific 46%

Europe 33%

Africa 93%

53%

North America and Caribbean 30%

IDF. IDF Diabetes Atlas, 6th edition revision, 2014. www.idf.org/diabetesatlas

Classification of diabetes

Diverse and complex patients with T2D are present in clinical practice

T2D, type 2 diabetes

? ?

Fasting plasma glucose

Postprandial glucose

Progression of Type 2 Diabetes

Diabetes

4–7 years

Diabetes Diagnosis

Impaired Glucose Tolerance

Hyperglycaemia

Adapted from Kendall DM et al. Am J Med 2009:122(6 Suppl):S37–S50

Insulin resistance

Insulin level

Fasting plasma glucose

Postprandial glucose

Beta-cell function

Progression of Type 2 Diabetes

Diabetes

4–7 years

Diabetes Diagnosis

Impaired Glucose Tolerance

Insulin dysfunction

Adapted from Kendall DM et al. Am J Med 2009:122(6 Suppl):S37–S50

HbA1c and Standardisation

• Laboratory methods are now well standardised and reliable

• National GlycohemoglobinStandardisation Programme

• A level ≥6% but <6.5% is sufficient to identify individuals at especially high risk for diabetes

Current

HbA1c

(%)

New HbA1c

(mmol/L)

6.0 42

6.5 48

7.0 53

7.5 59

8.0 64

9.0 75

Saudek C at el. A new look at Screening and Diagnosing Diabetes Mellitus. J Clin Endocrinol Metab.2008 93:2447-2453

Type 2 diabetes therapies

AGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist;SGLT-2i, sodium glucose co-transporter-2 inhibitor

1960s 1970s 1980s 1990s

Sulphonylureas

ThiazolidinedionesMetformin

1950s

Human insulin

GLP-1 RAs

DPP-4is

SGLT-2is

2000s 2010s

Insulin analogues;

AGIs; glinides

Addressing the Ominous Octet

DPP-4, dipeptidyl peptidase 4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose co-transporter-2; SU, suphonylureaDeFronzo RA. Diabetes 2009;58:773–795

Adipose tissue

Increased lipolysis

Skeletal muscle

Decreased glucose uptake

LiverInsulin resistanceDecreased insulin secretion

BrainNeurotransmitter dysfunction

PancreasImpaired insulin

secretion (beta cell decline)

GI tractDecreased incretin effect

KidneysIncreased glucose

reabsorption

Islet α-cellsIncreased glucagon

secretion

HyperglycaemiaEnergy homeostasis

SUs

GLP-1

DPP-4

Insulin

DPP-4

GLP-1 GLP-1GLP-1

Insulin

Metformin

GLP-1

DPP-4 Insulin

GLP-1

Insulin

GLP-1

Insulin

SGLT-2

SGLT2 inhibitors increase glycosuria to reduce hyperglycaemia

SGLT2 Inhibitors: Indirect Effects on Glucose Metabolism

American Diabetes Association/European Association for the Study of Diabetes Position Statement 2015

DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedioneInzucchi SE et al. Diabetes Care 2015;38:140−149

Healthy eating, weight control, increased physical activity, diabetes education

Not at target HbA1c after ~3 months

Two-drug combinations

Three-drug combinations

Combination injectable therapy

Initial monotherapy

Not at target HbA1c after ~3 months

Not at target HbA1c after ~3 months

GLP-1 RASGLT-2iDPP-4iTZDSU Insulin

Dis

ease p

rog

ressio

n

Metformin

SUTZD

Insulin

SUTZD

DPP-4iInsulin

SUTZD

SGLT-2iInsulin

SUDPP-4iSGLT-2i

GLP-1 RAInsulin

TZDDPP-4iSGLT-2i

GLP-1 RAInsulin

TZDDPP-4iSGLT-2i

GLP-1 RA

Metformin + basal insulin + meal-time insulin or GLP-1 RA

Considerations for individualised treatment

ADA/EASD position statement 2015

ADA, American Diabetes Association; AE, adverse event; EASD, European Association for the Study of Diabetes; HbA1c, glycated haemoglobin; T2D, type 2 diabetesAdapted from Inzucchi SE et al. Diabetes Care 2015;38:140−149

Hypoglycaemia and AE risks

Hyperglycaemia management approach

More stringent Less stringent

Long Short

Absent Severe

Important comorbidities

Highly motivated Less motivated

Resources and support system

Readily available Limited

HbA1c

7%

Life expectancy

Disease duration

Established vascular complications

Patient attitude and expectations

Few/mild

Absent SevereFew/mild

Newly diagnosed Long-standing

Low High

Usually

not

modifia

ble

Pote

ntia

lly

modifia

ble

SU TZD DPP-4i SGLT-2i GLP-1 RAInsulin(basal)

Physiological action(s)

↑ Insulin secretion

↑ Insulin sensitivity

↑ Insulin secretion†

↓ Glucagon secretion†

↓ Glucose

reabsorption

↑ Insulin secretion†

↓ Glucagon secretion*

Slows gastric

emptying↑ Satiety

↑ Glucose disposal

↓ Hepatic glucose

production

Efficacy (↓HbA1c)

High High Intermediate High High Highest

Hypoglycaemia risk

Moderate Low Low Low Low High

Weight effect

Major side effects

Hypogly-caemia

OedemaHeart failure

Bone fractures

RareGenitourina

ry infections

GI Hypoglycaemia

Choice of therapy after metformin

*Glucose dependentDPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin;SGLT-2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione; ↑, increase; ↓, decrease; ↔, neutralAdapted from Inzucchi SE et al. Diabetologia 2015;58:429–442

-3

-2

-1

0

Change in H

bA

1c(%

)

GLP-1 RA

(n=5783)1

DPP-4i

(n=13,847)1

AGI

(n=1120)1

TZD

(n=6655)1

SU

(n=5895)1

Glinides

(n=1050)1

Met

(n=4827)1

Basal

(n=21,615)1

Biphasic

(n=11,921)1

Prandial

(n=2597)1

Basal–bolus

(n=2967)1

SGLT-2i

(n=12,090)2,3*

Variability among drug classes in achievable HbA1c reductions

*Mean derived from clinical studies with dapagliflozin 5 mg and canagliflozin 100 mgAGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; Met, metformin; SU, sulphonylurea; TZD, thiazolidinedione1. Esposito K et al. Diabetes Obes Metab 2012;14:228–233; 2. US FDA Endocrinologic & Metabolic Advisory Committee: Dapagliflozin background Document. 13 Jun 2011; 3. US FDA Endocrinologic & Metabolic Advisory Committee: Canagliflozin background Document. Jan 2013

Insulin

Variability in adverse-event profiles for drug classes

*Potential for development of pancreatitisCHF, congestive heart failure; CKD, chronic kidney disease; CrCl, creatinine clearance; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedioneHandelsman Y et al. Endocr Pract 2015;21(Suppl. 1):1–87

SU TZD DPP-4i SGLT-2i GLP-1 RAInsulin(basal)

Renal impairment/GU

Increased risk of hypo-

glycaemia

May worsen

fluid retention

Potentially dose

adjustments necessary

Genitourinary infection risk

ExenatideContra

indicatedCrCl <30

mg/mL

Increased risk of

hypoglycaemia and fluid retention

GI adverse events

Neutral Neutral Neutral* NeutralModerate

*Neutral

CHF NeutralModerat

e

Neutral (potentially increased

CHF)

Neutral Neutral Neutral

CVD ? Neutral Neutral Neutral Neutral Neutral

Bone-related adverse events

NeutralModerate bone

lossNeutral Bone loss Neutral Neutral

Variability among T2D drug classes for incidence of hypoglycaemia

Add-on to metformin

CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MTC, mixed treatment comparison; OR, odds ratio; T2D, type 2 diabetesMcIntosh B et al. Open Med 2011;5:e35–48

GLP-1 RAs

Thiazolidinediones

Meglitinides

Sulphonylureas

DPP-4 inhibitors

Basal insulin

Biphasic insulin

-glucosidase inhibitors

Treatment MTC estimate(95% CI)

Favours treatment

Favours placebo

Difference in hypoglycaemic episodesOR (95% CI)

1.12 (0.33; 3.90)

11.01 (3.48; 40.43)

5.20 (1.48; 21.46)

0.39 (0.01; 6.67)

1.05 (0.56; 2.21)

1.10 (0.54; 2.27)

8.59 (3.47; 25.20)

8.22 (4.52; 16.63)

–10.0 0 10.0 30.020.0 40.0

GLP-1 RAs

Thiazolidinediones

Meglitinides

Sulphonylureas

DPP-4 inhibitors

Basal insulin

Biphasic insulin

-glucosidase inhibitors

Treatment MTC estimate(95% CI)

Favours treatment

Favours placebo

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

–1.79 (–3.43; –0.14)

2.96 (0.96; 5.00)

1.56 (–0.46; 3.63)

–0.92 (–2.35; 0.51)

0.57 (–0.45; 1.60)

2.59 (1.66; 3.51)

1.80 (0.35; 3.29)

2.01 (1.09; 2.94)

–5.0 –2.5 0 5.02.5

Variability among T2D drug classes in effect on body weight

Add-on to metformin

CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MTC, mixed treatment comparison; T2D, type 2 diabetesMcIntosh B et al. Open Med 2011;5:e35–48

Case:61 year old female

Patient characteristics

PMH: Waldenstroms macroglobulinaemia (6/52 chemotherapy – ibrutinib / dexamethasone 10mg IV - 4 days last dose 03/06/2016)

Nephrotic syndrome:

Therapy Prednisolone 20mg

HbA1c 45mmol/mol

Random glucose 15mmol/L

BMI 34.2 kg/m2

BMI, body mass index; HbA1c, glycosylated haemoglobin; T2D, type 2 diabetes

What is the diagnosis?

Choose one

A.Type 2 diabetes mellitus

B.Impaired fasting hyperglycaemia

C.Steroid induced hyperglycaemia

D.Normoglycaemia

E.Steroid induced diabetes

Steroid treatment and diabetes

• The use of steroid treatment in people with pre-existing diabetes will undoubtedly result in worsening glucose control; this may be termed steroid induced hyperglycaemia. This will warrant temporary additional and more active glycaemic management.

• A rise in glucose, related to steroid therapy occurring in people without a known diagnosis of diabetes is termed steroid induced diabetes. This may or may not resolve when the steroids are withdrawn.

Steroid Therapy and Inpatient Glycaemic

Control

• Steroids raised blood glucose via a number of mechanisms including:

– Increased hepatic gluconeogenesis

– Decreased peripheral tissue glucose uptake

– Decreased sensitivity to insulin in cells in the extremities (thought to be linked with body fat redistribution)

24

Steroid dose equivalents

Steroid Potency (Equivalent dose)

Duration of action (1/2 life)

Hydrocortisone 20mg 8

Prednisolone 5mg 16-36

Methylprednisolone 4mg 18-40

Dexamethasone 0.75mg 36-54

Betamethasone 0.75mg 26-54

N.B: Potency relates to anti – inflammatory action, which may not equate to hyperglycaemic effect

JBDS-IP: Managament of hyperglycaemia and steroid therapy 2014

Frequency of Hyperglycemia in Patients

Receiving High-Dose Steroids

26Donihi A, et al. Endocr Pract. 2006;12:358-262.

≥1 BG >11.1mmol/L ≥2 BG >11.1mmol/l

64

56

81

52

41

75

0

30

60

90

All No Hx DM Hx DM

Pati

en

ts (

%)

Predisposing factors to steroid induced diabetes / hyperglycaemia

1. Pre-existing type 1 or type 2 diabetes 2. People at increased risk of diabetes (e.g. obesity,

family history of diabetes, previous gestational diabetes

3. Ethnic minorities4. Polycystic ovarian syndrome5. Impaired fasting glucose or impaired glucose

tolerance, HbA1c 42-47mmol/mol6. People previously hyperglycaemic with steroid

therapy

All conditions: monitoring guidelines

*All patients should have a HBA1C at start of steroid treatment

Pre-existing diabetes

QDS capillary monitoring

If Capillary glucose levels >12mmol/L of two occasions escalate treatment

Without pre-existing diabetes

Once daily - (prior to lunch or evening meal or 1-2 hours after)

If Capillary glucose levels >12mmol/L increase to QDS monitoring

If Capillary glucose levels >12mmol/L on two occasions in 24 hours start treatment

JBDS-IP October 2014

Recommended glucose targets 6 – 10mmol/L (accepting 4-12mmol/L

RSCH: STARTING HIGH DOSE STEROIDS IN ONCOLOGY OUTPATIENTS Care pathway

Many of these patients will develop hyperglycaemia which may adversely affect their wellbeing and outcomes

HbA1c >47 in the last 3 months?

Send blood for • random glucose

(grey) • HbA1c (purple)

Is random plasma Glucose >11.0mmol?

• Advice leaflet

• Start capillary monitoring premeals.

Do any of the following apply:• BMI>30• FH diabetes• Previous

gestational DM• Pancreatic lesion

or PMH pancreatitis

• Advice leaflet

• Urine glucose testing pre lunch

Daily for first 2 weeks and weekly after that while on steroids

Possible pre-existing diabetes/impaired glucose tolerance.

Pre-existing diabetes/impaired glucose tolerance. High probability of insulin treatment

Moderate risk of developing steroid induced hyperglycaemia

Is urine glucose positive on 2 consecutive tests?

Risk not increased above normal

Are 2 tests >12 mmol?

• Advice leaflet

• Start capillary monitoring premeals.

refer DSN for insulin start

If 2 tests >12-20Start gliclazide80mg om

Are 2 tests >20mmol or poor response to gliclazide

Y

Y

Y

RISK ASSESSMENT BEFORE STEROIDS STARTED

WHAT IS THE RISK?

NEW: SCREENING GLYCOSURIA

CAPILLARY MONITORING TREATMENT

Without pre-existing diabetes and steroid treatment

Set capillary glucose targets (6-10mmol/L)

Gliclazide – titrate to 320mg daily (240mg in am + 80mg pm)

If still no improvement: consider 10units human insulin (humulinI or insulatard) in the morning. Titrate in increments of 10 -20%

If uncontrolled hyperglycaemia or multiple dosing of steroidconsider switching to basal analogue insulin or alternative regimen for example basal bolus or bd

Beware of nocturnal and early morning hypoglycaemia

JBDS-IP October 2014

Type 2 diabetes and steroid treatmentSet capillary glucose targets (6-10mmol/L)

If hyperglycaemic on non-insulin treatment

Gliclazide – titrate to 320mg daily (240mg in am + 80mg pm)

Add metformin to maximum 2g daily

If hyperglycaemic on insulin treatmentIf on once daily evening human insulin (humulin I or insulatard) consider switching to morning

If uncontrolled hyperglycaemia or multiple dosing of steroid consider switching to basal analogue insulin or alternative regimen for example basal bolus or bd

Beware of nocturnal and early morning hypoglycaemia

JBDS-IP October 2014

End of life diabetes care

• Steroid therapy is frequently used in palliative care for symptom control, usually as dexamethasone or prednisolone

• Regardless of the indication, the impact of steroids on glucose control can cause additional hyperglycaemic symptoms

Goals of treatment

• Preserve quality of life via prevention of acute signs of (polyuria, nocturia and polydipsia)

• Prevention of sub-acute complications of sustained hyperglycaemia such as infections, hypercoagulability, catabolic weight loss and osmotic diuresis

Diabetes UK (2013) End of Life Clinical Care Document 2nd Edition

End of life Diabetes Care Management

Summary

• Diabetes prevalence is increasing

• Considerations for individualised treatment

• HbA1c / risk assessment should be done on all patients starting high dose steroids

• Diabetes medication should be reduced towards end of life