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Therapeutics for Type 2 Diabetes: New Paradigms

Dr Ester Yeoh & Dr Wee Hui Chia

Diabetes Centre, KTPH

Diabetes GP Symposium 22 April 2017

Case Vignette: Mrs Y – 47 yrs old, Admin staff

• T2DM x 7 yrs – Cx by microalbuminuria, ACR 142

• Hpt, Hyperlipidaemia • PCOS • Obesity – BMI 29.7 (weight 76kg, height 1.6m) • Meds (Dec 2014)

– Glipizide 5mg BD, Metformin XR 2000 mg OD, Enalapril 10mg BD, Amlodipine 10mg OM, Simvastatin 10mg ON,

• Initial HbA1c 7-8% in 2012, slowly increased gradually to 8-9% by 2013-2014 – Promoted at work, more responsibilities, less time to look

after herself

Aug 2014 Dec 2014

HbA1c (%) 8.1 8.3

Weight (kg) 76 79.7

DM Meds Glip 5mg BD, Met XR 2000 mg OD

What would you do next?

A. Add on basal insulin therapy

B. Increase Glipizide to 10mg BD

C. Add on SGLT2 inhibitor

D. Add on DPP-4 inhibitor

E. Add on GLP1-RA

F. Reinforce lifestyle management

Main aims of treatment for Mrs Y

• Improve glycaemic control to achieve individualised target HbA1c of <7% in the long term

• Minimize weight gain and promote weight loss

• Maintain good renal fx/ reverse microalbuminuria and prevent other complications

Progress

Aug 2014

Dec 2014

Mar 2015

June 2015

Dec 2015

Jul 2016

Dec 2016

HbA1c (%)

8.1 8.3 8.7 7.6 6.8 7.2 7.1

Weight (kg)

76 77.4 79.7 78.3 78 76.6 76.5

DM Meds

Glip 5mg BD, Met XR 2000 mg OD

SGLT2 inh added

Reduced Glip 5mg OM, cont’ SGLT2 inh

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Added SGLT2 inh in March 2015 Improvement in urine ACR

What is your patient’s HbA1c target? Individualizing glycaemic targets

AACE, American Association of Clinical Endocrinologists; ADA/EASD, American Diabetes Association/European Association for the Study of Diabetes; HbA1c, glycosylated haemoglobin; T2D, Type 2 Diabetes.

1. Saydah SH, et al. JAMA. 2004;291:335–342. 2. ADA. Diabetes Care. 2013;36:S11–S66. 3. Inzucchi SE, et al. Diabetes Care. 2012;35:1364–1379. 4. AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19:736–737.

The majority of patients with T2D remain above glycaemic goals

63.0% of patients with T2D have HbA1c ≥ 7.0%

12.4% have HbA1c > 10%

20.2% have HbA1c > 9%

37.2% have HbA1c > 8%

ADA/EASD target < 7%

10.0

9.0

8.0

7.0

6.0

HbA1c

HbA1c, glycosylated haemoglobin; T2D, Type 2 Diabetes. *Diet initially, then sulfonylureas, insulin and/or metformin if fasting plasma glucose > 15 mmol/L. †ADA clinical practice recommendations. UKPDS 34, n = 1704. UKPDS 34 Study. Lancet. 1998;352:854–865.

T2D is a progressive disease

UKPDS 34 Study

Conventional* (n = 411) Glibenclamide (n = 277) Insulin (n = 409)

Metformin (n = 342)

Med

ian

Hb

A1

c (%

)

6

7

8

9

Years from randomisation 2 4 6 8 10 0

7.5

8.5

6.5

Recommended treatment target < 7.0%†

Barriers to Optimisation of Glycaemic Control

• Fear of hypoglycaemia

• Progressive weight gain

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T2D, Type 2 Diabetes. *Diet initially then sulphonylureas, insulin and/or metformin if fasting plasma glucose > 15 mmol/L. UKPDS 34 Study. Lancet. 1998;352:854–865.

Many therapeutic options for T2D are associated with weight gain

8

Ch

ange

in w

eig

ht

(kg)

0 3 6 9 12

6

4

2

0

Years from randomisation

UKPDS 34 Study

Conventional* (n = 411) Glibenclamide (n = 277) Insulin (n = 409)

Metformin (n = 342)

Metformin as first-line therapy: weight neutral effect, low risk of hypo

Schwartz, Diab Care 2016;39(2):179-186

Strategy: Least number of agents to target the greatest number of pathways leading to hyperglycaemia while preserving β-cells and reducing CV and other risk factors

T2DM treatment considerations

• The ‘ideal’ DM medication – Normalise plasma glucose – Minimal size effects (hypoglycaemia) – Prevent development of micro- and macrovascular

complications – Durable glucose lowering efficacy and preserve β-cell

function

• Proactive approach to therapy (rather than stepwise)

• Tailored to individual risk factors (eg obesity, CV, renal)

FOCUS ON SGLT2 INHIBITORS

SGLT2 Inhibitors increase urinary glucose excretion

18

Filtered glucose load >180 g/day

SGLT1

SGLT2 inhibitors reduce glucose reabsorption

in the proximal tubule, leading to urinary

glucose excretion and osmotic diuresis

SGLT2 inhibitor

~ 80 g *Loss of ~ 80-120 g of glucose per day = 300-400 cal/day.

Bakris GL et al. Kidney Int 2009;75;1272

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We accept that in most T2D patients, Metformin is first-line therapy. What is the best 2nd line agent after failure of Metformin monotherapy and lifestyle management? A. Sulphonylurea

B. DPP4 inhibitor

C. SGLT2 inhibitor

D. Insulin therapy

E. I am not sure.

Factors to consider: Starting HbA1c and symptoms, risk factors, medication efficacy and side effects How do SGLT2 inhibitors fare when compared to SU therapy? DPP4-i therapy? Or add-on to insulin therapy? How about combination DPP4 and SGLT2 inh?

Summary of evidence for SGLT2 Inh (1)

• As 2nd line treatment (after metformin monotherapy), SGLT2 inh vs. SU shows – Comparable or superior (~0.1%) efficacy in HbA1c

reduction – Less weight gain and less hypoglycaemia (5-6x) – Lower failure rate (requiring additional agent) in the

long term (4 years) (Cefalu et al, Lancet 2013; Prato et al, Diab Obes Metab 2015)

• As 3rd line treatment (after metformin and SU), SGLT2 inh vs. DPP4 inh – Superior HbA1c reduction (~0.4%) – Greater weight reduction (2-3kg) (Schernthaner G. et al Diabetes Care 2013)

• As add-on to insulin therapy (after Metformin + insulin – basal, basal-bolus), SGLT2 inh vs placebo – Further reduction in HbA1c (0.5-0.7%) and FPG (~1

mM) – Weight loss (1-3.5 kg) – Reductions in SBP (~3-4 mmHg) (Neal et al, Diab Care 2015, Rosenstock Diab Obes Metab 2015)

• Combination SGLT2 inh + DPP4 inh as 2nd line therapy (after Metformin monotherapy) – No synergistic or additive benefit of adding both – Only a small further reduction in HbA1c (~0.2%) – Not cost-effective (Rosenstock et al, Diab Care 2015; DeFronzo et al, Diab Care 2015)

Summary of evidence for SGLT2 Inh (2)

CV safety and benefits of SGLT2 inhibitors

• Study population in EMPA-REG, RCT – N=7020 T2D patients, mean HbA1c 8%, age 63 yrs, BMI

30.6, >50% had DM Duration > 10 yrs, ~50% were on insulin therapy

– High CV risk: Confirmed MI, multivessel/ single vessel CAD, unstable angina, stroke, PAD patients

• Primary outcome – 3-point MACE: Death from CV causes, non fatal MI, non

fatal stroke

• Reduction in

– CV mortality (38%)

– Hospitalization for heart failure (35%)

– Death from any cause (32%)

Awaiting CANVAS (CANaglifozin cardioVascular Assessment Study) in ADA 2017 and DECLARE-TIMI (Dapaglifozin on the incidence of Cardiovascular events) in 2019 to show ‘class effect’

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Nephropathy benefits of SGLT2 inhibitors

• Secondary outcome of the EMPA-REG OUTCOME trial: renal microvascular outcomes

– Incident or worsening nephropathy (progression to macroalbuminuria), doubling of serum Creat, eGFR ≤45, initiation of RRT or death from renal dz

SGLT2 inhibition slowed progression of kidney disease

• Compared to placebo, SGLT2 inh – 39% reduced risk of

new-onset or worsening renal dz

– 55% reduction in initiation of RRT

– 44% reduction in doubling of serum creatinine

– 38% reduction in progression to macroalbuminuria

55/yr old man with T2DM x 15 years, on s/c Mixtard (30/70) x 5 years, HbA1c 9-10%, weight increasing BMI 26.7. Started on SGLT2 inh in June 2016. HbA1c 10.2% (June) -> 8.8% (Sept).

Acute kidney injury from SGLT2i

• FDA drug safety warning • Mechanism and risk factors for AKI

– Reduced blood volume from diuresis/ dehydration – CKD, CCF – Concomitant use of diuretics, NSAIDs, ACE-i/ ARBs

• Precautions to take when starting SGLTi – Encourage adequate hydration – Consider stopping concomitant diuretics and NSAIDs – Monitor renal function 2-4 weeks after starting drug – If AKI (30% rise in Creatinine) – stop drug and monitor.

Majority will improve.

Other adverse effects: Eu-DKA

• Drug Safety Warning of increased risk of DKA in patients using SGLT2 inhibitors

• Characteristics of eu-DKA – Mild to moderate glucose elevations (euglycaemic DKA) – Potential triggers: Intercurrent illness, reduced food and fluid

intake, history of alcohol intake – Reductions in insulin doses due to poor appetite – Higher risk in those with long-standing T2DM with marked β-cell

insufficiency or LADA

• Precautions to take to avoid DKA – Stop SGLT2i temporarily if unwell/ poor oral intake – Stay well-hydrated – Those on insulin – to check BG more often and usual sick day

rules for insulin therapy

Rosenstock, Diab Care 2015; 38:1638-1642

Genito-urinary and urinary adverse effects

SGLT2 inh vs. Placebo

Female genital mycotic infections 3-4 x

Male genital mycotic infections 4-5 x

UTI 1.5 x

Increased urination 5 x

Low rates of discontinuation of drug (ranging 3-7%), no different from that of placebo. Precautions to take:

• Increase H2O intake when starting drug • Good perineal hygiene • Stop if having symptoms of GUI or UTI and see a Dr

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SGLT2 inhibitors and renal dose adjustment

Drug name eGFR (ml/min/1.72m2)

Dose (mg) adjustment

Canaglifozin, 100 mg vs 300 mg

≥ 60 100 (start dose) – 300

45-60 100

< 45 Not recommended

Dapaglifozin, 5mg vs 10 mg

≥ 60 5 (start dose) -10mg

< 60 Not recommended

Empaglifozin, 10mg vs 25 mg

≥ 45 10 (start dose) – 25

< 45 Not recommended

Summary of SGLT2 inhibitors

• Available in Singapore: Canaglifozin (Invokana), Empaglifozin (Jardiance), Dapaglifozin (Forxiga)

• Mechanism of action: Inhibits SGLT2 in the kidneys -> promoting glucosuria, and Na loss -> resulting in reductions in blood glucose and blood pressure

• Glycaemic efficacy: Effective – HbA1c reduction 0.5-1.5% (greater in higher HbA1c)

• Hypoglycaemia & weight effects: Beneficial – Low risk of hypoglycaemia and weight loss effects – Less effective in patients with moderate to severe renal

impairment (GFR < 60 ml/min)

• Additional benefits – CV and nephropathy benefits

• Adverse effects – Genital and urinary tract infections, osmotic diuresis (AKI) -

caution in elderly and concomitant diuretic use, eu-DKA (FDA/HSA caution: overall risk is < 0.1%)

Case Vignette: Mrs C – 40 yrs old, Business owner

• Obese ( 71kg, 150 cm, BMI: 31.6 kg/m2)

• DM diagnosed in early 2014 – Hb1c 9.5% on diagnosis

– Started on metformin 850mg BD and DPP4-inh

• Also diagnosed with hyperlipidaemia

• No microvascular and macrovascular complications

• Determined to lose weight and improve DM control

What other therapeutic options?

A. Increase metformin

B. Add glipizide

C. Add basal insulin

D. Add SGLT2 inhibitor

E. Add GLP1-RA

F. Refer weight management clinic

G. Advise to consider bariatric surgery

Mains aims of treatment for Mrs C

• Improve glycaemic control to achieve individualised target HbA1c of <7% in the long term

• Minimize weight gain and promote weight loss

• Prevent onset of complications

Progress

June 2014

Dec 2014

Mar 2015

June 2015

Dec 2015

Jan 2017

HbA1c (%)

9.5 9.2 6.4 7.6 6.8… 6.2

Weight (kg)

71 72.5 70.3 69 69.4 68.8

DM Meds

Met 850mg BD + DPP4 inh

GLP1 RA and Metformin 850mg BD

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CGM at baseline

CGM at 1 year FOCUS ON GLP1 RECEPTOR AGONISTS

Actions of GLP-1

GLP-1 Receptor Agonist

• Taking Liraglutide as an example

– Long-acting GLP-1 receptor agonist

– 97% homology to human GLP-1

– Half-life of 13 hours

– Once a day dosing

Glycaemic and weight loss benefits of GLP-1 Receptor Agonist

• Glycaemic benefits – HbA1c reduction of -0.8-1.5%

– Low hypoglycaemia risk • “glucose dependence” of insulin secretory effect

• Weight loss effect – Mean weight loss of ~3 kg

– Weight loss can be variable

JP H Wilding. Positioning SGLT2 Inhibitors/ incretin based therapies in treatment algorithm. Diab care 2016;39:S154-164

GLP-1 RA: Liraglutide

• Cardiovascular safety

• Dosing and administration

• Use in renal and hepatic impairment

• Side effects

• Warning and precautions/ Contraindications

• Practical consideration in clinical practice

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• Study population – 9340 T2DM patients, mean duration of diabetes of 12.8 years,

mean HbA1c of 8.7% – + High CV risk

• Age >50 years with at least one cardiovascular condition • Age >60 years with at least one cardiovascular risk factor

– Most patients on combination therapy (76% metformin, 50% SU’s, 44 % insulin)

– Randomly assigned in 1:1 ratio, to receive 1.8mg liraglutide or placebo once daily

• Primary outcome – First occurence of death from cardiovascular causes, nonfatal MI or

nonfatal stroke – Median follow up: 3.8 years

Cardiovascular conditons: CHD, CVD, PVD, CKD stage 3, CCF NYHA II or III Cardiosvascular risk factor: microalbuminuria, hypertension, LVH, LV systolic or diastolic dysfunction, ABI <0.9

Cardiovascular effects of liraglutide-LEADER trials

In comparison with placebo,

• Fewer death from cardiovascular causes, nonfatal MI or nonfatal stroke

• Lower HbA1c (mean difference 0.4%)

• Lower weight (mean difference 2.3kg)

• Lower systolic blood pressure (mean difference 1.2mmHg)

• Lower risk of hypoglycaemia (2.4% vs 3.3%)

Cardiovascular conditons: CHD, CVD, PVD, CKD stage 3, CHC NYHA II or III Cardiosvascular risk factor: microalbuminuria, hypertension, LVH, LV systolic or diastolic dysfunction, ABI <0.9

What are the contraindications for GLP1-RA?

A. Renal impairment

B. Hepatic impairment

C. Medullary thyroid cancer

D. Acute pancreatitis

E. T1DM

Liraglutide: Dosing and Administration

• Dosage:

– SC 1.8 mg /day (Victoza)

• FDA approved in 2010 for treatment of T2DM

• SC once daily at any time

– independent of meals

• Slow dose titration

– Initiated at 0.6mg for 1 week, with instructions to increase dose by 0.6mg weekly till 1.8mg is reached

Liraglutide: Use in renal impairment

• Liraglutide is not eliminated renally – Cleaved by DPP4 into peptides and amino

– No clear relationship between creatinine clearance and exposure to liraglutide

• In mild-mod renal impairment, liraglutide

(up to 1.8mg) did not affect renal function

• No dose adjustment required in CrCl > 30ml/min

• Use in caution in patients with severe renal impairment or end-stage renal disease

Lisbeth V J. Liraglutide in type 2 dm: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokenetics ( 2016 )55:657-662

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Liraglutide: Use in hepatic impairment

• Hepatic impairment is not associated with increased liraglutide exposure

• No dose adjustment in liver impairment

• However, therapeutic experience in hepatic impairment remains limited and should be use with caution in this group of patients

L..V. Jacobsen et al. Liraglutide in type 2 dm: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokiinet 2016): 55:657-672

Liraglutide: Side effects

• Nausea/ vomiting/ diarrhoea ( usually transient )

• Constipation/ abdominal pain/ dyspepsia/ flatulence

• Anorexia/ Decreased appetite

• Headache/ dizziness

• Rash/ injection site reaction

Liraglutide: Special warnings and precautions

• T1DM (off-lable use) and treatment of DKA

• Concomitant use of sulphonylurea and basal insulin

• Inflammatory bowel disease or diabetic gastroparesis

• Congestive heart failure NYHA I-II /AV block – Should not be used in NYHA III-IV

• Acute pancreatitis – Small increase in pancreatitis from RCT’s, but no causal

relationship

– Discontinue if pancreatitis is suspected during treatment

– Use with caution in patients with history of pancreatitis

Liraglutide: Contraindications

• Prior serious hypersensitivity reaction to liraglutide or to any of the product components

• Pregnancy and lactation

• Personal or family history of medullary thyroid cancer or MEN 2 – Thyroid C-cell hyperplasia and medullary

thyroid carcinoma were found in rodents, but no evidence in humans

Where does GLP-1 RA fit in current guidelines? ADA and EASD position statement

Where does GLP-1 RA fit in current guidelines? NICE guidelines

• Recommend GLP-1 RA in T2DM with:

– BMI > 35kg/m2 , or

– BMI <35kg/m2 if weight loss would help to improve obesity related comorbidities

• Continuation of GLP-1RA only if:

– > 1% reduction in HbA1c , and

– > 3% weight loss in 6 months

NICE: Type 2 diabetes in adults 2015

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Use of GLP-1 RA + other OHGAs

• Can be used in combination with metformin, sulphonyureas, TZDs

• Not recommended to combine GLP-1 RA with DPPIV inhibitor

– Duplication of mechanism of action

• Combined with SGLT-2 inhibitor

– DURATION-8 study (combination dapaglifozin and exenatide) showed improved glycaemic measures and CV risk factors after failure of metformin monotherapy

J PH Wilding., Care 2016;39:154-164; Frias et al, Lancet 2016

Use of GLP-1 RA + insulin

• GLP-1 RA in combination with basal insulin

– Better glycaemic target at reduced insulin dose

– Less hypoglycaemia

– Less weight gain

• Limited data to support the use of GLP-1 RA in combination with prandial insulin

J PH Wilding. Positioning SGLT2 inhibitors/ incretin based therapy in treatment algorithm. Diab Care 2016;39:154-164

In patients with optimized basal insulin in T2DM: GLP-1 agonist or bolus insulin? Insulin GLP-1 Agonist

More predictable effects on blood glucose

Less predictable effect on blood glucose

Can be titrated to a patient-specific dose to target a predetermined plasma glucose goal

Customization is not possible

High risk of hypoglycaemia Low risk of hypoglycaemia

Weight gain Weight reduction

How to add a GLP-1 receptor agonist to basal insulin? Practical considerations • Consider decreasing basal insulin dose when a GLP-1

Agonist is initiated • HbA1c < 8% with stable insulin dose

– Decrease basal insulin dose by 20% empirically – Waiting period may be appropriate before titrating basal

insulin dose • History or risk factor of hypoglycaemia/ at risk of hypoglycaemia

unawareness • Further titration during week 5-6

• HbA1c > 8% – Initiate GLP-1 agonist without empiric basal insulin dose

reduction – Dose reduction may be reasonable in history or risk factor

of hypoglycaemia/ at risk of hypoglycaemia unawareness Nicholas W et al. Combining a GLP-1 Agonist and basal insulin: study evidence and practical considerations. Drugs (2014) 74:2141-2152

Summary of GLP-1 RA

• Available in Singapore: Liraglutide (Victoza), Exenatide (Byetta), Lixisenatide (Lyxumia), Dulaglutide (Trulicity)

• Mechanism of action: Correct multiple components of the pathophysiology of T2DM

• Glycaemic efficacy: Effective – HbA1c reduction 0.8-1.5 % (greater in those with higher HbA1c)

• Hypoglycaemia & weight effects: Beneficial – Low risk of hypoglycaemia and weight loss effects

• Additional benefits – CV safety and benefits

– Generally safe in mod renal impairment and liver impairment

– Preserve beta-cell function

• Adverse effects – GI (nausea and vomiting) – most significant, lower starting dose

to reduce this AE (0.6 mg x 1 week -> 1.2 mg x 1 week -> 1.8 mg)

Take Home Messages

• More proactive approach in minimizing weight gain, hypoglycaemia, preserving β-cell function and reducing CV mortality , morbidity and nephropathy – Choosing agents which can combine improvements in glycaemic

parameters + weight loss + CV and nephropathy outcome benefits

– Advocate lifestyle measures every step of the way

• Considering cost-benefit analysis and patient’s preference, time to move away from ‘traditional’ agents towards these ‘newer’ agents

• Consideration for metabolic surgery for patients who fulfill criteria (Recommended in BMI≥40; or BMI 35-39.9 with uncontrolled hyperglycaemia despite lifestyle and medications; Considered in those with BMI 30-34.9 with uncontrolled hyperglycaemia despite lifestyle and medications; Reduce by 2.5 for Asians)

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THANK YOU

QUESTIONS?