4/20/2017 1 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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– 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.
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)
~ 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
• 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
• 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
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)