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T2DM NICE guidance and focus
on oral agents
Dr Parijat De
Consultant in Diabetes & Endocrinology
SWBHT
NICE AND OTHER TYPE 2 DIABETES
MANAGEMENT GUIDELINES
NICE guidance on oral agents....
After Metformin and lifestyle, you can add from
any one of the following oral agents:
• 1) Sulphonylurea - Gliclazide
• 2) Gliptin – Sita/Saxa/Lina/Alogliptin
• 3) Glitazone - Pioglitazone
• 4) SGLT2 inhibitor – Dapa/Canagliflozin
NICE Clinical Guideline for type 2
diabetes in adults
2nd December 2015
Clinical Guideline Update NG28
NICE oral agent continuation criteria
• Continue therapy only if there is a reduction
of ≥ 0.5 percentage points in HbA1c in 6
months.
Initial drug treatment
• Offer standard-release metformin as the initial
drug treatment for adults with type 2
diabetes. [new 2015]
• Gradually increase the dose of standard-release
metformin over several weeks to minimise the
risk of gastrointestinal side effects in adults with
type 2 diabetes. [new 2015]
• If an adult with type 2 diabetes experiences
gastrointestinal side effects with standard-release
metformin, consider a trial of modified-release
metformin. [new 2015]
In adults with type 2 diabetes, if metformin is
contraindicated or not tolerated, consider initial
drug treatment[3] with:
• a dipeptidyl peptidase-4 (DPP-4) inhibitor or
• pioglitazone[4]or
• a sulfonylurea [new 2015]
FIRST intensification:
• In adults with type 2 diabetes, if initial drug treatment with
metformin has not continued to control HbA1c to below the
person's individually agreed threshold (58) for intensification,
consider dual therapy with:
• metformin and a DPP-4 inhibitor or
• metformin and pioglitazone[4]or
• metformin and a sulfonylurea. [new 2015]
• If metformin is contraindicated or not tolerated and initial drug
treatment has not continued to control HbA1c to below the
person's individually agreed threshold (58) for intensification,
consider dual therapy[5] with:
• a DPP-4 inhibitor and pioglitazone[4]or
• a DPP-4 inhibitor and a sulfonylurea or
• pioglitazone[4]and a sulfonylurea. [new 2015]
Second intensification:
• In adults with type 2 diabetes, if dual therapy
with metformin and another oral drug has not
continued to control HbA1c to below the person's
individually agreed threshold (58) for
intensification, consider either triple therapy
with:
• metformin, a DPP-4 inhibitor and a
sulfonylurea or
• metformin, pioglitazone[4]and a sulfonylurea or
• starting insulin-based treatment [new 2015]
Implications for GLP-1 RA Therapy
•
•
There are several changes that could impact GLP-1 receptor agonist (RA) usage:
This guidance is an update of NICE guideline CG87 (published May 2009) and
replaces it. This guidance also updates and replaces NICE technology appraisal
guidance 203 and NICE technology appraisal guidance 248” (page 49 of
guideline), referring to liraglutide and exenatide once-weekly respectively.
–
–
–
•
mandatory funding associated with the STA for both liraglutide and exenatide once-weekly will no
longer apply such that PCOs will no longer be obliged to keep these particular medicines on the
formulary.
the non-recommendation by NICE of the 1.8mg dose of liraglutide will no longer stand
the recommendations for the use of liraglutide as dual therapy, according to TAG 203, no longer
stands
The main change from NICE CG 87 is the recommendation that GLP-1 RAs should
be used as triple therapy following on from full oral intensification to third line
(see orals section of this briefing). Essentially, this means that the GLP-1 RA class
is now recommended as 4th line where previously they were recommended third
line after metformin and SU.
–
GLP-1 RAs are still recommended as triple therapy in combination with metformin and SU, as the
GLP-1 RA would be expected to replace one of the oral agents.
Implications for GLP-1 RA Therapy (2)
•
•
•
Clinicians will be expected to prescribe either a pioglitazone, DPP4 or SGLT2 in
combination with metformin or an SU before prescribing a GLP-1 RA, irrespective
of baseline BMI.
Once a patient is no longer controlled on 3rd line combination therapy with either
pioglitazone, DPP4 or SGLT2 then the clinician will be expected to replace the third
line oral treatment with a GLP-1 RA, but only where the following BMI criteria
apply:
– have a BMI of 35 kg/m2 or higher (adjust accordingly for people from black,
Asian and other minority ethnic groups) and specific psychological or other
medical problems associated with obesity or
– have a BMI lower than 35 kg/m2 and: for whom insulin therapy would have
significant occupational implications or weight loss would benefit other
significant obesity-related comorbidities. [new 2015]
Stopping rules for GLP-1 RAs remain as in the previous guideline
– Only continue GLP-1 mimetic therapy if the person with type 2 diabetes has
had a beneficial metabolic response (a reduction of at least 11 mmol/mol
[1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6
months). [2015]
Implications for GLP-1 RA Therapy (3)
• Where metformin is not tolerated and therefore has
not been prescribed then GLP-1 RA should not be used
and the patient should be started on insulin based
therapy, irrespective of their BMI.
• It recommends clinicians “only offer a GLP-1 mimetic
in combination with insulin with specialist care advice
and ongoing support from a consultant-led
multidisciplinary team” where “a consultant-led
multidisciplinary team may include a wide range of
staff based in primary, secondary and community care.
Implications for Insulin Therapy
• In the main the recommendations for starting insulin, for both human and
analogue, remain very similar as in NICE CG87.
• Regarding insulin initiation the following apply:
• Maintain the patient on metformin
• Start NPH once or twice daily
• Consider starting both NPH and short-acting insulin (particularly if the
person’s HbA1c is 75 mmol/mol [9.0%] or higher), administered either:
– separately or
– as a pre-mixed (biphasic) human insulin preparation.
• The criteria to start with or switch to analogue basal (only glargine and
detemir, degludec is not mentioned) remain the same as it was before
• The criteria to start with or switch to premixed (biphasic) analogue remain
the same
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
1. Patient-Centered Approach
“...providing care that is respectful of and responsive to
individual patient preferences, needs, and values ensuring that patient values guide all clinical decisions.”
• Gauge patient’s preferred level of involvement.
• Explore, where possible, therapeutic choices.
• Utilize decision aids.
• Shared decision making – final decisions re: lifestyle
choices ultimately lies with the patient.
Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
•
Glycemic targets
-
HbA1c < 7.0% (53 mmol/mmol)
-
Pre-prandial PG <7.2 mmol/l
- Post-prandial PG <10.0 mmol/l
-
Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, co-morbidities,
hypoglycemia prone, etc.
PG = plasma glucose
Avoidance of hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012
T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April
2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Co-morbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: CVD benefit
(UKPDS)
 Avoid hypoglycemia
 ? SUs & ischemic
preconditioning
 ? Pioglitazone &  CVD events
 ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Co-morbidities
- Coronary Disease
 Metformin: May use unless
- Heart Failure
condition is unstable or severe
 Avoid TZDs
 ? Effects of incretin-based
therapies
- Renal disease
- Liver dysfunction
- Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Co-morbidities
- Coronary Disease
- Heart Failure
 Increased risk of hypoglycemia
- Renal disease
 Metformin & lactic acidosis
- Liver dysfunction
- Hypoglycemia
 UK:  dose @GFR <45 &
stop @GFR <30
 Caution with long acting SUs
 DPP4s – Linagliptin safest, dose
adjust for most others
 Avoid GLP1
Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Co-morbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Most drugs not tested in
advanced liver disease
 Linagliptin safe
 Pioglitazone may help
steatosis
 Insulin best option if disease
severe
Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Co-morbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Emerging concerns regarding
association with increased
mortality
 Proper drug selection in the
hypoglycemia prone
 Pio, Gliptins, SGLTi, GLP1 safe
Diabetes Care, Diabetologia. 19 April 2012
Type 2 Diabetes medications:
pros and cons?
NICE 2008: where do we stand with Sulphonylureas?
– Consider as first line, if
• Not overweight (BMI < 25)
• Metformin not tolerated (or contraindicated)
• Rapid response to therapy required
– hyperglycaemic symptoms
– Once-daily, long-acting SU in drug concordance concerns
– Educate risk of hypoglycaemia
• Particularly in renal impairment and elderly
Use short acting agents like GLICLAZIDE 40/80 mg bd
(do not use Glibenclamide or other LA sulphonylureas)
NICE 2008: Blood-glucose-lowering Therapy
Oral glucose control therapies (1) R26-39
• Metformin
– START in obese or overweight T2DM (along with diet/
exercise)
– CONSIDER as option in non-overweight T2DM
– Step-up therapy over weeks – reduce GI effects
• Trial of extended-absorption metformin
NICE 2008: Metformin
• Metformin – titrate up to dose 2 grams/day
– Renal Impairment
• Review dose (decrease to 500mg bd) – eGFR 30-45
• Stop – eGFR < 30; creatinine > 150
• Caution prescribing for those at risk of sudden fall in
eGFR
NICE 2008: Blood-glucose-lowering Therapy
Oral glucose control therapies (1) R40-46
• Thiazolidinediones (glitazones)
– Add-on to SU, if metformin not tolerated
– Add-on to metformin, if hypoglycaemia with SU a
potential concern
– Add-on to SU & metformin, if insulin
unacceptable/ ineffective
– Add-on to high dose insulin therapy
NICE 2008: Blood-glucose-lowering Therapy
Oral glucose control therapies (1) R40-46
• Thiazolidinediones
– Advise of risk of oedema, and action to take
– Do not commence or continue in people
• evidence of heart failure
• higher risk of fracture
– Up-to-date information to be applied in use
– IHD is NOT a contraindication (good CV protective
properties – PROACTIVE study)
Incretin-based therapies
DPP-4 inhibitors
GLP-1 receptor agonists
Protect native GLP-1 from
inactivation by DPP-4
Mimic native GLP-1
Sitagliptin
Vildagliptin
Saxagliptin
Linagliptin
Drucker DJ, Nauck MA. Lancet 2006;368:1696−1705
Exenatide
(Exendin-based therapy)
Bydureon
Liraglutide
(Human GLP-1 analogue)
dfhdfdhcharacteristics
DPP-4 inhibitors
(saxagliptin, sitagliptin, vildagliptin, linagliptin)







Can be used 2nd line after Metformin
HbA1c reduction 0.5-1.0%
Weight neutral
Oral administration
No significant GI side effects
Low rates of hypoglycaemia
Improved meal-related insulin secretion, reduce glucagon release
GI = gastrointestinal; ↑ = increased; ↓ = decreased.
Adapted from Kendall DM, et al. Am J Med. 2009;122:S37-S50.
Where does a Gliptin fit in?
• Second line after Metformin, particularly for obese (BMI 25-28) Type 2
diabetics
– Where further weight gain will be a major issue
– Where odema/fluid retention/CCF is a concern
• Second line with Glitazones
• Triple oral therapy with Metformin and SU or with Metformin and
Glitazone
• Some specific gliptins in those with renal impairment
• In those with needle phobia
SGLT2 inhibitors
(prevents reabsorption of glucose by
kidney tubules, causing glycosuria)
EMPA-REG OUTCOME® Results
EMPA-REG OUTCOME®
• Randomised, double-blind, placebo-controlled CV outcomes trial
• Objective
To examine the long-term effects of empagliflozin versus placebo,
in addition to standard of care, on CV morbidity and mortality in
patients with type 2 diabetes and high risk of CV events
CV, cardiovascular
Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
Trial design
Screening
(n=11531)
Randomised and
treated
(n=7020)
Placebo
(n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
•
Study medication was given in addition to standard of care
– Glucose-lowering therapy was to remain unchanged for first 12 weeks
•
•
Treatment assignment double masked
The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event
Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
Key inclusion and exclusion criteria
• Key inclusion criteria
–
–
–
–
Adults with type 2 diabetes
BMI ≤45 kg/m2
HbA1c 7–10%*
Established cardiovascular disease
• Prior myocardial infarction, coronary artery disease,
stroke, unstable angina or occlusive peripheral arterial
disease
• Key exclusion criteria
– eGFR <30 mL/min/1.73m2 (MDRD)†
†Empagliflozin should not be initiated in patients with an eGFR < 60ml/min. In patients tolerating empagliflozin
whose eGFR falls persistently below 60ml/min, the dose of empagliflozin should be adjusted to or maintained
at10mg once daily.
Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
Pre-specified primary and key secondary
outcomes
• Primary outcome
– 3-point MACE: Time to first occurrence of CV death, non-fatal MI or nonfatal stroke
• Key secondary outcome
– 4-point MACE: Time to first occurrence of CV death, non-fatal MI, nonfatal stroke or hospitalisation for unstable angina
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event
Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
Cardiovascular outcomes
Primary outcome: 3 point MACE
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.04*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio: RRR: Relative risk reduction; ARR: Absolute risk reduction.
* Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
RRR: 14%; ARR: 1.6% (CER – EER): Incidence of 3P-MACE: 10.5% (empagliflozin) vs. 12.1% (placebo). CER: Control event rate; EER: Experimental event rate.
Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.001
RRR: 38%; ARR: 2.2%. (CER – EER) Rates of CV death: 3.7% (empagliflozin) vs. 5.9% (placebo)
Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.002
Cumulative incidence function. HR, hazard ratio; RRR: Relative risk reduction; ARR: Absolute risk reduction; CER: Control Event Rate; EER:
Experimental Event rate. RRR: 35%; ARR: 1.4% (CER – EER). Incidence of HHF: 2.7% (empagliflozin) vs. 4.1% (placebo)
All-cause mortality
HR 0.68
(95% CI 0.57, 0.82)
p<0.001
Kaplan-Meier estimate. HR, hazard ratio; RRR: Relative risk reduction; ARR: Absolute risk reduction. CER: Control Event Rate;
EER: Experimental Event rate. RRR: 32%; ARR: 2.6% (CER – EER). Incidence of All-cause mortality: 5.7% (empagliflozin) vs. 8.3% (placebo)
EMPA-REG OUTCOME®: Summary
• Empagliflozin and standard of care reduced the relative
risk of hospitalisation for heart failure by 35% versus
placebo and standard of care
• Empagliflozin and standard of care reduced the relative
risk of CV death by 38% versus placebo and standard of
care
• Empagliflozin and standard of care improved survival
by reducing the relative risk of all-cause mortality by
32% versus placebo and standard of care
CV, cardiovascular
Greatest potential for use of a Gliflozin?
1) Early on in Metformin-uncontrolled patients who are obese and need
weight loss
2) In Gliptin-uncontrolled patients who need weight loss
3) As an alternative to injectable GLP-1 for weight loss
1-4
4) In obese patients with type 2 diabetes uncontrolled on Insulin
.
• Significant and sustained HbA1c reductions
• Secondary benefit of weight loss
Factors which determine choice of
therapy after Metformin
•
•
•
•
•
•
•
•
Pre-existing weight/BMI
Hypoglycemia
Weight gain
Efficacy of glycemic control
Durability of glycemic control
Long term safety
Cardiovascular benefits
Cost
A practical way forward:
 After Metformin, if HbA1c is >7.5% (58) and BMI 25-28,
think of Pioglitazone given all its major CV benefits and
evidence (Gliptin or Gliflozin are alternatives)
 After Metformin, if HbA1c is >7.5% (58) and BMI 28-30,
add a Gliflozin (given its weight loss properties)
 After Metformin, if HbA1c is >7.5% (58) and BMI > 30-35,
add GLP-1 analogue like Liraglutide/Exenatide/Bydureon
 There is a significant role of Glitazones, Gliptins &
Gliflozins as triple oral therapy – delays use of insulin