1. T2DM NICE guidance and focus on oral agents
Dr Parijat De
Consultant in Diabetes & Endocrinology
SWBHT

2. NICE AND OTHER TYPE 2 DIABETES MANAGEMENT GUIDELINES

3. 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

4. Clinical Guideline Update NG28
NICE Clinical Guideline for type 2 diabetes in adults 2nd December 2015
Clinical Guideline Update NG28

6. NICE oral agent continuation criteria
Continue therapy only if there is a reduction of ≥ 0.5 percentage points in HbA1c in 6 months.

7. 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]

8. 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]

9. 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]

10. 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]

11. 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.

12. 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]

13. 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.

14. 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

15. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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

16. 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 ( %) - younger, healthier
Looser targets ( %+) - older, co-morbidities, hypoglycemia prone, etc.
Avoidance of hypoglycemia
PG = plasma glucose
Diabetes Care, Diabetologia. 19 April 2012

17. T2DM Anti-hyperglycemic Therapy: General Recommendations
Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs.
Diabetes Care, Diabetologia. 19 April 2012
T2DM Anti-hyperglycemic Therapy: General Recommendations

18. 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

19. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Co-morbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Metformin: May use unless condition is unstable or severe
Avoid TZDs
? Effects of incretin-based therapies
Diabetes Care, Diabetologia. 19 April 2012

20. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
Co-morbidities
Coronary Disease
Heart Failure
Renal disease
Liver dysfunction
Hypoglycemia
Increased risk of hypoglycemia
Metformin & lactic acidosis
UK:  <45 & <30
Caution with long acting SUs
DPP4s – Linagliptin safest, dose adjust for most others
Avoid GLP1
Diabetes Care, Diabetologia. 19 April 2012

21. 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

22. 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

23. Type 2 Diabetes medications: pros and cons?

24. 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)

25. JAN-2007-W SS
4/12/ :55 PM
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
JAN-2007-W SS

26. Metformin – titrate up to dose 2 grams/day
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

27. Thiazolidinediones (glitazones)
JAN-2007-W SS
4/12/ :55 PM
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
JAN-2007-W SS

28. JAN-2007-W SS
4/12/ :55 PM
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)
JAN-2007-W SS

29. Incretin-based therapies
DPP-4 inhibitors
Protect native GLP-1 from inactivation by DPP-4
GLP-1 receptor agonists
Mimic native GLP-1
Sitagliptin
Vildagliptin
Saxagliptin
Linagliptin
Exenatide (Exendin-based therapy)
Bydureon
Liraglutide
(Human GLP-1 analogue)
The circulating levels of native GLP-1 decrease rapidly because of inactivation, mainly by dipeptidyl peptidase-4 (DPP-4) (1). To be effective, native GLP-1 would need to be infused continuously. Consequently, it is of limited clinical utility.
There are two other ways to restore the GLP-1 response:
Protect GLP-1 from inactivation by DPP-4
Develop GLP-1 receptor agonists that are resistant to DPP-4 and can mimic native GLP-1.
Both of these strategies have now been introduced into clinical practice by the development of DPP-4 inhibitors and GLP-1 receptor agonists respectively. Both classes of drug are described as incretin-based therapies.
The GLP-1 receptor agonists include exenatide and liraglutide (1). Exenatide is an exendin-based therapy. Liraglutide is a human GLP-1 analogue.
Reference
1. Drucker DJ, Nauck MA. Lancet 2006;368:1696−1705
Drucker DJ, Nauck MA. Lancet 2006;368:1696−1705 29

30. dfhdfdhcharacteristics
DPP-4 inhibitors
(saxagliptin, sitagliptin, vildagliptin, linagliptin)
Can be used 2nd line after Metformin
HbA1c reduction %
Weight neutral
Oral administration
No significant GI side effects
Low rates of hypoglycaemia
Improved meal-related insulin secretion, reduce glucagon release
This slide compares and contrasts the main characteristics of the GLP-1 agonists and the DPP-4 inhibitor classes of glucose-lowering therapies
Reference:
Kendall DM, et al. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122:S37-S50.
GI = gastrointestinal; ↑ = increased; ↓ = decreased.
Adapted from Kendall DM, et al. Am J Med. 2009;122:S37-S50. 30

31. 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

32. SGLT2 inhibitors (prevents reabsorption of glucose by kidney tubules, causing glycosuria)32

36. EMPA-REG OUTCOME® Results

37. 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
Notes:
This was a randomized, double-blind, placebo-controlled trial to assess the effect of once-daily empagliflozin (at a dose of either 10 mg or 25 mg) versus placebo on cardiovascular events in adults with type 2 diabetes at high cardiovascular risk against a background of standard care.
CV, cardiovascular Zinman B et al. N Engl J Med 2015 DOI: /NEJMoa

38. Randomised and treated
Trial design
Placebo (n=2333)
Screening
(n=11531)
Randomised and treated
(n=7020)
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
Notes:
This was a randomized, double-blind, placebo-controlled trial to assess the effect of once-daily empagliflozin (at a dose of either 10 mg or 25 mg) versus placebo on cardiovascular events in adults with type 2 diabetes at high cardiovascular risk against a background of standard care.
Patients were treated at 590 sites in 42 countries.
Zinman B et al. N Engl J Med 2015 DOI: /NEJMoa

39. 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)†
Notes:
Patients had T2D and were drug naïve or on background glucose-lowering drugs.
All patients were at high risk for CV events.
Age criteria were ≥ 20 years in Japan and ≤ 65 years in India.
History of MI (> 2 months prior to enrolment).
Evidence of multi-vessel CAD in ≥ 2 major vessels or left main coronary artery.
Evidence of single-vessel CAD with no scheduled revascularisation/previously unsuccessful revascularisation and:
Positive non-invasive, functional stress test for ischaemia (ECG, echo or nuclear); or
Hospital discharge due to unstable angina pectoris ≤ 12 months before enrolment.
Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CAD.
History of stroke (ischaemic or haemorrhagic) > 2 months prior to consent.
Occlusive peripheral artery disease documented by:
Limb angioplasty, stenting or bypass surgery; limb or foot amputation due to circulatory insufficiency; evidence of significant peripheral artery stenosis in 1 limb; ankle brachial index < 0.9 in ≥ 1 ankle.
Abbreviations
BMI, body mass index; CAD, coronary artery disease; CV, cardiovascular; ECG, electrocardiogram; echo, echocardiogram;
EMPA-REG OUTCOME™, cardiovascular outcomes trial of empagliflozin;
†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: /NEJMoa

40. Pre-specified primary and key secondary outcomes
Primary outcome
3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke
Key secondary outcome
4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina
Notes:
The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke. The key secondary outcome was a composite of the primary outcome plus hospitalization for unstable angina.
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event
Zinman B et al. N Engl J Med 2015 DOI: /NEJMoa

41. Cardiovascular outcomes

42. Primary outcome: 3 point MACE
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.04*
Notes:
The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) than in the placebo group (282 of 2333 [12.1%])
(hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P<0.001 for noninferiority and P=0.04 for superiority)
Primary outcome: 3P-MACE, 3-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)
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: /NEJMoa

43. CV death HR 0.62 (95% CI 0.49, 0.77) p<0.001 Notes:
As compared with placebo, empagliflozin resulted in a significantly lower risk of death from cardiovascular causes (hazard ratio, 0.62; 95% CI, 0.49 to 0.77; P<0.001)
The benefit of reduced rates of CV death was apparent early within the trial.
Sub analyses showed that these results were consistent across both empagliflozin doses (10 mg and 25 mg)
RRR: 38%; ARR: 2.2%. (CER – EER) Rates of CV death: 3.7% (empagliflozin) vs. 5.9% (placebo)

44. Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85)
p=0.002
Notes:
As compared with placebo, empagliflozin resulted in a significantly lower risk of hospitalization for heart failure (hazard ratio, 0.65; 95% CI, 0.50 to 0.85; P=0.002)
The benefit of reduced rates of hospitalisation for heart failure was apparent early within the trial.
Sub analyses showed that these results were consistent across both empagliflozin doses (10 mg and 25 mg)
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)

45. All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p<0.001 Notes:
As compared with placebo, empagliflozin resulted in a significantly lower risk of death from any cause (hazard ratio, 0.68; 95% CI, 0.57 to 0.82, P<0.001)
Sub analyses showed that these results were consistent across both empagliflozin doses (10 mg and 25 mg)
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)

46. 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
Notes:
In conclusion, patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had significantly lower rates of the primary composite cardiovascular outcome and of death from any cause than did those in the placebo group when the study drugs were added to standard care.
CV, cardiovascular

47. 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
4) In obese patients with type 2 diabetes uncontrolled on Insulin
Significant and sustained HbA1c reductions
Secondary benefit of weight loss
1-4 . 47

48. 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

49. A practical way forward:
After Metformin, if HbA1c is >7.5% (58) and BMI , 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 , 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