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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