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“SAFE & Smart” Use of Sulfonylureas • Practice Points for optimal use of this essential class of drugs in T2DM – Place of SU in current diabetes management – Addressing concerns with SU treatment • Hypoglycemia, Weight changes, Durability, CV risk, etc – Choosing among the SUs – Translating evidence into practice • Patient selection, drug selection, dose selection, patient empowerment & physician empowerment • Executive Summary released at the 2nd SAFES Summit, Dhaka on 24 April, 2015 Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. Situational Assessment… Sulfonylureas In South Asia • Majority of population in South Asia is treated with OHAs, either as monotherapy or in combination. • Both conventional and modern SUs remain the choice of OHA prescription. • Conventional SUs are listed alongside metformin, in the NLEM of these nations • Tolbutamide, one of the oldest SU, is still being prescribed in Sri Lanka • Recent studies from India/ Pakistan report SU+Metformin are more efficacious than DPP4i+metformin combinations. • During 2014, SUs (as combination therapy) constituted the majority of OHAs market in India, with glimepiride combinations posting a growth higher than the market Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. A: Indications of SUs A1. SUs are an effective, safe, well tolerated, affordable & convenient therapeutic option in the management of T2DM. A2. SUs are effective second line agents after metformin, in the management of T2DM. SU monotherapy as first line may be considered in Type 2 Diabetes with metformin intolerance/ contraindication and in patients with MODY. A3. Modern SUs should be initiated early in the course of T2DM, to achieve maximum glycemic benefits and obtain the benefits of metabolic memory. A4. SU- containing dual or triple FDCs, if available, (with drugs that have complementary modes of action) reduce cost, offer convenience, and improve patient adherence. Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. Place Of Sulfonylureas In Diabetes Therapy Placement Initial therapy Approach Monotherapy 2nd line therapy Combination therapy with metformin Add on therapy Subsequent add on therapy Special consideration Add on to combination Indication Contraindication to metformin Intolerance to metformin High blood glucose levels at presentation Inadequate glycaemic control with metformin Biological factors Inadequate glycaemic control with existing oral therapy Age> 60 Psychosocial factors Gluco-phenotype Renal impairment Neonatal diabetes MODY-3 Ramadan* Fasting hyperglycemia – prefer long-acting SUs Post prandial hyperglycemia – prefer shortacting SUs *preferred SUs include modern SUs like Glipizide MR, Gliclazide, Gliclazide MR, Glimepiride Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. B. Preferred SUs B1. Modern SUs should be preferred over conventional SUs in view of the reduced mortality, better CV outcomes, and renal protection. B2. Modern SUs should be preferred over conventional SUs in T2DM patients at increased risk of hypoglycemia. B3. Modern SUs should be the preferred choice of SU in overweight/obese T2DM patients. B4. Modern SUs should be preferred over conventional SUs in patients at increased risk of CVD or with CVD. Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. C. SUs In Co-morbid Conditions C1. Shorter acting drugs, especially those metabolized in the liver (glipizide), should be the preferred SU in patients with moderate/severe renal impairment. In mild/ moderate renal impairment, gliclazide and glimepiride may also be used, preferably at lower doses. C2. Reduction of dose, and longer intervals between dose adjustments for SUs, are recommended in patients with mild/moderate hepatic impairment. C3. SUs with lower risk of hypoglycemia such as gliclazide MR and glimepiride are recommended in elderly patients. Alternately, short acting SUs, or SUs in low dose can be used. C4. SUs are not indicated for use in children and adolescents, and should be avoided in pregnancy & lactation Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. Strengths And Timing Of Administration Of SUs Including In Comorbidity SUs Strengths Recommended dose available (mg) Dose Titration Dose Glipizide IR: 5, 10 ER: 2.5, 5, 10 Before breakfast Adult: 5 mg daily Geriatric: 2.5 mg daily Adult IR: 2.5-5 mg as frequently as No adjustment every few days Adult ER: adjustments no more frequently than every 7 days Geriatric IR: 2.5-5 mg every 1-2 weeks as needed Geriatric ER: Conservative titration Gliclazide Tablet: 80 MR: 60 Adults: 40 mg daily in the morning MR: 30-120 mg at breakfast With breakfast or first main meal Adult: 2.5-5 mg daily Adult Micro:1.5-3 mg daily Geriatric: 1.25-2.5 mg daily Renal Impairment increased if necessary up to 320mg (4 tablets) daily > 160 mg: morning and evening Glibenclamide Tablet: 1.25, Adult: no more than 2.5 mg/day at 2.5, 5 weekly intervals Micronized Adult Micro: no more than 1.5 tablet: 1.25, mg/day at weekly intervals 2.5, 5 Geriatric: 1.25-2.5 mg, 1-3 weeks Glimepiride 1, 2, 4 With breakfast or first main meal Adult: 1-2 mg every 1-2 weeks as Adult: 1-2 mg daily needed Geriatric: 1 mg daily Geriatric: conservative titration Renal: conservative titration Glipizide + 2.5/250 With meals As with individual agents Metformin 2.5/500 As with individual agents 5/500 2.5-10/250-2000 Glibenclamide 1.25/250 With Meals As with individual agents + 2.5/500 As with individual agents Metformin 5/500 1.25/250-20/2000 Glimepiride + 0.5/500, Once daily with breakfast or first As with individual agents Metformin 1/500, 1/850, main meal 2/500, 2/850, As with individual agents 3/850, 4/1000 1/500-2/500 Pioglitazone+ 30/2 Once daily with First main meal As with individual agents Glimepiride 30/4 As with individual agents 30/2-4 15/1 Tablet and MR: Not indicated in severe cases Not recommended in CrCl <50 mL/min 1 mg daily As with individual agents Hepatic Impairment 2.5 mg daily Tablet and MR: Not indicated in severe cases Avoid in severe impairment No adjustment needed in minor. Contraindicated in severe impairment As with individual agents As with individual agents As with individual agents As with individual agents As with individual agents As with individual agents As with individual agents Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. D. SUs in Ramadan/Religious fasting D1. SUs may be used during Ramadan, with appropriate counseling and dose modification. Modern SUs are preferred as they confer lower risk of hypoglycemia. D2. Individuals on once daily SU should take their medications at Iftar. The dose may remain unchanged or reduced depending upon their pre-Ramadan glycemic status. D3. Individuals on twice daily SUs, with higher doses in the morning and a smaller dose in the evening, may shift the higher morning dose to Iftar, and the smaller evening dose, or its half, to Suhur. The Suhur dose may be reduced further, if control is adequate. D4. Individuals with good control on conventional SUs do not require major changes in drug regimen, except for dose titration. Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. E. Practical Tips For Using SUs E1. Practice a ‘start low, step-up slow’ approach, up titrating gradually. E2. SU titration should be based on glucose monitoring: – once in two weeks –for responders with no hypoglycemia – once a week –for non-responders, with or without hypoglycemia E3. Timing of administration of SUs before the first, and subsequent major meals of the day, is important. Importance of adherence must be explained. E4. Patients/ family members should be educated on sick day management, need to carry diabetes identity cards, recognition and management of hypoglycemia, including de-escalation of SU doses, if required. Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. Practical Considerations For The Use Of Sulfonylureas Pragmatic Use of SUs Posology • Begin with low doses and up-titrate slowly, at weekly or fortnightly intervals • Avoid using more than half-maximal doses Prescription • SUs should ideally be used if one or two other drug classes fail to achieve glycaemic targets • Avoid using SUs in conjunction with another SU and/or premixed or rapid acting insulin and/or meglinitides • SUs can be prescribed as part of BIDS (bedtime insulin, day time SU) regime Adapted from: Kalra S and Gupta Y. Sulfonylureas. J Pak Med Assoc. 2015;65:101-4. Practical Considerations For The Use Of Sulfonylureas Hypoglycaemia • Educate the patient with diabetes, and their family members, about hypoglycaemia • Enquire about symptoms suggestive of hypoglycaemia at each visit Lifestyle • Advise a 3+3 meal pattern, especially with longer acting SUs • Avoid physical activity during the time interval between SU administration and meal intake and in the first few hours after SU ingestion • Avoid missing meals Weight • Measure weight at every clinic visit • Request the patient with diabetes to inform the physician in case of sudden, unexplainable weight gain Adapted from: Kalra S and Gupta Y. Sulfonylureas. J Pak Med Assoc. 2015;65:101-4. Practical Considerations For The Use Of Sulfonylureas Pragmatic Use of SUs Cardiovascular health • Assess cardiovascular health prior to SU prescription • Educate patients with diabetes, and family member, about symptoms of angina • Monitor cardiovascular health regularly Fixed dose combination (FDCs) • Prefer FDCs if available • Prefer scored FDCs if available • Empower the patient with diabetes to self-titrate the dose if hypoglycaemia occurs Adapted from: Kalra S and Gupta Y. Sulfonylureas. J Pak Med Assoc. 2015;65:101-4. To Conclude… • This initiative by SAFES aims to encourage rational, safe and smart prescription of SUs • Considering their efficacy, safety, pleiotropic benefits, and low cost of therapy, SUs should be considered as recommended therapy for the treatment of diabetes in South Asia. • Modern SUs (glimepiride, gliclazide MR) are backed by a large body of evidence, experience, and most importantly, outcome data, which supports their role in managing patients with diabetes. • Person-centred care, i.e., careful choice of SU, appropriate dosage, timing of administration, and adequate patient counseling, will ensure that deserving patients are not deprived of the advantages of this well-established class of antidiabetic agents Kalra S, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. Thank You