Uncontrolled Diabetes management with OAD- Initiating and Titrating basal insulin therapy. Bowo Pramono

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1 Uncontrolled Diabetes management with OAD- Initiating and Titrating basal insulin therapy Bowo Pramono

2 Case: 48-year-old Asian female History of present illness Known T2DM for 7 years Complained of poor glycemic control, with - HbA1C ~9 10% over the past year - FPG ~ mg/dl Antidiabetic medications included: - Glimepiride 4 mg/day - Metformin 2000 mg/day She had tried pioglitazone but discontinued it owing to excessive weight gain and edema

3 Case: 48-year-old Asian female Relevant past medical history, comorbidities Hypertension and dyslipidemia for 3 years Medication: - Losartan - Amlodipine - Simvastatin Found to have overt proteinuria for 1 year Estimated glomerular filtration rate: 68 ml/min/1.73 m 2 Family history: Both parents had diabetes

4 Case: 48-year-old Asian female Current findings BMI: 23 kg/m 2 BP: 130/85 mmhg Fundi: Moderate, non-proliferative diabetic retinopathy Extremities: Decreased pinprick sensation over both feet Normal Ankle Brachial Index (ABI) Current laboratory results HbA 1c : 10.4 % FPG: 230 mg/dl LDL-C: 84 mg/dl

5 Question 1 How would you manage this patient? 1. Increase dose of glimepiride 2. Add DPP-4 inhibitors 3. Add SGLT2 inhibitors 4. Begin insulin therapy Answer Option 4

6 Non-insulin anti-hyperglycemic agents for T2DM Class HbA 1C Reduction Hypoglycemia Weight Change Dosing (times/day) Other Safety Issues Metformin 1.5 No Neutral 2 GI, lactic acidosis Sulfonylureas 1.5 Yes Gain 1 Secondary failure Thiazolidinediones No Gain 1 Edema, CHF, fractures GLP-1 Receptor Agonists ~1.5 No Loss 1 GI, pancreatitis,?mtc DPP-4 inhibitors No Neutral 1 Pancreatitis SGLT-2 inhibitors No Loss 1 GTI, DKA, AKI Adapted from: Nathan DM, et al. Diabetes Care. 2007; 30(3): Nathan DM, et al. Diabetes Care. 2006; 29(8): Nathan DM, et al. Diabetes Care. 2009; 32(1): ADA. Diabetes Care. 2008; 31:S12 S54. Buse J, et al. Lancet. 2009; 374(9683): Inzucchi SE Diabetes Care 2015;38:

7 Metformin atau obat lini pertama yang lain Metformin atau obat lini pertama yang lain obat lini kedua Algoritme Pengelolaan DM Tipe 2 di Indonesia Modifikasi pola hidup sehat HbA1c < 7.5% HbA1c 7.5% Monoterapi* dengan salah satu dibawah ini Metformin Agonis GLP-1 Penghambat DPP-IV Penghambat Glikosidase Alfa! Penghambat SGLT-2**! Tiazolidindion! Sulfonilurea Glinid Jika HbA1c > 6.4% dalam 3 bulan tambahkan obat ke 2 (kombinasi 2 obat) Kombinasi 2 obat* dengan mekanisme kerja yg berbeda Agonis GLP-1 Penghambat DPP-IV! Tiazolidindion! Penghambat SGLT-2**! Insulin basal Kolsevelam Bromokriptin QR Penghambat Glukosidase Alfa Jika belum memenuhi sasaran dalam 3 bulan, masuk ke kombinasi 3 obat *Obat yang terdaftar disarankan penggunaannya sesuai urutan (hierarki) **Berdasarkan 3 fase data percobaan lain Kombinasi 3 obat Agonis GLP-1 Penghambat DPP-IV! Tiazolidindion! Penghambat SGLT-2**! Insulin basal Kolsevelam Bromokriptin QR Penghambat Glukosidase Alfa Jika belum memenuhi sasaran dalam 3 bulan, mulai terapi insulin atau intensifikasi terapi insuln HbA1c 9.0% Gejala ( - ) Gejala ( + ) Kombinasi 2 obat Kombinasi 3 obat Insulin ± Obat jenis lain Mulai atau intensifikasi Insulin = Efek samping minimal atau keuntungan lebih banyak Keterangan! = digunakan dengan hati-hati Penghambat SGLT2 dan Kolesevelam belum tersedia di Indonesia Bromokriptin QR umunya digunakan pada terapi tumor hipof

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9 Case continued After discussion with her physician, the patient decided to start insulin therapy: Was prescribed premixed human insulin (70/30) to be taken before dinner, as dinner was her largest meal Starting dose was set at 10 U at 5.30 p.m., since she had dinner at around 6 p.m. The patient was instructed to up-titrate the insulin dose until a target FBG of around 100 mg/dl was met However, she was unable to do so as when the dose of insulin was increased to around 25 U, leading to an FBG of around 150 mg/dl, she began to feel very hungry and started to experience palpitations at around 1 a.m.

10 Question 2 How would you manage this patient now? 1. Instruct the patient to increase intake of complex carbohydrates at dinner 2. Instruct the patient to consume snacks at bedtime 3. Reduce the dose of premixed insulin 4. Switch to insulin glargine Answer Option 4

11 Physiologic Insulin Secretion

12 Mean HbA 1c (%) Hypoglycemia with insulin glargine vs premixed insulin (BIAsp 30) Episodes/patient-yr At similar glycemic control, insulin glargine therapy was well tolerated, with lower rates of overall hypoglycemia, less weight gain 1.7 kg, lower insulin dose, and convenient with fewer injections needed Baseline 24 weeks % 1.3% P< Gla BIAsp 30 P<0.05 P=NS QD (n=143) Gla + Met + secretagogues BID (n=137) BIAsp 30 + Met Gla, insulin glargine; BIAsp 30, biphasic insulin aspart 70/30; Met, metformin Randomized, controlled study in T2DM patients uncontrolled (mean HbA 1c : 9.0%; mean FBG: 9.9mmol/L) on previous treatment with basal insulin (glargine or NPH OD-BD + OADs) for at least 3 months. * Median end-of-study total daily insulin dose 0.0 Overall Minor (<3.1 mmol/l) Nocturnal Ligthelm RJ, et al. Endocr Pract 2011; 17:41 50.

13 Case continued Patient was switched from premixed insulin to insulin glargine and was able to further uptitrate the dose to 30 U/d without experiencing hypoglycemia Her FBG level at this stage was 144 mg/dl and HbA 1c = 8.1%

14 Question 3 What is the most appropriate next step of management? 1. Further up-titrate the dose of insulin glargine to reach a target of FBG ~ 100 mg/dl 2. Continue the current dose of insulin 3. Add a prandial insulin before main meal 4. Add DPP-4 inhibitor Answer Option 1

15 HbA 1c (%) 10 Insulin glargine trials: Effective dose titration consistently reduces HbA 1c to target Baseline Study endpoint INITIATE 6 Treat-To- LANMET 2 APOLLO 3 LAPTOP 4 Triple INSIGHT 8 Target 1 Therapy 5 n=367 n=61 n=204 n=177 n=104 n=58 n=624 n= Riddle M, et al. Diabetes Care 2003; 26:3080 6; 2. Yki-Järvinen H, et al. Diabetologia 2006; 49:442 51; 3. Bretzel RG, et al. Lancet 2008; 371:1073; 4. Janka H, et al. Diabetes Care 2005; 28:254 9; 5. Rosenstock J, et al. Diabetes Care 2006; 29:554 9; 6. Yki-Jarvinen H, et al. Diabetes Care 2007; 30: ; 7. Standl E. et al. Horm Metab Res 2006; 38: 172 7; 8. Gerstein H, et al. Diabetic Medicine 2006; 23:

16 Insulin dosages using the treat-to-target method with insulin glargine 80 Units/day Units/kg/day T-T-T 1 n=367 INSIGHT 2 n=206 APOLLO 3 n=204 INITIATE 4 n=121 Mean daily requirement: 0.4 to 0.6 units/kg 1. Riddle M, et al. Diabetes Care 2003; 26:3080; 2. Gerstein HC, et al. Diabetes Med 2006; 23:736; 3. Bretzel RG, et al. Lancet 2008; 371: Yki-Järvinen H, et al. Diabetes Care 2007; 30:1364.

17 Dose optimization in guidelines Up-titration ADA/EASD : increase dose by 2 4 U once or twice weekly IDF : Self-titration regimen: insulin dose increases of 2 U every 3 days Physician led: biweekly or more frequent contact with a health-care professional AACE/ACE : Fixed regimen: increase total daily dose of basal insulin by 2 U every 2 3 days Adjustable regimen Titrate insulin every 2 3 days according to: FBG>180 mg/dl: increase total daily dose by 20% FBG mg/dl: increase total daily dose by 10% FBG mg/dl: increase dose by 1 U Down-titration: hypoglycemia ADA/EASD : decrease dose by 4 U AACE/ACE : BG<70 mg/dl: decrease total daily dose by 10 20% BG<40 mg/dl: decrease total daily dose by 20 40% AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes Association; BG, blood glucose EASD, European Association for the Study of Diabetes; FBG, fasting blood glucose 1. Inzucchi SE, et al. Diabetes Care 2015; 38:140 9; 2. International Diabetes Federation. Global Guideline for Type 2 Diabetes. 2012; Available at: (accessed October 2015); 3. Garber AJ, et al. Endocr Pract 2016; 22:

18 Up-titration of insulin dose and effect on FPG in the Treat-to-Target Trial Insulin dose (U/day) Fasting plasma glucose (mg/dl) Insulin dosage FPG Weeks Mean insulin dose 0.45 u/kg Riddle MC, et al. Diabetes Care 2003; 26:

19 Episodes per patient-year Rates of hypoglycemia with insulin glargine during titration and maintenance period Insulin glargine therapy is well tolerated during up-titration and maintenance PG-cut-off (mg/dl): 7.0 <70 <56 <70 <56 <36 <70 <56 <70 <56 <36 <70 <56 <70 <56 < PG, plasma glucose Overall Nocturnal Severe Overall Nocturnal Severe Overall Nocturnal Severe 0 12 weeks 1 (titration) weeks 1 (maintenance) weeks 2 (n=2837) Owens DR, et al. Diabetes Res Clin Pract 2014; 106: DeVries H, et al. Endocrinol 2014; 10:23 30.

20 FINE = First Basal Insulin Evaluation in Asia: FINE Asia study Prospective, observational study in insulin-naive T2DM patients in 11 Asian countries Patients ( 20 years) who were inadequately controlled (HbA1c 8.0%) with OHAs received: Insulin glargine (n = 2,196) NPH (n = 637) Detemir (n = 75) Efficacy and safety parameters were measured at baseline, 3 and 6 months Tsai ST, et al. J Diabetes 2011; 3:

21 Baseline adjusted HbA 1c at 6 months (%) Change in HbA 1c : FINE Asia study 0.0 Glargine (BL: 9.7%) NPH (BL: 10.1%) Detemir (BL: 10.2%) Rates of hypoglycemia were numerically similar between glargine and detemir Tsai ST, et al. J Diabetes 2011; 3:

22 Case continued After discussion with the patient, the insulin glargine dose was further up titrated. The final insullin dose was 38 U/day, which kept her fasting glucose level at around 110 mg/dl and HbA1c 7.2 g/dl She did not experience hypoglycemia and satisfied with the regimen However after approximately 2 years after treatment, her HbA1c gradually increased and this was despite following a strict diet with regular exercises Her fasting glucose level was still approximately 130 mg/dl

23 Early T2D: OAD Established T2D: OAD + Basal Late T2D: Basal + Bolus

24 Question 4 What is the most appropriate next step of management for this patient? 1. Further up-titrate the dose of insulin glargine to reach a target of FBG mg/dl 2. Switch to a premixed insulin regimen 3. Add a prandial insulin before the main meal 4. Add a prandial insulin before each meal Answer Option 3

25 Inzucchi SE, et al. Diabetes Care 2015; 38: ADA/EASD 2015: approach to starting and adjusting insulin in type 2 diabetes ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FBG, fasting blood glucose; GLP-1, Glucagon-like peptide-1; HbA 1c, glycated hemoglobin; PPG, postprandial glucose; RA, receptor agonist; SMBG, self-monitoring of blood glucose

26 Event-rates per person-yr ALL TO TARGET: Symptomatic hypoglycemia 15 * P < 0.05 vs. Premixed BG < 70 mg/dl BG < 50 mg/dl * Premixed Basal + 1 shot * * * Basal shot Basal + prandial Insulin had significantly less hypoglycemia compared to premixed

27 Summary Basal insulin regimens are a simple and effective strategy for glycemic control in T2DM patients who fail to control their diabetes using oral agents Basal insulin regimens using an insulin analog result in significantly less hypoglycemia, compared to premixed insulin regimens Insulin dose should be up-titrated to achieve a fasting glucose target of 100 mg/dl If target fasting glucose has been reached but HbA 1c is still above target, a prandial insulin should be added Glargine and Glulisine are effective to improve glycemic control Healthcare professionals should evaluate patients who are planning to fast and ensure that they understand the importance of glucose monitoring throughout the fast and how to prevent hypoglycemia

28 Recommendations for Insulin Regimens During Fasting Duration of Fasting Prolonged fastingsunrise to sundown (eg,ramadan) Type of Insulin Used Recommendation Long- or intermediateacting (glargine, detemir,regular) Twice-daily long- orintermediate- Short-acting (lispro,aspart, glulisine) Reduce dose by 15%-30%; take at predawn meal Reduce one of the doses (morning or evening) by 50% depending on blood glucose readings Reduce evening dose by 50%; normal dose at predawn meal Use to correct glucose >250 mg/ml on fasting day International Diabetes Federation and Diabetes and Ramadan International Alliance. Diabetes and Ramadan: Practical Guidelines. April 2016