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Insulin Initiation and Intensification Neil Skolnik, M.D. Associate Director Family Medicine Residency Program Abington Memorial Hospital Professor of Family and Community Medicine Temple University School of Medicine Disclosure • Dr. Neil Skolnik has an financial relationship or interest with a commercial entity that may have a direct interest in the subject matter of this session. Dr. Skolnik sits as part of a consultant or advisory board partnership, a Speaker’s Bureaus, and receives research grants or supports. Dr. Skolnik has a relationship with AstraZeneca, Sanofi, Lilly, Teva, and Amgen. No conflict of interest exists. Objectives • Review the place of Insulin in current guidelines • Review initiation of insulin management • Describe methods for intensifying insulin management in patients with type 2 diabetes in a clinical setting • Describe new alternatives for intensification of therapy for patients who do not reach goal with the use of basal insulin 1 When starting Insulin in patients with Type 2 DM, the recommended way to initiate insulin is: A. Start with long‐acting insulin at a dose of 0.4 ‐ 0.5 mg/kg/d, have patient call with blood sugars for dose adjustment B. Start with long‐acting insulin at a dose of 10 u, if fasting Glu > 130, have patient increase Insulin by 2 u every 3 days. Follow‐up in office in 2‐4 weeks C. Start with long‐acting insulin at a dose of 0.3 mg/kg/d, along with pre‐meal short acting insulin Consider stopping titration of basal insulin and adding additional therapy when: A. After 3‐6 months of titration, A1c is greater than goal B. Fasting Glucose at target or low, and A1c greater than goal C. Daily insulin dose exceeds 0.5 u/kg/d. D. Numbers 1 and 2 above E. All of the above Case Study Question • 55 year old male, weight 255 lbs with Type 2 Diabetes and hypertension is on Metformin 850 mg bid and Insulin Glargine 60 u daily daily. His A1c is 8.2 and his fasting A.M. blood sugars have been ranging from 90‐110. 2 Of the following choices, which would be the best recommendation: A. Accept the A1c of 8.2 B. Increase Insulin Glargine slowly over the next month to 70‐ 80 u to try to decrease his A1c C. Add an SGLT‐2 inhibitor D. Add a GLP‐1 Agonist Case • 55 year old male with Type 2 Diabetes and hypertension. • Meds: Metformin 850 mg bid; Glipizide 10 mg daily • A1c –6.9 Case –One year Later • 55 y.o. Type 2 Diabetes ,hypertension. Gained 10 pounds over the past year • Meds: Metformin 850 mg bid; Glipizide 10 mg A1c –8.2 • What Next? • Lots of choices ‐TZD, DPP4, GLP‐1, SGLT2, Insulin • Physician chose Sitagliptin 100mg daily 3 Case 6 m later • 55 y.o. Type 2 Diabetes ,hypertension. • Meds: Metformin 850 mg bid; Glipizide 10 mg A1c –8.2; Sitagliptin 100mg • A1c –8.0 • What next? Why Basal Insulin In Type 2 Diabetes? Role of Basal Insulin in Type 2 Diabetes: Beta-cell function declines as Type 2 diabetes progresses 100 Diagnosis Beta-cell decline exceeds 50% 75 by time of diagnosis IGT Insulin Beta-cell 50 initiation function (%) Postprandial 25 Hyperglycemia Type 2 Diabetes 0 12 84 04 8 12 Years from diagnosis Lebovitz H. Diabetes Rev 1999;7:139-153. 4 Insulin in Type 2 Diabetes • Many type 2 patients will require insulin if they live long enough -5 years or more post diagnosis -A1C >8 to 9% -Function of many non-insulin meds based on presence of native insulin production by the pancreas ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI‐HYPERGLYCEMIC THERAPY • Therapeutic options: Insulin Rapid (Lispro, Aspart, Glulisine) Short (Regular) level Intermediate (NPH) Insulin Long (Detemir) Long (Glargine) Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection Basal Insulin in Type 2 Diabetes • Glargine (Lantus),Detemir (Levemir), Glargine U-300 (Toujeo), Degludec (approved in Europe, not FDA approved in US) • (NPH) • Good, potent add-on for improved A1C • Second line agent for some patients • A1C >8 to 9, diabetes duration longer than 5 years 5 Practical Insulin Management: Starting Insulin Starting Insulin Start long acting insulin Starting Dose: 10 u or 0.1- 0.2 u/kg If fasting Glu > 130, increase Insulin by 2 u every 3 days. Can increase insulin by 4 u every 3 days if fasting Glu > 180 If hypoglycemia, or Fasting A1C < 7, Glu < 70, decrease insulin continue by 4 u, or 10% of dose if, whichever is greater regimen A1C ≥ 7 Diabetes Care, August 2006;29(8):1963 Diabetes Care, Dec 2008;31:1-11 What to do with Oral Meds when Starting Insulin • Metformin –may continue metformin –less weight gain than with insulin alone • SU –do not improve A1c or decrease weight gain or hypoglycemia when used with insulin. Usually reasonable to stop, once insulin is started. May continue initially and then stop. • TZD – reduce dose or stop to avoid edema and weight gain, though may help in using less insulin in some patients. • Incretin Mimetics –May be helpful with insulin in decreasing weight gain and decreasing insulin dose. Increased cost. 6 When to Look Up • After 3‐6 months of titration, A1c greater than goal • Fasting Glucose at target or low, and A1c greater than goal –this is an indication of post‐prandial glucose excursion • Overnight hypoglycemia • The need for prandial insulin becomes more likely as the daily insulin dose exceeds 0.5u/kg/d. Moving Toward Multiple Daily Injections (MDI) • As type 2 patients take larger doses of basal insulin, temptation is to split basal dose and give BID Alternative “next steps”: • Can do basal + 1 bolus (rapid acting) • Can do basal + GLP-1 Adding Bolus Insulin for Meals in Type 2 Diabetes Rapid Acting Insulin • Lispro (Humalog) • Aspart (Novalog) • Glulisine (Apidra) • Why might bolus insulin be important in some Type 2 patients? 7 Fasting and Postprandial Glycemic Excursions as a Function of A1C 80 Postprandial hyperglycemia Fasting hyperglycemia 60 40 20 Contribution (%) 0 1 2 3 4 5 (<7.3) (7.3–8.4) (8.5–9.2) (9.3–10.2) (>10.2) Monnier L et al. Diabetes Care. 2003;26:881-885. A1C (%) Quintiles Insulin Post Prandial Blood Sugar vs. Fasting Blood Sugar • Basal long acting insulin best addresses fasting blood sugar • Bolus rapid acting insulin addresses post prandial blood sugar 3 Ways to Intensify Insulin In Type 2 Diabetes • Simple: 90/10: 2 injections – 1 basal, 1 bolus (w/biggest meal) • Advanced: Non-Carb Counting – 1 basal, 3 boluses estimated dosing based on meal “size” • Sophisticated: Carb-counting – 1 basal, 3 boluses (+ maybe snack boluses) – calculated on carb intake + premeal blood glucose value 8 Initiate of Basal-Bolus Therapy • 90/10 rule (90% basal, 10% bolus) for 2 injection regimen (or just start with 4 u bolus) • Start with largest meal of the day • If A1c <8%, consider decrease basal by same number of units adding to pre-meal insulin Edelman S. Diabetes Care August 2014;37:1–9 Harris SB. Diabetes Care March 2014;37:1–7 Inzucchi S. Diabetes Care 2015;38:140–149 Titrating 90/10 Rule • Targeting 2 hour post meal blood glucose (after bolus rapid acting) to <130 consistently • Increase by 1 u daily if post-prandial blood glucose is over target AUTONOMY: The First Randomized Trial Comparing Two Patient‐Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes • Two independent, multinational, parallel, open‐label studies, identical in design • 18–85 years old Type 2 DM (study A: N = 528; study B: N = 578), • On basal insulin plus oral antidiabetic drugs for ‡3 months • HbA1c 7.0% to £12.0% Edelman S. Diabetes Care August 2014;37:2132–2140 9 • Optimized on insulin glargine, then randomized to one of two self‐titration algorithm groups adjusting lispro either: – every day (Q1D) or – every 3 days (Q3D) • 24 weeks. • Q1D algorithm: self‐titrated daily based on premeal glucose from the previous day; for example, when adjusting the prebreakfast dose, subjects used their prelunch reading from the day before • Premeal target glucose: 85–114 mg/dL. • If target not achieved, increase dose 1 unit/day until target is reached. Edelman S. Diabetes Care August 2014;37:2132–2140 • If blood glucose 56–84 mg/dL, the dose was decreased by 1 unit, if < 56 mg/dL, the dose was decreased by 2 units. Edelman S. Diabetes Care August 2014;37:2132–2140 10 • Q3D algorithm: self‐titrated every 3 days based on the median blood glucose readings from the 3 days before – Used average of pre‐meal blood glucoses Edelman S. Diabetes Care August 2014;37:2132–2140 Blood Glucose (mg/dl) Adjust Insulin <56 Decrease 4u 56‐84 Decrease 2u 85‐114 No change 115‐144 Increase 2u >145 Increase 4 u Edelman S. Diabetes Care August 2014;37:2132–2140 Results Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D – 0.96%, Q1D –1.00% ) The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. Edelman S. Diabetes Care August 2014;37:2132–2140 11 Take Home Point • Many Methods to Increase to Multi‐dose Insulin Clinical Inertia in People With Type 2 Diabetes • Retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. • Median time from above HbA1c cutoff to intensification of Therapy Diabetes Care 36:3411–3417, 2013 Time to Intensification of Therapy Baseline Regimen A1c>7.0 A1c>7.5 A1c>8.0 One Oral Agent 2.9 years 1.9 years 1.6 years Two Oral Agents 7.2 years 7.2 years 6.9 years Time to Insulin (base one, two or 7.1 years 6.1 years 6.0 years three oral agents) Diabetes Care 36:3411–3417, 2013 12 Take‐home Point : When to Look Up • After 3‐6 months of titration, A1c greater than goal • Fasting Glucose at target or low, and A1c greater than goal –this is an indication of post‐prandial glucose excursion • Overnight hypoglycemia • The need for prandial insulin becomes more likely as the daily insulin dose exceeds 0.5u/kg/d.
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  • Is the Use of DPP-4 Inhibitors Associated with an Increased Risk for Heart Failure?

    Is the Use of DPP-4 Inhibitors Associated with an Increased Risk for Heart Failure?

    S210 Diabetes Care Volume 39, Supplement 2, August 2016 Is the Use of DPP-4 Inhibitors Guntram Schernthaner,1 Avivit Cahn,2 and Itamar Raz2 RECENT OUTCOME STUDIES Associated With an Increased Risk for Heart Failure? Lessons From EXAMINE, SAVOR-TIMI 53, and TECOS Diabetes Care 2016;39(Suppl. 2):S210–S218 | DOI: 10.2337/dcS15-3009 About 40 years ago, the Framingham study first documented that the risk for heart failure (HF) in patients with diabetes was about twofold higher in men and fivefold in women compared with individuals without diabetes (1). The UK Prospective Di- abetes Study (UKPDS) reported that the incidence of hospital admission for HF was similar to that of nonfatal myocardial infarction and nonfatal stroke (2). A more recent 6-year follow-up study of 65,619 patients with type 2 diabetes treated with insulin reported that the hospital admission rate due to HF (243 of 10,000) was higher than that due to myocardial infarction (97 of 10,000) or stroke (151 of 10,000) (3). The pathogenesis of HF in diabetes is multifactorial but can largely be attributed to four key factors: coronary artery disease (CAD), hypertension, diabetic cardio- myopathy, and extracellular fluid volume expansion (4,5). Remarkably, type 2 di- abetes itself is a recognized risk factor for HF, independent of CAD and hypertension (4), suggesting that glycemic control may influence the development of HF. Hyper- glycemia can exert deleterious effects on the myocardium and has been shown to increase oxidative stress, promote accumulation of advanced glycation end prod- ucts, and cause interstitial fibrosis (6).