Initiation of Basal Insulin- not bolus Review as stated INTERNAL TRAINING USE ONLY. NOT FOR DISTRIBUTION.

Basal Analogs Offer Advantages for Individuals Who Need Basal Insulin From PRB 1014-00023511-1: Getting Patients to Goal: When Is It Time to Intensify With Insulin?(Pending final approval) -Updated formatting, added training disclaimer Basal Analogs Offer Advantages for Individuals Who Need Basal Insulin Inzucchi P4-5 Table 1 Theoretical insulin profile1 NPH Basal analog 24 Time (h) Serum insulin level Insulin is associated with the greatest expected decrease in A1C as well as a high risk for hypoglycemia2 Compared to NPH, basal insulin analogs provide3,4: Reduced rate of hypoglycemia Once-daily dosing in type 2 diabetes Similar reduction in FPG Basal Analogs Offer Advantages for Individuals Who Need Basal Insulin Insulin is associated with the greatest expected decrease in A1C as well as a high risk for hypoglycemia1 Compared to NPH, long-acting insulin analogs provide a reduced rate of hypoglycemia, once-daily dosing in type 2 diabetes, and a similar reduction in FPG2,3 A theoretical basal analog and NPH profile over 24 hours is shown here4 References Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379. Duckworth W, Davis SN. Comparison of insulin glargine and NPH insulin in the treatment of type 2 diabetes: a review of clinical studies. J Diabetes Complications. 2007;21(3):196-204. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–183. Brunton S, Carmichael B, Funnell M, Lorber D, Rakel R, Rubin R. Type 2 diabetes: the role of insulin. J Fam Pract. 2005;54(5):445-452. NPH=neutral protamine Hagedorn. 1. Brunton S et al. J Fam Pract. 2005;54(5):445-452. 2. Inzucchi SE et al. Diabetes Care. 2012;35(6):1364-1379. 3. Duckworth W et al. J Diabetes Complications. 2007;21(3):196-204. 4. Hirsch IB. N Engl J Med. 2005;352(2):174-183. INTERNAL TRAINING USE ONLY. NOT FOR DISTRIBUTION.

From PRB approved 0712-00010390-1: Why Mealtime Matters – Updated formatting, added training disclaimer Basal Insulin May Not Cover Postprandial Excursions and May Increase Risk for Hypoglycemia Time Plasma insulin (µU/mL) 75 50 25 4:00 8:00 12:00 16:00 20:00 24:00 Basal insulin Dinner Lunch Breakfast High postprandial readings at every meal because mealtime insulin response is absent Increased risk for hypoglycemia if diet changes or meals are missed Basal Insulin May Not Cover Postprandial Excursions and May Increase Risk for Hypoglycemia High levels of basal insulin therapy may not provide PPG control In this hypothetical diagram, normal insulin physiology is represented by yellow curves. If basal insulin is raised to high levels (red line), high postprandial readings remain, and there is an increased risk for hypoglycemia if diet changes or meals are missed and insulin levels are too high Reference Garber AJ. Insulin intensification strategies in type 2 diabetes: when one injection is no longer sufficient. Diabetes Obes Metab. 2009;11(suppl 5):14-18. Garber AJ. Diabetes Obes Metab. 2009;11(suppl 5):14-18. INTERNAL TRAINING USE ONLY. NOT FOR DISTRIBUTION.

“Overbasalization” May Lead to Inadequate Glycemic Control From PRB approved 0414-00021174-1: Teaching Patients to Self-Titrate Rapid-Acting Insulin – Updated formatting, added training disclaimer “Overbasalization” May Lead to Inadequate Glycemic Control Overbasalization can be described as continued titration of basal insulin without any appreciable improvement in glucose control1 Continued titration of basal insulin may not achieve A1C goals and may require a change in treatment strategy1 Overbasalization increases the risk of adverse reactions, such as hypoglycemia2 “Overbasalization” May Lead to Inadequate Glycemic Control Multiple steps can be taken to identify patients who may be overbasalized and may require prandial insulin When the titration of basal insulin achieves a fasting glucose level between 80 and 100 mg/dL and the patient is still not at A1C goal, a more intensive therapy needs to be initiated to control postprandial blood glucose In some patients, basal insulin exceeds 50% of the estimated required daily insulin dose without achieving fasting plasma glucose goals Reference LaSalle JR. Empowering patients during insulin initiation: a real-world approach. J Am Osteopath Assoc. 2010;110(2):69-78. 1. LaSalle JR. J Am Osteopath Assoc. 2010;110(2):69-78. 2. LaSalle JR, Berria R. J Am Osteopath Assoc. 2013;113(2):152-162. INTERNAL TRAINING USE ONLY. NOT FOR DISTRIBUTION.

A Basal-Bolus Regimen Mimics the Body’s Physiologic Insulin Response From PRB approved 144084: Approaches in Managing Mealtime Insulin: Why and When – Updated formatting, added training disclaimer A Basal-Bolus Regimen Mimics the Body’s Physiologic Insulin Response Normal plasma glucose profile Rapid-acting insulin analog profile Long-acting insulin analog profile BUT-- A Basal-Bolus Regimen Mimics the Body’s Physiologic Insulin Response Basal-bolus insulin therapy can mimic a body’s physiologic insulin response with rapid-acting insulin (orange line) covering meals and long-acting insulin (green line) providing coverage for up to 24 hours As you can see by the chart, this insulin strategy matches the body’s normal glucose profile (blue lines) Reference Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81(2):442-448. 8 AM-12 PM 12 PM-6 PM 6 PM-12 AM Adapted from Polonsky KS et al. J Clin Invest. 1988;81(2):442-448. INTERNAL TRAINING USE ONLY. NOT FOR DISTRIBUTION.

. Treat with Least Number of agents that address most Number of Mechanisms of hyperglycemia 2. Treat across natural history of Diabetes Delay Need for Insulin No need for Early Insulin If need Insulin, Continue Non-Insulin RX OR WITH USE NEW GLP-1 BASAL COMBO (Avoids need for Meal-Time Insulin- (Decrease Risk Hypoglycemia 85%- Garber) 4. Get Patients off insulin who had been given early Insulin Treat across natural history of Diabetes Patient-Centric, eventually Precision Medicine Least # Agents Rx’ing Most # mechanisms Hyperglycemia NO SU/ Insulin only if don’t respond to 3-4 non-Hypoglycemic Agents

2. No need for Early Insulin 3. If need Insulin, Continue Therapeutic Principles Across Continuum of Care eg: Right Drug for Right Patient and vice versa DETERMINE INSULIN DEPENDENCY- (DKA, c-peptide,? Other) DETERMINE Patient Specific Mechanisms of Hyperglycemia Treat ? For prevention/ Treat pre-diabetes Treat as many of the Egregious 11 Targets as needed, with least # of agents, to get lowest sugars/HgA1c as possible without undue weight gain or hypoglycemia Early Combination Therapy- Patient Centric- even 6.5-7.5 HgA1c Efficacy, - CV event reduction, Weight Loss (Not first-second-third line; Not competition between classes) Treat with agents that address FBS AND PPG Can Modify therapy after 1m-not 3m-use Fructosamie Ideally agents will stabilize, preserve β-cells, the CORE DEFECT ( NO SU/GLINIDES)- Ideally agents will have potential to synergistically decrease in CV risk factors / outcomes 1. Delay Need for Insulin 2. No need for Early Insulin 3. If need Insulin, Continue Non-Insulin RX (Avoids need for Meal-Time Insulin- Decrease Risk Hypoglycemia 85%- 4. Get Patients off insulin who had been given early Insulin

Philosophy for Reduced Insulin Need in T2DM Have more Beta-Cells In Patients with T2DM than we had been Taught 1. No Perfect Insulin- Exogenous insulin not put in portal system; no fine-tuning a la Beta Cell 2. Leads to Insulin Resistance (suppresses dopamine in ‘biologic clock’ of hypothalamus)– leads to Increased Weight, Hypoglycemia Risk 3. So Goal of all Insulin Therapy- Least Hypoglycemia, Least Weight Gain 4. Old Logic- use Early Insulin to reduce Glucotoxicity, Lipotoxicity but GLP-1 RAs and SGLT-2 Inh. do that first day!!, with no weight gain, no hypoglycemia 5. Therefore no need for Early Insulin- use 3-4 Non-Insulin therapy before go to Basal Insulin; keep Non-Insulin Therapies and 95% of T2DM won’t need Bolus Insulin (by avoiding bolus insulin reduce hypoglycemic risk 85%)

Hypoglycemia In BEGIN BB Trial: 88% of daily hypoglycemia due to bolus insulin Hypoglycemia with glargine Hypoglycemia with degludec Confirmed: 13.6/pt.yr Nocturnal: 1.8/pt.yr Nocturnal/Confirmed % = 13.2% of total Confirmed: 11.1/pt.yr Nocturnal: 1.4/pt.yr Nocturnal/Confirmed % = 12.6% of total Garber A et al Lancet 2012; 379: 1498-1507 Presentation title

So Might one not expect ? 90-95% to goal with 3 agents ?  Basal + other Agents% to Goal So Might one not expect ? 90-95% to goal with 3 agents ? 

And If see Patient Given Early Insulin get them off insulin  If willing to start NCS diet, dec. insulin 25% If hypoglycemic (sx’ic, asymptomatic, dec. insulin 25% Take this new estimated insulin dose requirement: Dec 25% as strart GLP-1 RA Dec 20% if start SGLT-2 inhibitor If estimated dose <12u/d, stop insulin As loses weight, reduce insulin doses until <12u/d, Stop Insulin

So Based on above Data and Logic: 1. Hyperinsulinemia may be a pivotal defect 2. All exogenous insulin therapy results in hyperinsulinemia 3. Hyperisulinemia has adverse CV and Other Consequences There becomes a CLEAR Pathophysiologic Implication to ‘Delay’ Insulin Therapy, Avoid Early Use, Avoid Bolus even if need basal Insulin