NATURAL HISTORY OF BETA CELL FAILURE IN T2DM BUT We’ve been taught: ‘Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated’ Helps ‘confirm’ impression that most T2DM patients will need insulin

Belfast Diet Study-Bi-phasic Loss of B-Cell FUNCTION My Translation- Glucotoxicity 2% /yr decline 18%/yr decline DX DM Deteriorating beta-cell function in type 2 diabetes: a long-term model. Bagust A, Beale S. QJM. 2003 Apr;96(4):281-8

UKPDS: Patients Requiring Insulin Over the Course of Their Diabetes From PRB approved 0212-0007434-1: Basal ELITE – Updated formatting, added training disclaimer UKPDS: Patients Requiring Insulin Over the Course of Their Diabetes 60 Chlorpropamide Glipizide 40 Patients Requiring Additional Insulin (%) 20 UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin As the study period progressed, a greater number of patients required insulin to be added to their treatment: At year 3, the proportion of patients requiring insulin was 35% in the chlorpropamide group, and 38% in the glipizide group. At year 6, 53% required additional insulin therapy, with no significant difference between those allocated to chlorpropamide and glipizide (49 vs. 56%, p = 0.28) Adapted from Wright A, Burden AC, Passey RB, et al for the UKPDS group. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes on the UKPDS (UKPDS 57). Diabetes Care. 2002;25:330-336. 1 2 3 4 5 6 Years from Randomization But remember, SU’s cause Beta-Cell APOPTOSIS Adapted from: Wright A, et al. Diabetes Care. 2002;25:330–336.

But even after 15 years of DM, MOST have >40% of beta cell mass

Beta-Cell Mass Reduced, but most have > 20% nml; Non-DM DM J. Rahier , Diabetes, Obesity, Metab 10 2008: 32-42

Type 2 Diabetes Is Progressive We’ve been taught DM is progressive Lose of 50% of function by Dx Type 2 Diabetes Is Progressive

CV Risk of SU and Insulin In ‘Real World Use’ So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use- would not pass current FDA guidelines for CV risk with a new agent Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

Value to Early Insulin Therapy- Outweighed By Hypoglycemia Weight Gain Especially when one can reduce lipotoxicity and Glucotoxicy , just as fast, with new anti-hyperglycemic agents

Initial Triple Combination Therapy is Superior to ADA Guideline Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia compared to subjects receiving Conventional Therapy. Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6 kg weight gain (p=0.02) in subjects on Conventional Therapy. Diabetes Obes Metab. 2014 Nov 26. doi: 10.1111/dom.12417. [Epub ahead of print] Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Abdul-Ghani MA1, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA

Some Small Number WILL need Basal Insulin Diabetes Disease Progression An Alternative Approach Start BASAL insulin Include Incretin This slide is a simplified illustration of an alternative stepwise approach to the treatment of type 2 diabetes. In this alternative approach, patients receive initial treatment with an oral agent, typically metformin, then, as the disease progresses and the A1C increases above the target level, patients add a glucagon-like peptide-1 (GLP-1) receptor agonist or dipeptidyl peptidase-4 (DPP-4) inhibitor. When dual combination therapy fails to adequately maintain the A1C below the target level, patients add insulin for triple combination therapy.1,2 References 1. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocrine Pract. 2009;15:540-559. 2. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm for glycemic control. Available at: http://www.aace.com/pub/pdf/GlycemicControlAlgorithmPPT.pdf. Accessed 1/27/10. Start 1-3 non-insulin Therapy(ies) Diet/exercise DPP-4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor. Rodbard HW et al. Endocrine Pract. 2009;15:540-559. Available at: http://www.aace.com/pub/pdf/GlycemicControlAlgorithmPPT.pdf. December 2009 update.

Issues 1. Tells you CONSIDER stopping SU- MUST 2. Doesn’t tell you what to do with other non-insulin therapies-CONTINUE 3. Doesn’t tell you use other non insulin agents before use prandial insulin since >80-90 % (conservative) of type 2 pts won’t require bolus insulin if on GLP-1 RA with SGLT-2 inhibitor +/- other

INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT- Lose 80% of function by DX 30 20 10 40 NGT <100 <120 <140 Obese Lean ∆ INS/ ∆ GLU ÷ IR IGT <200 <160 <180 <240 <280 <360 <320 >400 <400 T2DM 2-Hour PG (mg/dl)

Lose Mass, but not to same degree as Function SUMMARY Individuals with IGT: Are maximally/near-maximally insulin resistant Have lost ~80% of their beta cell function (DeFronzo) Have lost significant beta cell mass –but not as much as most believe BUT, note, Lose Mass, but not to same degree as Function