Insulin and Oral Antidiabetic Drugs Including SGLT2 Inhibitors

Insulin and Oral Antidiabetic Drugs Including SGLT2 Inhibits S. S E THU K. R E D DY, M D, M B A, F R C P C, FAC P, M AC E PAST-CHIEF O F ADULT D I ABETES, J OSLIN D I ABETES C E N TER PAST-CHAIR O F ENDOCRINOLO GY, D I ABETES & M E TABOLISM, C L E V E LAN D C L I N IC S E THU. K. R EDDY@GMAIL.C O M

Objectives: By participating in this activity, one should be able to: Determine the clinical utility of new insulin into one's practice Choose appropriate al agents beyond metfmin in a patient-centric manner Interpret the clinical relevance of recent cardiovascular outcome trials in diabetes

Questions Is insulin atherogenic? Carcinogenic? What are advantages of newer insulins? What to choose after metfmin? Should we start earlier combination therapy? What do recent CV safety trials mean f me in the clinic? What s new with SGLT inhibits?

To insulin Not to insulin? Insulin and Cancer Sty Diabetes / Obesity insulin resistance linked to increased incidence of a variety of solid cancers Hyperinsulinemia potentially leading to IGF-1 recept activation Many tums expressing insulin recepts;? Insulin use leading to growth of pre-existing tum cells Optimal route of insulin delivery? Precision medicine approach to cancer and insulin therapy CLINICAL JUDGMENT: At present, the metabolic benefits outweigh the potential concerns of insulin therapy

Insulin and Atherosclerosis High insulin levels crelated with greater atherosclerosis Is the problem endogenous hyperinsulinemia exogenous hyperinsulinemia? Role of pro-insulin Insulin is a potent anabolic hmone f FAT as well Challenge of interpreting insulin therapy trials since patients requiring insulin often have me severe and longer duration diabetes CLINICAL JUDGMENT: No clear data that exogenous insulin increases clinical cardiac events and the metabolic benefits outweigh theetical concerns.

Atherosclerosis. Relevant animal model: Hyperinsulinemia with nmal insulin sensitivity with exposure to atherogenic diet Christian Rask-Madsen et al. Arterioscler Thromb Vasc Biol. 2012;32:1124-1131 Copyright American Heart Association, Inc. All rights reserved.

What are we looking f in insulin? Predictable in onset Predictable in duration Basal vs Prandial coverage Delivery devices to increase adherence and dosing accuracy Affdable CLINICAL JUDGEMENT: We can wk with any insulin if we could rely on its absption, distribution and metabolism.

Concentrated Insulins U-500 Regular Insulin Basal and bolus properties High risk of errs in dosing due to availability in a vial U-300 Insulin Glargine Slow initial onset and up to 5 days until steady state 15% higher doses than U-100 glargine (but unit-unit conversion initially advised) Less glycemic variability results in slightly less nocturnal hypoglycemia vs U-100 insulin glargine U-200 Insulin Degludec Similar anticipated benefits of reduced nocturnal hypoglycemia U-200 Insulin Lispro Rapid-acting Bioequivalent to U-100 insulin lispro 8

U-500 Regular Humulin R U-500 is highly concentrated and contains 5 times as much insulin in 1 ml as standard U-100 insulin Both have onset of action at 30 minutes U-500 insulin exhibits a delayed and lower peak effect relative to U-100 U-500 insulin typically has a longer duration of action compared with U-100 (up to 24 hours following a single dose) Clinical experience has shown that U-500 insulin frequently has time-action characteristics reflecting both prandial and basal activity 9

degludec Available only as FlexTouch pens U-200: 600 units/pen, max 160 units/inj U-100: 300 units/pen, max 80 units/inj Duration of action > 42 hours Half-life ~25 hours Detectable f at least 5 days Steady state in 2-3 days 10

U-300 glargine FDA approved February 2015 Available only as a pen: 450 Units/1.5 ml Maximum 80 units per injection Smaller depot surface area leading to a reduced rate of absption Provides flatter and prolonged pharmacokinetic and pharmacodynamic profiles and me consistency Onset after first dose ~ 6 hours Half-life is ~23 hours Steady state in 4-5 days Duration of action 36 hours 11

U-300 glargine Changing from QD long-acting intermediateacting insulin: Initial dose can be same as QD long-acting dose, f patients controlled on U-100 insulin glargine Expect that a higher daily dose of U-300 insulin glargine will be needed to maintain the same level of glycemic control (~15% higher) Changing from BID NPH insulin: Initial dose is 80% of the total daily NPH dosage (similar to conversion to U-100 insulin glargine) 12

Access to Insulin Quixotic Quest Po access Consider medical assistance programs Consider R and N (caveats re. mixing and timing) Full access Analogs Pens Newest Brands 13

Pathophysiology of Type 2 Diabetes: The Classic Triumvirate b-cell Dysfunction Hyperglycemia Increased Hepatic Glucose Production Decreased Glucose Uptake

Multiple, Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA _? hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

What Comes After Metfmin? Depends Patient characteristics Degree of hyperglycemia Risk of hypoglycemia Weight Combidities (renal, cardiac, hepatic) Access to treatment Patient preferences Agent characteristics BG lowering efficacy & durability Risk of inducing hypoglycemia Effect on weight Contraindications & side effects Cost and coverage Other

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Metfmin Thiazolidinedione high low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare high Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration high Metfmin GLP-1 recept agonist high low risk loss GI high Metfmin Insulin (basal) highest high risk gain hypoglycemia variable Triple therapy Metfmin Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Metfmin Thiazolidinedione SU Metfmin DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Metfmin Figure 2. Anti-hyperglycemic Basal Insulin Mealtime Insulin GLP-1-RA therapy in T2DM: General Diabetes Care 2015;38:140-149; Diabetologia

Some Rules of Thumb f Sequential Therapy The first agent added will be the most efficacious. The next agent will likely reduce A1c by 0.7 0.8 % The third agent added will likely reduce A1c by 0.5 0.6 %. Sulfonylureas: Optimal dose is half-maximal dose. Metfmin: Optimal dose is app. 1750 mg per day

Development and Progression of Type 2 Diabetes and Related Complications 1,a Progression of Type 2 Diabetes Mellitus 4 7 years Insulin resistance Hepatic glucose production Insulin level Beta-cell function Postprandial glucose Fasting plasma glucose Development of Microvascular Complications Development of Macrovascular Complications Impaired Glucose Tolerance Frank Diabetes Diabetes Diagnosis a Conceptual representation. 1. Reprinted from Primary Care, 26(4), Ramlo-Halsted BA, Edelman SV, The natural histy of type 2 diabetes. Implications f clinical practice, 771 789, 1999, with permission from Elsevier. 23

Precedents Evolution of Therapeutic Approach Cancer Congestive Heart Failure Think of a Plane Maintenance: Fuel Landing gear Wing control Tail-fin control Engine Oil

LS Mean (±SE) Change in HbA 1C From Baseline, % Initial Therapy With Sitagliptin/Metfmin FDC vs Metfmin Monotherapy: HbA 1c Results Over 18 Weeks 1 0 FAS Population a 1 2 LS means difference 0.6; P<0.001 3 0 6 12 18 Week Sitagliptin/metfmin FDC 50/1,000 mg bid (n=559) Mean baseline HbA 1c =9.9% Metfmin 1,000 mg bid (n=564) Mean baseline HbA 1c =9.8% bid=twice a day; FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard err. a Excludes data obtained after initiation of additional antihyperglycemic agents. 1. Used with permission from Blackwell Publishing Ltd. Reasner C et al. Diabetes Obes Metab. 2011;13:644-652. Copyright 2011 Blackwell Publishing Ltd. 25

Absolute Value in HbA 1c Over Time (LS Mean ±SE), % Sitagliptin Plus Metfmin FDC Resulted in Significant HbA 1c Reductions Through 44 Weeks 1 0 FAS Population Including data after initiation of additional OHA therapy 1 LS mean change from baseline a 1.8; 95% CI (-1.9, -1.6) 2 3 0 6 12 18 Week 31 44 Sitagliptin/metfmin FDC 50/1,000 mg sbid Metfmin 1,000 mg bid (n=569) (n=560) Mean baseline HbA 1c = 9.8% Mean baseline HbA 1c = 9.9% bid=twice daily; FAS=full-analysis-set; FDC=fixed-dose combination; LS=least-squares; OHA=al antihyperglycemic agent; SE=standard err. a Primary end point f this study was the change from baseline in HbA 1c at week 44. 1. Used with permission from Blackwell Publishing Ltd. Olansky L et al. Diabetes Obes Metab. 2011;13:841-849. Copyright 2011 Blackwell Publishing Ltd. LS mean difference 0.5; LS mean change from P<0.001 baseline a 2.3; 95% CI (-2.4, -2.1) 26

2nd line Antidiabetic Combination Therapy Principle: Two differently acting al anti-diabetic agents can have additive glucose-lowering effects if sufficient β-cell function remains 1st line Metfmin TZD SU / Glinides Acarbose Insulin Obesity Metfmin Yes* Yes Yes Yes Yes TZD Yes Yes Yes Yes Yes SU / Megl Yes Yes Yes Yes Yes Exenatide DPP4-I Yes Yes Yes (Yes) (Yes) (Yes) Acarbose Yes Yes Yes Yes Yes Insulin Yes Yes Yes Yes Yes Obesity Yes Yes Yes Yes Yes * TZD given if metfmin not tolerated. Anti-obesity agent (listat, sibutramine, rimonabant) not specifically indicated with an anti-diabetic agent, but widely used.

Journal of Diabetes and Its Complications 30 (2016) 1177 1185

Multiple, Complex Pathophysiological Abnmalities in T2DM GLP-1R agonists incretin effect DPP-4 inhibits A G I s gut carbohydrate delivery & absption Metfmin hepatic glucose production _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA Bile acid sequestrants Insulin Glinides S U s Amylin mimetics renal glucose excretion _ DA agonist s T Z D s? peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Change in mean HbA1c level (A), weight (B), and total daily INS dose (C) in INS-treated type 2 diabetic patients after 4 months of dual therapy using INS MET ( ) INS TGZ ( ) and after 4 months of triple therapy using INS, MET, and TGZ [INS MET add TGZ ( ), INS TGZ add MET ( )]. *P < 0.05 vs. baseline, P < 0.05 vs. week 16, P < 0.05 vs. Suzanne M. Strowig et al. Dia Care 2004;27:1577-1583 2004 by American Diabetes Association

Mean HbA1c values befe and during 6 months intervention in type 2 diabetic patients treated with either NPH MIX insulin twice daily (, control group) with insulin aspart befe meals, metfmin, and rosiglitazone (, triple therapy group). Mikael Kjær Poulsen et al. Dia Care 2003;26:3273-3279 2003 by American Diabetes Association

Fig. 1. Netwk plot of available diabetes treatment combinations f studies with a treatment duration of 6 12 months (20 54 weeks). The number of studies available per direct comparison is provided in the netwk. The size of the node reflects the number of... Crystal Man Ying Lee, Mark Woodward, Stephen Colagiuri Triple therapy combinations f the treatment of type 2 diabetes A netwk meta-analysis Diabetes Research and Clinical Practice, Volume 116, 2016, 149 158 http://dx.doi.g/10.1016/j.diabres.2016.04.037

Fig. 4. Surface under the cumulative ranking curve (SUCRA) values of HbA1c by body weight f all triple therapies with data f HbA1c and body weight f studies with a treatment duration of 6 12 months (20 54 weeks). Higher SUCRA values f HbA1c indicate gr... Crystal Man Ying Lee, Mark Woodward, Stephen Colagiuri Triple therapy combinations f the treatment of type 2 diabetes A netwk meta-analysis Diabetes Research and Clinical Practice, Volume 116, 2016, 149 158 http://dx.doi.g/10.1016/j.diabres.2016.04.037

Multiple, Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA? _ hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Treating the Pathophysiological Abnmalities in T2DM GLP-1R agonists incretin effect Glinides Insulin S U s pancreatic insulin secretion DPP-4 inhibits A G I s gut carbohydrate delivery & absption Amylin mimetics _ pancreatic glucagon secretion HYPERGLYCEMIA DA agonists? Metfmin Bile acid sequestrants hepatic glucose production renal glucose excretion _ T Z D s peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects me stringent low Approach to the management of hyperglycemia HbA1c 7% less stringent high Disease duration newly diagnosed long-standing Life expectancy long sht Usually not modifiable Imptant combidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment effts highly motivated, adherent, excellent self-care capacities less motivated, non-adherent, po self-care capacities Potentially modifiable Resources and suppt system Readily available limited Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-

HbA 1c,% Earlier and Appropriate Intervention May Improve Patients Chances of Reaching Goal 1 Diet and exercise Published Conceptual Approach OAD monotherapy OAD up-titration OAD combination OAD basal insulin OAD multiple daily insulin injections 10 9 Mean HbA 1c of patients 8 7 6 Conventional stepwise treatment approach Duration of Diabetes Earlier and proactive intervention approach OAD=al antidiabetic agent. 1. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345 1355. Copyright 2005. Adapted with permission of Blackwell Publishing Ltd. HbA 1c goal of 7%

Adapted from Juutilainen A et al. Diabetes Care 2007;30:292 Increased Hepatic Glucose Production Reduced Glucose Disposal Hyperglycemia Glucose ROS* Aging, Smoking Central obesity Dyslipidemia Microvascular complications Retinopathy Heart microangiopathy Insulin resistance FFA Macrovascular complications Nephropathy Aging, Smoking Central obesity Dyslipidemia *ROS = reactive oxygen species Courtesy of dr. M. Laakso

Type 2 Diabetes and Cardiovascular Risk Many studies in patients with DM have demonstrated that improved glucose control reduces microvascular complications. Does any particular glucose-lowering strategy is safe from a CV standpoint can actually lower macrovascular complications (e.g., MI, stroke, CV death)?. Expectation: Controlling f degree of glucose control, anti-diabetic agents are NEUTRAL with respect to development of CV disease.

Study Summary of 4 Main Trials T2DM DM Duration (yrs) Follow Up (yrs) Baseline A1c (%) Micro Vascular CVD Mtality UKPDS New 10 7.1 UKPDS-FU New 10 No diff ADVANCE 5 8 7.5 ACCORD 3.4 10 8.1 VADT 5.6 11.5 9.4 42

Meta-Analysis Diabetic Medicine, Sept. 2015 Seidu et al 19 RCTs App. 80,000 subjects Intensive control reduced risk of non-fatal MI by 10% (CI = 0.83 0.96) No impact on all-cause CV mtality Multiple RF intervention reduced risk of non-fatal stroke by 47% (CI = 0.32 0.87)? Impact of baseline CV risk and duration of diabetes 43

Diabetes with Heart Disease: Same Label but a different wine 60 y.o. male, with 15 yr histy of diabetes, with known histy of hypertension developed angina at age 57; A1c of 8% on double therapy 60 y.o. male with 25 yr histy of hypertension and hypercholesterolemia; noncompliant; Admitted with new onset angina and found to have elevated fasting glucose of 180 mg/dl Reddy, S. Personal Opinion 44

CV death, MI ischemic CVA (%) Primary end point 14 12 HR 1.00 [0.89-1.12] P<0.001 (non-inferiity) 10 8 6 4 2y KM Saxagliptin 7.3% Placebo 7.2% 2 Placebo 8212 6 12 18 24 Months 7983 7761 7267 4855 Saxagliptin 8280 8071 7836 7313 4920 Scirica BM, Bhatt DL Braunwald et al, Sexagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-1326

Primary end point White WB, Cannon CP, Heller SR et al, Alogliptin after acute conary syndrome in patients with type 2 diabetes. N Engl J Med. 2013 Oct 3;369(14):1327-1335

P R I M A RY R E S U LT S 8 T H J U N E 20 1 5

Glycemic Control Least Squares Mean HbA1c ± 1SD Overall LS Mean difference -0.29% (-0.32, -0.27), p<0.0001 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Primary Composite Cardiovascular Outcome* PP Analysis f Non-inferiity * CV death, nonfatal MI, nonfatal stroke, hospitalization f unstable angina Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Secondary Composite Cardiovascular Outcome* ITT Analysis f Superiity * CV death, nonfatal MI, nonfatal stroke Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Hospitalization f Heart Failure* ITT Analysis * Adjusted f histy of heart failure at baseline Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Individual end points Significantly me patients in the saxagliptin group than placebo were hospitalized f heart failure 2-year KM rate (%) Placebo (N=8 212) Saxagliptin (N=8 280) HR P-value f superiity CV death 2.9 3.2 1.03 (0.87-1.22) 0.72 MI 3.4 3.2 0.95 (0.80-1.12) 0.52 Ischemic stroke 1.7 1.9 1.11 (0.88-1.39) 0.38 Hosp f c. revasc 5.6 5.2 0.91 (0.80-1.04) 0.18 Hosp f UA 1.0 1.2 1.19 (0.89-1.60) 0.24 Hosp f heart failure 2.8 3.5 1.27 (1.07-1.51) 0.007 All-cause mtality 4.2 4.9 1.11 (0.96-1.27) 0.15 Scirica BM, Bhatt DL Braunwald et al, Sexagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-1326

Hospitalization f heart failure: pooled analysis Sattar N, Results from SAVOR and EXAMINE. DPP-4 inhibits and CVD, EASD 2013 Sep 26.

Summary of DPP-4-i CVOT SAVOR-TIMI, EXAMINE, TECOS Conclusions No increased cardiac mtality in predominantly white, > 60 yrs, with established CVD and DM f 7-10 years 3.5% vs. 2.8% f admission f heart failure in saxa group Caveats Studies designed to meet FDA requirements and not patient/physician needs Median Follow-up f 3 years Minimal glucose control differences High penetrance of CV risk reduction strategies Hirshberg and Katz Curr Diab Rep (2015) 15:87 54

FDA: Two diabetes drugs may be linked to heart failure risk April 5, 2016

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure Kristian B. Filion, Ph.D., Laurent Azoulay, Ph.D., Robert W. Platt, Ph.D., Matthew Dahl, B.Sc., Colin R. Dmuth, Sc.D., Kristin K. Clemens, M.D., Nianping Hu, M.D., Ph.D., J. Michael Paterson, M.Sc., Laura Targownik, M.D., M.S.H.S., Tanvir C. Turin, M.D., Ph.D., Jacob A. Udell, M.D., M.P.H., and Pierre Ernst, M.D., f the CNODES Investigats * N Engl J Med 2016; 374:1145-1154 UK, Canada and the US 29,741 of the patients were hospitalized f heart failure, representing an incidence rate of 9.2 events per 1000 persons per year. The study finds that the rate of hospitalization f heart failure did not increase with the use of incretin-based drugs as compared with al antidiabetic-drug combinations among patients with a histy of heart failure (hazard ratio, 0.86), among those without a histy of heart failure (hazard ratio, 0.82). DPP-4 inhibits and GLP-1 analogues had similar results. On top of the standard of care in the real wld, that these new sugar lowering drugs do not raise the risk of heart failure compared with other options in our medicine cabinet.

Docts: Blowing in the Wind

? Effects on glucagon physiology

EMPA- REG Study Glycated Hemoglobin Levels. Zinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720

Implications Relevance of outcomes from High-risk CV patients to usual clinic patients? Implications of varying lengths of the trials? Glucose Equipoise? As me trials are completed, implications f FDA Guidance 60

Cardiovascular Outcomes and Death from Any Cause. CV Outcomes with CVOT Empagliflozin MACE, CV Death, All Death and Hosp. f Heart Failure Zinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720

SGLT2 inhibitrs and Anti-atherosclerosis

SGLT-2 inhibits Potential and novel pathways associated with CV effects Decreased BP Decreased uric acid Decreased SNS activity Decreased weight Decreased Glucose Decreased albuminuria Decreased oxidative stress Increased LDL Increased HDL Novel biomarkers?? Silvio E Inzucchi et al. Diabetes and Vascular Disease Research 2015;1479164114559852 Copyright by SAGE Publications

What does all this mean f the clinician?

SGLT2 Inhibits

Clinical Caveats All appear to be well tolerated: Clinically indistinguishable Could be added to MF SFU Many are using in those taking insulin: achieving a better A1c with minimal intervention.? Less impact in those with A1c < 7.7%? Used to maintain A1c around 7.5% so? 4 X greater genital fungal infections in those with pri histy of Difficult to compare infection rates within class

Meta-analysis of SGLT2 inhibits led to 0.5 to 0.7% reduction in A1c vs. placebo active comparats Reduction in BP and uric acid levels touted Promotion of some weight loss Increase in LDL-cholesterol (app 5%) :? Significance

SGLT2i and DKA Type 1 DM Off-label use Euglycemic DKA Occ. ketones and Lower Bicarb: not necessarily DKA Type 2 DM Although many case repts, overall incidence not a surprise Baseline me severe hyperglycemia; me dehydration Mild increase in glucagon levels noted; leading to slightly higher glucagon/insulin ratio

SGLT2 inhibits (SGLT2i) decrease glucose by an insulin-independent mechanism. To minimize the risk of hypoglycemia, T1D patients may need to decrease their insulin dose, which is predicted to increase the rate of adipose tissue lipolysis and hepatic ketogenesis. In addition, SGLT2 inhibits have been demonstrated to increase plasma glucagon levels in T2D patients (12, 13), possibly to compensate f increased urinary excretion of glucose. In addition, it has recently been repted that SGLT2 inhibits increase preproglucagon gene expression by acting directly upon pancreatic α-cells (14). Furtherme, phlizin (a nonselective inhibit of SGLT1 and SGLT2) has been demonstrated to increase renal tubular reabsption of acetoacetate (9). If selective SGLT2 inhibits mimic this action of phlizin, it is possible that they could also decrease renal clearance of ketone bodies. Published in: Simeon I. Tayl; Jenny E. Blau; Kristina I. Rother; The Journal of Clinical Endocrinology & Metabolism 2015, 100, 2849-2852. DOI: 10.1210/jc.2015-1884; Copyright 2015

Advice f All

Hyperglycemia Three Dimensional View Type 2 Diabetes and CVD Point of CVOT Intervention Where we Should Intervene 0 Reddy, S. Personal Duration (Years) Int J Clin Pract. 2010 Feb; 64(3): 295 304. 72 30

Perspectives on SGLT2 Inhibition Potential advantages Insulin Independence Combined with other glucose lowering agents Utility independent of duration of DM Weight loss (75g urine glucose = 300kcal/day) Low risk of hypoglycemia Blood pressure lowering? Concerns Polyuria Electrolyte disturbances Low BP Increased hematocrit Bacterial urinary tract infections Fungal genital infections Increased LDL cholesterol Malignancies

? Effects on glucagon physiology

Problem with Cardio-centric view of the Wld 60 y.o. patient with established CVD and only 7 year histy of Type 2 DM indicates a DIFFERENT patient from general internal medicine endocrinology Controlling glucose in these subjects is akin to rapidly hoping that once a nuclear warhead is detonated, peace talks can rapidly prevent the explosion Reddy, S. Personal Opinion 75