Stephen Clement M.D. CDE Medical Director, Endocrine Services Inova Fairfax Hospital

Stephen Clement M.D. CDE Medical Director, Endocrine Services Inova Fairfax Hospital

Financial Disclosures Consulting Panel for GSK on Hepatitis Vaccines

Case Study BH is a 67 y/o female with T2 DM for 15 years, treated with metformin and glyburide No self testing of BGs at home A1C 8-9% No microvascular complications h/o MI, PTCA Presents to community hospital with 10/10 substernal chest pain ECG T wave inversions V1-V6 Cardiac Cath severe multivessel disease, no occlusion

Case Study Questions: What intervention should she have for her multi-vessel disease? Going forward, what are the goals for her diabetes and medical therapy for ASCVD based on recent Randomized Clinical Trials and Guidelines?

Outline RCTs/Clinical Guidelines CABG vs. PTCA Trials Glucose Control Studies: UKPDS ACCORD CV Outcome Trials for new medications How to Treat?

RCT/Clinical Practice Guideline Trends Retrospective studies are good for hypothesis generating, but suffer from.. o Bias from ascertainment of cases/controls, other biases o Potential biases are a particular concern in comparative effectiveness research (i.e., confounding by indication) Large multicenter randomized studies are still the Gold Standard RCTs now often required for changing practice guidelines

American Diabetes Association Clinical Practice Guidelines Recommendations with an A rating are based on large well-designed clinical trials or well-done meta-analyses. Generally, these recommendations have the best chance of improving outcomes when applied to the population to which they are appropriate. Diabetes Care 37, supplement 1, 2014

Case Study BH with T2DM Multi-vessel disease with acute coronary syndrome (unstable angina) Prior RCTs: BARI, BARI 2D, CARDia, SYNTAX? PCI with drug eluting stents vs. CABG?

FREEDOM STUDY Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel Disease Diabetes with Multivessel Dz Randomized to: PCI with drug-eluting stents (serolimus or paxlitaxel) followed by abciximab and dual antiplatelet Rx, or CABG Outcome: MACE

Kaplan Meier Estimates of the Composite Primary Outcome and Death. Farkouh ME et al. N Engl J Med 2012;367:2375-2384.

Freedom Study Conclusion: For patients with diabetes and advanced CAD, CABG was superior to PCI in that it significantly reduced rate of death, MI, with a higher rate of stroke.

Case Study BH with T2DM Multi-vessel disease with acute coronary syndrome (unstable angina)? Send for CABG What about her diabetes management? What should her target A1C be? Are there Rx s (OHA, Insulin, incretin agonists) that confer better outcomes?

% of Patients With an Event UKPDS Myocardial Infarction Fatal or Non-fatal MI, Sudden Death 573 of 3867 Patients (15%) 30 Conventional Intensive 20 10 Risk Reduction 16% (0%-29%) P=0.052 0 0 3 6 9 12 15 Years From Randomization UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.

HR Myocardial Infarction Hazard Ratio (fatal or non-fatal MI or sudden death) 1.4 1.2 Intensive (SU/Ins) vs Conventional Glucose Control MI HR=0.84 p=0.052 HR=0.85 p=0.014 1.0 HR (95%CI) 0.8 0.6 0.4 Number of Events Con: 168 212 239 271 296 319 Int: 387 450 513 573 636 678 1997 1999 2001 2003 2005 2007 UKPDS 80. N Eng J Med 2008;359:1577 89

The ability to show a difference in a clinical trial depends upon: The Hazard Rate of the outcome The Effect Size of the intervention The Exposure to the intervention The Confounding therapies provided to the participants 18

Comparison of Studies Standard Group Event Rates ACCORD ADVANCE VADT Primary Outcome Macrovascular Outcome Primary Outcome Predicted 2.9% per yr 3.0% per yr 6.7% per yr Observed 2.3% per yr 2.2% per yr 5.6% per yr % Reduction 21% 27% 16%

A1c (%) ACCORD: Treatment Effects on Glucose Control 9.0 8.5 8.0 Standard therapy 7.5 7.0 6.5 6.0 0 Time (Years) Intensive therapy 0 1 2 3 4 5 6 ACCORD Study Group. N Engl J Med 2008;358:2545 59

Patients with Events (%) ACCORD: Treatment Effect on All-Cause Mortality 25 20 15 10 5 HR 1.22 (1.01 1.46) P=0.04 Intensive Therapy Standard Therapy 1.41%/yr 1.14%/yr 0 0 1 2 3 4 5 6 Time (Years) HR = hazard ratio Gerstein HC, et al. N Engl J Med. 2008;358(24):2545-2559. Copyright 2008 Massachusetts Medical Society.

ACCORD: Deaths in Intensive vs Standard Glycemic Control Groups Standard Glycemic Control Intensive Glycemic Control Deaths, n 203 (11/1000/y) 257 (14/1000/y) (0.011 /y) (0.014/y) Median A1c 7.5% 6.4% National Heart, Lung, and Blood Institute. ACCORD Telebriefing Prepared Remarks. Bethesda, MD: NHLBI; February 6 2008.

Risk of Death Over a Range of Average A1c Adjusted log (HR) by Treatment Strategy Relative to standard at A1c of 6% Steady increase of risk from 6% to 9% A1c with intensive strategy 1 Intensive strategy 0 1 Standard strategy 6 7 8 9 Average A1c % Excess risk with intensive strategy vs standard occurred above A1c 7% Riddle MC, et al. Diabetes Care. 2010;33(5):983-990. Copyright 2010 by the American Diabetes Association.

Observations from ACCORD Investigators Many patients not able to adhere to complex oral/insulin regimens The degree of disarray in the patient s house predicted a major AE Personal communication 2013

Approach to management of hyperglycemia. American Diabetes Association Dia Care 2014;37:S14-S80 Copyright 2011 American Diabetes Association, Inc.

Approach to management of hyperglycemia. Goals should be individualized based on: Duration of DM Age/life expectancy Comorbid conditions Known CVD or advanced microvascular complications Individual patient considerations More or less stringent glycemic goals may be appropriate for individual patients American Diabetes Association Dia Care 2014;37:S14-S80 Copyright 2011 American Diabetes Association, Inc.

Outline RCTs/Clinical Guidelines CABG vs. PTCA Trials Glucose Control Studies: UKPDS ACCORD CV Outcome Trials for new medications

Ongoing Outcomes Trials of Diabetes Therapies Class Patients Drugs Est. N DPP4i GLP1a Diabetes Diabetes saxagliptin sitagliptin alogliptin linagliptin MK3102 lixisenatide liraglutide exenatide (extended) dulaglutide semaglutide 50,000 40,000 SGLT2i Diabetes canagliflozin empagliflozin dapagliflozin 25,000 PPARαγ Diabetes Prediabetes aleglitazar 25,000 AGI IGT acarbose 7,500 TZD IR pioglitazone 4,000 GPR40 Diabetes fasiglifam 5,000

Incretin-Based Therapy: CV Outcomes Studies Study Name Drug Evaluated Estimated Enrollment Estimated Duration SAVOR-TIMI 53 Saxagliptin 16,500 May 2010 July 2013 EXAMINE Alogliptin 5,400 Oct 2009 Dec 2013 TECOS Sitagliptin 14,000 Dec 2008 Dec 2014 LEADER Liraglutide 9,340 Aug 2010 Jan 2016 EXSCEL Exenatide once weekly 9,500 June 2010 Mar 2017 CAROLINA Linagliptin 6,000 Oct 2010 Sept 2018 Clinical Trials.gov Accessed Jan 2014

Approved SGLT-2 inhibitors Drug Name Sponsor Trade Name Empagliflozin Lilly Jardiance Dapagliflozin BMS/AZ Farxiga Canagliflozin J&J Invokana

NEJM 373:2117-28, 2015

Zinman B et al. N Engl J Med 2015;373:2117-2128 Cardiovascular Outcomes and Death from Any Cause.

Zinman B et al. N Engl J Med 2015;373:2117-2128 Glycated Hemoglobin Levels.

Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.

Benefits/Limitations of SGLT-2 Inhibitors Benefits: Lowers glucose in a glucose dependent fashion Modest weight reduction Effect is additive to metformin? CV protection Limitations: Safety

Posted 12/4/2015 FDA.gov

How to Treat?

Initial drug monotherapy Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Two drug combinations* Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs Three drug combinations Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): Metformin Metformin Metformin Metformin Metformin Sulfonylurea high moderate risk gain hypoglycemia low Sulfonylurea Thiazolidinedione high low risk gain edema, HF, fx s high Thiazolidinedione DPP-4 Inhibitor intermediate low risk neutral rare high DPP-4 Inhibitor GLP-1 receptor agonist Insulin (usually basal) highest high risk gain hypoglycemia variable If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin Metformin Metformin Metformin Metformin TZD SU GLP-1 receptor agonist high low risk loss GI high SU SU Insulin (usually basal) TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA or Insulin or Insulin If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents: More complex insulin strategies T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia 19 April 2012. [Epub ahead of print] Insulin # (multiple daily doses)

Initial drug monotherapy Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Two drug combinations* Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs Three drug combinations Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): Metformin Metformin Metformin Metformin Metformin Sulfonylurea high moderate risk gain hypoglycemia low Sulfonylurea Thiazolidinedione high low risk gain edema, HF, fx s high Thiazolidinedione DPP-4 Inhibitor intermediate low risk neutral rare high DPP-4 Inhibitor GLP-1 receptor agonist Insulin (usually basal) highest high risk gain hypoglycemia variable If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin Metformin Metformin Metformin Metformin TZD SU GLP-1 receptor agonist high low risk loss GI high SU SU Insulin (usually basal) TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA or Insulin or Insulin If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents: More complex insulin strategies T2DM Antihyperglycemic Therapy: General Recommendations ADA/EASD Position Statement. Diabetes Care June 2012. Insulin # (multiple daily doses)

Cost for 30 Days Treatment DPP4 Inhibitors: $360-$404 SGLT-2 Inhibitors: $381-$443 GLP-1 Agonists: $300-$740

Minimizing Risk for Hypoglycemia with Insulin Prescribe insulin that has physiologic action at the lowest possible dose Patient education (when to eat, carry carbs, know symptoms) Consider early use of insulin sparing medications (metformin, incretins, acarbose,? SGLT-2 inhibitors)

Insulin and the Elderly Interview and involve caregivers Set realistic goals with patient and family Facilitate roles of caregivers Simplify regimen (next slide) Halter F. Hypoglycemia in the Elderly, ADA Scientific Sessions June 2015

Elderly: Simplify Regimen Take basal insulin in the AM when caregivers are present Have caregiver give insulin using vial and syringe Check-mark when insulin is taken Use pre-filled syringes Take prandial insulin after meal Have prepared meals Re-assess what works Medha Munshi, ADA Scientific Sessions, 2015

Conclusions RCTs play a greater role in our clinical decisions for diabetes care Advances in pathophysiology have provided new targets for glucose management Newer may not always be better Individualize treatment goals Start with low doses Cost considerations After metformin, individualize therapy

Questions??

Acknowledgements My Former Team: GU Colleagues and coauthors My new Team: GU and GW Chief Residents Shirley Kalwaney MD Madeline Erario MD J.P. Verderese MD Brian Hazen MD Chappy Venkatasen MD Hospitalists and Surgical Colleagues Zobair Younossi MD