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 AssociationClinical 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 STUDYFuture 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 abciximaband 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?

UKPDS – Myocardial Infarction

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.

Risk Reduction 16% (0%-29%)

P=0.052

30

20

10

0

0 3 6 9 12 15

Years From Randomization

% o

f P

atie

nts

Wit

h a

n E

ven

t ConventionalIntensive

Fatal or Non-fatal MI, Sudden Death 573 of 3867 Patients (15%)

Myocardial Infarction Hazard Ratio(fatal or non-fatal MI or sudden death)

Intensive (SU/Ins) vs Conventional Glucose Control

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577–89

0.4

0.6

0.8

1.0

1.2

1.4

1997 1999 2001 2003 2005 2007

HR

MIHR=0.84p=0.052

HR=0.85p=0.014

Number of EventsCon: 168 212 239 271 296 319Int: 387 450 513 573 636 678

18

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

Comparison of StudiesStandard Group Event Rates

ACCORD ADVANCE VADT

Primary Outcome MacrovascularOutcome

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%

ACCORD: Treatment Effects onGlucose Control

A1c

(%

)

Time (Years)

Standard therapy

Intensive therapy

6

9.0

8.5

8.0

7.5

7.0

6.5

6.0

00 1 2 3 4 5

ACCORD Study Group. N Engl J Med 2008;358:2545–59

ACCORD: Treatment Effect onAll-Cause Mortality

Time (Years)

25

0

20

15

10

5

01 2 3 4 5 6

Standard Therapy

Intensive TherapyHR 1.22 (1.01–1.46)

P=0.04

1.41%/yr

1.14%/yr

Patients

with

Events

(%

)

HR = hazard ratioGerstein 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

National Heart, Lung, and Blood Institute. ACCORD Telebriefing Prepared Remarks. Bethesda, MD: NHLBI; February 6 2008.

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%

Risk of Death Over a Range of Average A1c

Riddle MC, et al. Diabetes Care. 2010;33(5):983-990. Copyright © 2010 by the American Diabetes Association.

Average A1c %

Adjusted log (HR) by Treatment StrategyRelative to standard at A1c of 6%

Standard strategy

6 8 97

Excess risk with intensive strategy vs standard occurred above A1c 7%

Intensive

strategy

1

0

–1

Steady increase of risk from 6% to 9% A1c with intensive strategy

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.

American Diabetes Association Dia Care 2014;37:S14-S80

Copyright © 2011 American Diabetes Association, Inc.

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

Outline RCTs/Clinical Guidelines

CABG vs. PTCA Trials

Glucose Control Studies:

UKPDS

ACCORD

CV Outcome Trials for new medications

Ongoing Outcomes Trials of Diabetes

TherapiesClass Patients Drugs Est. N

DPP4i Diabetes saxagliptin sitagliptin alogliptin

linagliptin MK310250,000

GLP1a Diabeteslixisenatide liraglutide exenatide

(extended)dulaglutide semaglutide

40,000

SGLT2i Diabetes canagliflozin empagliflozin dapagliflozin 25,000

PPARαγDiabetes

Prediabetesaleglitazar 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

EnrollmentEstimated 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 onceweekly

9,500 June 2010 – Mar 2017

CAROLINA Linagliptin 6,000 Oct 2010 – Sept 2018

Clinical Trials.gov – Accessed Jan 2014

Approved SGLT-2 inhibitorsDrug Name Sponsor Trade Name

Empagliflozin Lilly Jardiance

Dapagliflozin BMS/AZ Farxiga

Canagliflozin J&J Invokana

NEJM 373:2117-28, 2015

Cardiovascular Outcomes and Death from Any Cause.

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

Glycated Hemoglobin Levels.

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

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 12/4/2015FDA.gov

How to Treat?

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

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 +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ 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:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):

T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia 19 April 2012. [Epub ahead of print]

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

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 +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ 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:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):

T2DM Antihyperglycemic Therapy: General RecommendationsADA/EASD Position Statement. Diabetes Care June 2012.

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