Treating Diabetes To Lower Cardiovascular Disease Risk · Treating Diabetes To Lower Cardiovascular...

Treating Diabetes To Lower

Cardiovascular Disease Risk

Anne Peters, MD

Professor, USC Keck School of Medicine

Director, USC Clinical Diabetes Programs

Disclosure of Financial Relationships—2015

Consultantship

Abbott Diabetes Care

Amgen

BD, Biodel

Janssen, Lexicon, Lilly

Medscape, Merck

NovoNordisk

Sanofi, Takeda

FDA

Speakers Bureau

Janssen

Research Funding

Janssen

Medtronic Foundation

Gregg EW et al. N Engl J Med 2014;370:1514-1523

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Preventive care for adults with diabetes has improved substantially in recent decades. We examined trends in the incidence of

diabetes-related complications in the United States from 1990 through 2010.

We used data from the National Health Interview Survey, the National Hospital Discharge Survey, the U.S. Renal Data System,

and the U.S. National Vital Statistics System to compare the incidences of lower-extremity amputation, end-stage renal disease,

acute myocardial infarction, stroke, and death from hyperglycemic crisis between 1990 and 2010, with age standardized to the

U.S. population in the year 2000.

Rates of all five complications declined between 1990 and 2010, with the largest relative declines in acute myocardial infarction

(−67.8%; 95% confidence interval [CI], −76.2 to −59.3) and death from hyperglycemic crisis (−64.4%; 95% CI, −68.0 to −60.9),

followed by stroke and amputations, which each declined by approximately half (−52.7% and −51.4%, respectively); the smallest

decline was in end-stage renal disease (−28.3%; 95% CI, −34.6 to −21.6). The greatest absolute decline was in the number of

cases of acute myocardial infarction (95.6 fewer cases per 10,000 persons; 95% CI, 76.6 to 114.6), and the smallest absolute

decline was in the number of deaths from hyperglycemic crisis (−2.7; 95% CI, −2.4 to −3.0). Rate reductions were larger among

adults with diabetes than among adults without diabetes, leading to a reduction in the relative risk of complications associated

with diabetes. When expressed as rates for the overall population, in which a change in prevalence also affects complication

rates, there was a decline in rates of acute myocardial infarction and death from hyperglycemic crisis (2.7 and 0.1 fewer cases

per 10,000, respectively) but not in rates of amputation, stroke, or end-stage renal disease.

Rates of diabetes-related complications have declined substantially in the past two decades, but a large burden of disease

persists because of the continued increase in the prevalence of diabetes. (Funded by the Centers for Disease Control and

Prevention.)

ORIGINAL ARTICLE

Changes in Diabetes-Related Complications in the United States, 1990–2010Edward W. Gregg, Ph.D., Yanfeng Li, M.D., Jing Wang, M.D., Nilka Rios Burrows, M.P.H., Mohammed K. Ali, M.B., Ch.B., Deborah Rolka, M.S.,

Desmond E. Williams, M.D., Ph.D., and Linda Geiss, M.A.

N Engl J Med 2014; 370:1514-1523 April 17, 2014 DOI: 10.1056/NEJMoa1310799

Twenty-one years ago, the Diabetes Control and Complications Trial (DCCT) showed that intensive glycemic control could

reduce the microvascular complications of type 1 diabetes mellitus. Subsequent studies showed that macrovascular and

microvascular complications could be substantially reduced with tight control of glucose levels, blood pressure, and lipid levels in

adults with type 2 diabetes. Collectively, these studies focused attention on diabetes as a public health problem, with a course

that could be altered by a combination of changes in clinical care (e.g., intensive management of risk factors), the health system

(e.g., organization of care), health promotion (e.g., support for patients in modifying lifestyle), and society (e.g., tobacco-control

policies). These studies were followed by steady improvements in diabetes care, self-management behaviors, and risk-factor

control and by the dissemination of new, effective pharmacologic approaches and medical procedures, such as statin use and

coronary revascularization. Given these important trends, we assembled data on four sentinel indicators of diabetes-related

Abstract

Article

1

2-5

6-8

8-10

NEJM — http://www.nejm.org/doi/full/10.1056/NEJMoa1310799?viewT...

1 of 8 4/25/14, 10:05 PM

LDL Cholesterol Targets in Diabetes

Residual Risk of CVD

? Role of other lipid and non-lipid factors

Risk Attributable

to LDL-C

60 80 100 120 140 160 180 200 220

LDL Cholesterol (mg/dl)

Clin

ical E

ven

t R

ate

4S

CARE

HPS

LIPID

CARDS

Post CABG

ASCOT

PROVE IT

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.009 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

UKPDS: “Legacy Effect” of Insulin/Sulfonylurea

Therapy

RRR = Relative Risk Reduction P = Log Rank

Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

After median 8.8 years post-trial followup

UKPDS: “Legacy Effect” of Insulin/Sulfonylurea

vs Metformin Therapy

Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

Ray KK, et al. Lancet. 2009;373:1765-1772.

Meta-Analysis of Glycemic Control Trials

and Coronary Heart Disease

Why haven’t trials shown CHD risk reduction?

• Possible reasons that individual trials failed to

show a beneficial effect on CHD

– Event rates were lower than expected

– Differences in glycemic control were not large enough

– The intervention or observation period was too short

– Need to start intervention earlier in natural history of

the disease

Mazzone T. Lancet. 2009. 23;373:1737-1738.

Management of Hyperglycemia in

Type 2 Diabetes, 2015:

A Patient-Centered Approach

Update to a Position Statement of the American Diabetes Association (ADA)

and the European Association for the Study of Diabetes (EASD)

Diabetes Care 2015;38:140–149

Diabetologia 2015;10.1077/s00125-014-3460-0

The ADA/EASD Position Statement on Management of

Hyperglycemia in Type 2 Diabetes

ADA EASD

Richard M. Bergenstal MDInt’l Diabetes Center, Minneapolis, MN

John B. Buse MD, PhDUniversity of North Carolina, Chapel Hill, NC

Anne L. Peters MDUniv. of Southern California, Los Angeles, CA

Richard Wender MDThomas Jefferson University, Philadelphia, PA

Silvio E. Inzucchi MD (co-chair)

Yale University, New Haven, CT

Michaela Diamant MD, PhDVU University, Amsterdam, The Netherlands

Ele Ferrannini MDUniversity of Pisa, Pisa, Italy

Michael Nauck MDDiabeteszentrum, Bad Lauterberg, Germany

Apostolos Tsapas MD, PhDAristotle University, Thessaloniki, Greece

David R. Matthews MD, DphilOxford University, Oxford, UK

1. Patient-Centered Approach“...providing care that is respectful of and responsive to individual patient preferences, needs, and values -

ensuring that patient values guide all clinical decisions.”

• Gauge patient’s preferred level of involvement.

• Explore, where possible, therapeutic choices. Consider using decision aids.

• Shared Decision Making – a collaborative process between patient and clinician, using best available evidence and taking into account the patient’s preferences and values

• Final decisions regarding lifestyle choices ultimately lie with the patient.

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Impact of Intensive Therapy for Diabetes:

Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS

DCCT /

EDIC*

ACCORD

ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)

Lessons from Accord

Severe Hypoglycemia and Mortality Risk

ACCORD ADVANCE VADT

Severe Hypo Intensive Standard Intensive Standard Intensive Standard

(%/ year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

Intensive

Standard

1.3%

1.0%

2.8%

4.9%

Annual mortality

Bonds et al. BMJ 2010;340:b4909

Severe Hypoglycemia in ACCORD

• “Patients with type 2 diabetes who experience

symptomatic, severe hypoglycaemia are at

increased risk of death, regardless of the intensity of

glucose control.”

• “The increased risk of death seen in the ACCORD

trial among participants in the intensive glycaemia

control arm cannot be attributed to the increased

rate of severe hypoglycaemia in intensive arm

participants.”

Bonds et al. BMJ 2010;340:b4909

3. ANTI-HYPERGLYCEMIC THERAPY

• Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key:

Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc.

- Avoidance of hypoglycemia

PG = plasma glucose

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

more

stringent

less

stringent

Patient attitude and

expected treatment efforts highly motivated, adherent,

excellent self-care capacities

less motivated, non-adherent,

poor self-care capacities

Risks potentially associated

with hypoglycemia and

other drug adverse effects

low high

Disease durationnewly diagnosed long-standing

Life expectancylong short

Important comorbiditiesabsent severefew / mild

Established vascular

complications absent severefew / mild

Readily available limited

Usually not

modifiable

Potentially

modifiable

HbA1c7%

PATIENT / DISEASE FEATURES

Approach to the managementof hyperglycemia

Resources and support

system

Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnormalities in T2DM

_

_

+renal glucose excretion

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnormalities in T2DM

_

_

+renal glucose excretion

DA agonists

T Z D sMetformin

S U sGlinides

DPP-4 inhibitors

GLP-1Ragonists

A G I s

Amylinmimetics

Insulin

Bile acidsequestrants

Healthy eating, weight control, increased physical activity & diabetes education

Metforminhigh

low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denoteany specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-ior

or

or GLP-1-RA

high

low risk

loss

GI

high

GLP-1 receptoragonist

Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denoteany specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, addbasal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin+

Combinationinjectabletherapy‡

GLP-1-RAMealtime Insulin

Insulin (basal)

+

Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0


Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-ior

or

or GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+


GLP-1-RAMealtime InsulinFigure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Insulin (basal)

+


Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-ior

or

or GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+



Insulin (basal)

+



Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+



HbA1c ≥9%

Metformin intolerance or

contraindication

Uncontrolled hyperglycemia

(catabolic features, BG ≥300-350 mg/dl,

HbA1c ≥10-12%)

Insulin (basal)

+

or

or

or



Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+



Figure 2B. Anti-hyperglycemic therapy in T2DM: Avoidance of hypoglycemia

or

or

or

Insulin (basal)

+



Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+



Figure 2B. Anti-hyperglycemic therapy in T2DM: Avoidance of weight gain

Insulin (basal)

+

or

or

or



Metforminhigh

low risk

neutral/loss


low


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

high

low risk

gain

edema,HF, fxs

low

Thiazolidine-dione

intermediate

low risk

neutral

rare

high

DPP-4 inhibitor

highest

high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-ior

or

or GLP-1-RA

high

low risk

loss

GI

high


Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

or

or

DPP-4 Inhibitor

+SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin+



Figure 2C. Anti-hyperglycemic therapy in T2DM: Minimization of costs

Insulin (basal)

+


LookAHEAD Study Objective

The Look AHEAD Research Group. N Engl J Med 2013;369:145-154

To determine the long-term effects (up to

13.5 years) of an intensive lifestyle

intervention program designed to produce

weight loss and increase physical activity

on cardiovascular morbidity and mortality

in overweight or obese persons with

type 2 diabetes.

Seattle

Los

Angeles

San AntonioHouston

Baton Rouge

Minneapolis

Memphis

Birmingham

Winston-Salem

Baltimore

PhiladelphiaNew York

Providence

Boston

Pittsburgh

Clinical

Site

Coordinating

Center

Denver

16 Clinical Sites

PhoenixShiprock

Results: Weight Loss

The Look AHEAD Research Group. N Engl J Med, June 24, 2013

Mean F/U 9.6 years

1-yr wt loss: 8.6% ILI0.7% control group

Study end:6.0% ILI3.5% control group

Results: Primary Outcome

The Look AHEAD Research Group. N Engl J Med, June 24, 2013

Events/100 person-yrs:

1.83 ILI1.92 Control

Hazard ratio 0.95(95% CI 0.83-1.09, P=0.51)

N=174

(19.6%)

+2

0

2

4

6

8

10

12

14

16

18

1 2 3 4

Pe

rce

nta

ge

We

igh

t L

os

s4-Yr Wt Loss Trajectories of 887 ILI Participants

Who Lost ≥ 10% Initial Weight at Yr 1 (~35%)

Years

0-5%

5-6.9%

7-

10%

≥ 10%

Gained

N=374

(42.2%)

N=152

(17.1%)

N=99

(11.2%)

N=88

(9.9%)

+4

Mean Annual Number of

Meal Replacements Used

in Years 2-4

p < .05

0

20

40

60

80

100

120

140

> 10% 5 - 9.9% 0 - 4.9% Gained

Weight Change- Year 4

Me

al R

ep

lac

em

en

ts

p < .02

125.7 103.2 80.8 84.2

Mean Weekly Kcal

Expenditure at Year 4 (as

Determined by Paffenbarger)

0

500

1000

1500

2000

2500

> 10% 5 - 9.9% 0 - 4.9% Gained

Weight Change- Year 4

Kca

l/w

k o

f A

cti

vit

y

1997.9 1406.2 1127.3 949.3

p < 0.005 for all

comparisons

with > 10%

group

Metformin: The Only Choice in Type 2 DM?

• Most commonly used therapy for T2 DM (2/3rds of

patients)

• Clinical effects

• Lowers A1C 1-2% (especially at high baseline A1C), no weight gain

• Maximal clinical effect at 1500-2000 mg/day

• Possible side effects and precautions

• GI side effects common – less well tolerated by up to 10%

• Not advised if significant renal or liver disease, heart failure (~20%)

• Other features

• Lower CV risk in obese patients (UKPDS)

• Extensive clinical experience and lower cost

• ? Favorable impact on cancer risk and mortality

Sulfonylureas and the SecretagoguesHow Do We Use Them Now?

• Most common (traditional) 2nd agent in T2 DM

• Stimulate insulin release – during hyperglycemia and post-meal

• Clinical Use

• Inexpensive and commonly used, rapid glucose lowering

• Limited dose effect and limited “durability” of effect

• Side effects

• Associated with weight gain and risk of hypoglycemia

• Precautions and contraindications

• Associated with risk of severe hypoglycemia (elderly, renal disease)

• Highest risk of hypoglycemia with GLYBURIDE

• May not be good for those at CVD risk (longstanding discussion)

Thiazolidinediones (TZDs) Do We Target Insulin Resistance?

• Clinical application

• Targeted patients with clinical markers of insulin resistance

• Dyslipidemia, HTN, established CVD, central obesity

• May limit CVD risk and alter progression of diabetes

• Adverse effects and considerations

• Significant weight gain and increase risk of edema and HF

• Increased risk of long-bone fractures

• Macular edema

• Patient selection

• Higher CVD risk – particularly with dyslipidemia, est. CVD

• Those at lower risk for fracture and with central obesity, NASH

Grey A et al. J Clin Endocrinol Metab. 2007;92:1305-1310.

Summary Of Pioglitazone Clinical TrialsCenter for Drug Evaluation & Research, July 30, 2007

Hazard Ratio0.5 0.75

PIO Meta-analysis

- without PROactive

PROactive

PIO Meta-Analysis

plus PROactive

0.83

0.84

0.75

375 450

8554 7836

1.0

PIO COMP

#CV Events

# of Subjects

DPP-4 Inhibitors: Sitagliptin (Januvia), Saxagliptin

(Onglyza), Linagliptin (Tradjenta) and Alopglitin (Nesina)

• Clinical Use

• Moderate effectiveness (A1C reduction ~0.5-0.8%)

• Use in both combo and mono therapy

• Unique Features

• Limited side effect profile, very well tolerated, pancreatitis?

• Weight neutral, no significant weight loss, no hypoglycemia

• Variable clinical response (A1C reduction 0.2-1.1%)

• Reduced dosing in chronic kidney disease (except for linagliptin)

• Saxagliptin increased risk of CHF in high risk population

GLP-1 RA’s: Exenatide (Byetta, Bydureon), liraglutide

(Victoza), albiglutide (Tanzuem), dulaglutide (Trulicity)

• Clinical Use

• Lowers A1C 1 – 1.5%

• Often associated with weight loss

• Side Effects/Features

• Injected once or twice daily or once weekly

• GI side effects common; rare hypoglycemia

• Warnings: pancreatitis; MCT

• Drug-specific features

• Potential CVD benefits

Potential Cardiovascular Effects of GLP-1-Based Therapies

Improved weight, SBP, lipids

Improved endothelial function

Increased vasorelaxation

Increased peripheral and coronary flow

Increased ventricular function

Decreased microvascular permeability

Reduced inflammation

Okerson T, Chilton R. Cardiovasc Ther 30:e146-55, 2012

Incretin Cardiovascular Outcome Trials

EXSCEL - Exenatide LAR n=14,000

LEADER - Liraglutide n=9,340

REWIND - Dulaglutide n=9,622

ELIXA -Lixisenatide n=6,000

TECOS - Sitagliptin n=14,000

SAVOR-TIMI 53 - Saxagliptin n=16,500

EXAMINE -Alogliptin n=5,400

CAROLINA (vs SU) - Linagliptin n=6,000

September 2013

September 2018

December 2014

September 2013

April 2018

April 2019

January 2015

October 2015

SUSTAIN 6 - Semaglutide n=3,297 January 2016

Risk Factors Stable CAD-CVD-PAD ACS patients

CARMELINA (vs pbo) - Linagliptin n=8,300

January 2018

SGLT-2 Inhibitors—Canagliflozin, Dapagliflozin, Empagliflozin

Clinical Effects

• Novel mechanism of action/oral agent

• Most will respond—action independent of beta-cell function

• A1C reduction ~1% with 2-3 kg weight loss

Possible Side Effects and Precautions

• Mycotic genital infections

• Findings due to volume depletion

• Don’t use if eGFR <45%

Other Features

• Lowers BP slightly

• Raises LDL cholesterol

Jacobsen LV, et al. Br J Clin Pharmacol. 2009;68:898-905. Linnebjerg H, et al. Br J Clin Pharmacol. 2007;64:317-327.

Screening

T2DM on metformin alone

HbA1c >6.8% at screening

< 10 years duration at randomization

Randomization

n=5000 eligible subjects

Sulfonylurea

(glimepiride)

n=1250

DPP-IV inhibitor

(sitagliptin)

n=1250

GLP-1 analog

(liraglutide)

n=1250

Insulin

(glargine)

n=1250

HbA1c 6.8-8.5% at final run-in visit

Glycemia Reduction Approaches in Diabetes:

A Comparative Effectiveness Study

Metformin run-inTitrate metformin to 1000 (min) – 2000 (goal) mg/day

Reducing CVD Risk Treating T2DM

o Use statins, control BP, give aspirin

o Use diabetes drugs that don’t cause

hypoglycemia or minimize hypos in drugs that do

o Improve control early and maintain it

o Never forget importance of lifestyle

RxList, 2014.

Thank You

RxList, 2014.

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