Smoldering Insulin Resistance: Strategies to Optimize ... · Smoldering Insulin Resistance: Strategies to Optimize Cardiometabolic Health Thomas Dayspring, MD, FACP, FNLA, NCMP Chief

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Thomas Dayspring MD, FACP, FNLA1

Smoldering Insulin Resistance: Strategies to Optimize

Cardiometabolic Health

Smoldering Insulin Resistance: Strategies to Optimize

Cardiometabolic Health

Thomas Dayspring, MD, FACP, FNLA, NCMP

Chief Academic OfficerTrue Health Diagnostics

Richmond, VA

Thomas Dayspring, MD, FACP, FNLA, NCMP

Chief Academic OfficerTrue Health Diagnostics

Richmond, VA

Disclosures (Last 12 months)

► Employment► True Health Diagnostics

► Lecture Bureau Sanofi Regeneron

As diabetes develops, we currently waste the first ∼10 years of the natural history

If we found prediabetes and early diabetes when they first presented and treated them more effectively, we

could prevent or delay the progression of hyperglycemia and the development of complications



► The earliest stage of type 2 diabetes is prediabetes(impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]), where glucose levels are higher than normal but not in the diabetes range

► Prediabetes tends to progress to diabetes, and over time, persistent hyperglycemia leads to the complications that are the major source of morbidity, mortality, and cost

► This natural history reflects underlying loss of β-cell function due in part to factors such as elevated glucose and lipid levels, inflammation, amyloid, and oxidative and endoplasmic reticulum stress

Natural History of Type 2 Diabetes

Philips LS et al. Diabetes Care 2014;37:2668–2676

► Unfortunately, we waste the first 10 years of the n atural history when the disorder is easiest to treat

► There are 79 million Americans with prediabetes and 7 million with early T2DM who are largely unrecognized because we do not screen to find these states of dysglycemia

► Moreover, when we do make the diagnosis, we do not treatin a way that lowers glucose levels to normal and as a consequence, the disease tends to progress, and patients need more and more medications





Prediabetes Diabetes Complications

Dev

elop

men

t of

Dia

bete

s,

Dia

bete

s C

ompl

icat

ions

Years

Prediabetes is glucose > normal but not as high as diabetes

Underlying loss of β-cell function and mass (apoptosis) due to high glucose and lipids, inflammation and oxidative and ER stress

Diagram illustrating the natural history of

diabetes from progression from

prediabetes to diabetes and development of

diabetes complications over time without

interventions




Diagram illustrating the natural history of diabetes

from progression from prediabetes to diabetes

and development of diabetes complications

with interventions such as lifestyle change or a

glucose-lowering medication that are

successful in decreasing progression from

prediabetes to diabetes, but then are stopped



Dev

elop

men

t of

Dia

bete

s,

Dia

bete

s C

ompl

icat

ions

Start


↓ progression with interventions that ↓ glucose

Benefit persists after treatments stop

“Legacy effect”

Stop

Rx, diet, exercise


Diagram illustrating the natural history of diabetes

from progression from prediabetes to diabetes and

development of diabetes complications over time

with interventions that are titrated to keep glucose

and A1C levels in the normal range and are not

stopped



Dev

elop

men

t of

Dia

bete

s,

Dia

bete

s C

ompl

icat

ions

Start


Obtain benefit for years

Don’t stop Continue

↓ progression and ↓ complications by ↓glucose

Systematic treatment

Rx, diet, exercise, Rx - ? More Rx


Cumulative diabetes incidence

in the DREAMstudy, where subjects with

prediabetes were given rosiglitazone

or placebo, including time

points before and after the primary

study was stopped


Study ended, drug stopped

Benefit sustained

Control Rosiglitazone

Cum

ulat

ive

Dia

bete

s In

cide

nce

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5 6

Years

DREAM = Diabetes Reduction Assessment With Ramipril and R osiglitazone Medication




Cumulative incidence of severe diabetic retinopathy

in the Da Qing IGT & Diabetes study,

showing subjects with prediabetes

who were randomized to

receive instruction in diet/exercise or to be

control subjects, including time points before and after the primary study was

stopped


Control Diet + exercise

Inci

dent

sev

ere

retin

opat

hy (

%)

18

16

12

2

42Follow Up (Years)

14

10Study ended

Benefit sustained8

6

4

00 181612 141086 20

► In the Diabetes Prevention Project subject population, achieving normal glucose levels appeared to be particularly beneficial

► Among subjects who had not developed diabetes at the end of the primary study, those who achieved normal fasting and 2-h oral glucose tolerance test (OGTT) glucose levels at least once during the average 3.2 years of the primary study had a 56% decrease in development of diabetes during follow-up after the primary study ended

► It did not matter how normal glucose was achieved, as the reduction in the tendency to develop diabetes was comparable among subjects in the lifestyle change, metformin, and control groups who achieved normal glucose levels at least once




Cumulative diabetes incidence

in the U.S. Diabetes

Prevention Project study, showing subjects with

prediabetes who were given

troglitazone or placebo, including time points before

and after the primary study was

stopped


Control Troglitazone

Cum

ulat

ive

Dia

bete

s In

cide

nce

(%) 40

Years since randomization

- Drug stopped at 0.9 years -Study ended

(for these subjects)

Benefit sustained

02.0 3.0 4.01.00.0

30

20

10

0

During 0.9 years of treatment with

troglitazone, the diabetes incidence

rate was 3.0 cases/100 person-years, considerably

lower than the rate of 12.0 cases/100

person years with placebo

However, during the 3 years after

troglitazone was stopped, the diabetes incidence was virtually identical to that of the placebo group without evidence of “catch-up”



► As the natural history of diabetes – the tendency for the disease to get worse and for complications to develop –reflects underlying loss of β-cell function, which is due in part to glucotoxicity, treatment that normalizes glucose levels should help preserve β-cell function

► Indeed studies have shown that attaining normal glucose levels was predicted somewhat more strongly by better β-cell function than by better insulin sensitivity, although both were statistically significant



Changing the Natural History of Diabetes How Medical Practice Should Change


► Screening to identify early diabetes and prediabetes should become routine

► Oral glucose tolerance tests - most sensitive, least convenient

► Fasting plasma glucose - lowest cost, intermediate sensitivity and convenience

► A1C - most convenient, least sensitive

► Patients who are at high risk and have health prospects justifying improved glucose control should have management aimed to keep glucose levels as close to normal as possible without causing hypoglycemia

► Begin with lifestyle change

Changing the Natural History of Diabetes How Medical Practice Should Change


► Include medications if appropriate

► Begin with metformin for patients with diabetes

► Consider metformin for patients with prediabetes if there is:

► IFG and

► IGT and

► At least one risk factor for progression to diabetes (age < 60 years, BMI ≥ 35 kg/m2, a family history of diabetes, elevated triglycerides, reduced HDL-cholesterol, hypertension, or A1C > 6.0%)

► Other medications that may be appropriate (DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 analogs, α-glucosidase inhibitors, and possibly basal insulin and thiazolidinediones)

No FDA Indications



Changing the Natural History of Diabetes Stepped Care Strategy


► Insulin is typically added relatively late in the natural history

► Use of home glucose monitoring to guide management varies and often is not initiated until patients are treated with insulin relatively late in the natural history

► All patients with prediabetes and early diabetes should have management of cardiovascular risk factors, use of aspirin (if appropriate), screening for eye and renal complications, and education in medical nutrition management

We believe we are at a time when we can change the natural history of type 2 diabetes

Doing so should benefit the health of millions of patients and might also benefit health care systems, by reducing

resource use and costs

CONCLUSIONS

► The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority, however, the predictors of diabetes risk are insufficiently understood

► We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors

► This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment

PLOS one 2014 5(4): e10100



► A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5)

► It also improved discrimination of the model (IDI = 0.0149, p < 0.0001) and reclassification of diabetes risk [Net reclassification Index (NRI) = 11.8%, p = 0.006]

► Gender-specific analyses suggested that the best score differed between men and women

► Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001)

► Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin which gave an NRI of 13.6% (p = 0.041)

Salomaa V et al. PLOS one 2014 5(4): e10100

Biomarker Testing for Clinically Incident Diabetes

Salomaa V et al. PLOS one 5(4): e10100

Biomarker Testing for Clinically Incident Diabetes

► The biomarker score, composed as a linear combination of four biomarkers, was associated with doubling of the relative hazard of diabetes in the independent validation cohort

► The prediction of absolute risk of diabetes produced a significantly improved net reclassification and discrimination, especially in gender-specific analyses, with the model including the biomarker score

► This information may help with identifying individuals at high risk of developing diabetes

Progression of Insulin Resistance

Fasting Glucose & HbA1c

Fasting

Insulin

Lipoprotein

Abnormalities

Beta-Cell Function

TIME

(months to decades)

Prediabetes

FG = 100-125Diabetes

FG > 125 (mg/dL)

Beta-Cell Failure

Beta-Cell Strain Beta-Cell Dysfunction

Insulin

Resistance

↑LDL-P (apoB)↑ small LDL-P↑ sdLDL-C

↑Large VLDL-P↓ HDL-P↓HDL2-C

Bergenstal R et al. Diabetes Endocrinol 2005;7(2)

Lipoproteins in Diabetes Mellitus Jenkins, Toth, Ly ons. Humana Press 2014



Lipoprotein Dynamics in Insulin Resistant States

TG-rich VLDL

(CETP)

Large LDL

Large HDL

TG

(CETP)

TG

CE

CE

TG-enriched Cholesterol-depleted

particles

TG-depleted, cholesterol-rich

VLDL

Lipoprotein Lipase

Smaller cholesterol-rich VLDL remnants

Triglyceride Cholesteryl ester

There is now less cholesterol per LDL & HDL

particle than previously

LDL-C & HDL-C

VLDL-C

apoB

apoCII

apoE

Apo A-V

Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014

TG-rich VLDL

(CETP)

Large TG-rich LDL

Large HDL

TG

Small LDL

Hepatic Lipase(CETP)

TG

CE

CE

TG-enriched Cholesterol-depleted

particlesLipoprotein Lipase


~ LDL-C, ↑ sdLDL-C

Small & total LDL-P


Triglyceride Cholesteryl esterDayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014

TG-rich VLDL

(CETP)

Large TG-rich LDL

Smaller HDL

Large TG-rich HDL

TG

Small LDL

Hepatic Lipase

Hepatic Lipase

(CETP)

TG

CE

CE

Lipoprotein Lipase


HDL-C

HDL2-C

HDL-P

ApoA-I

Triglyceride Cholesteryl ester


Free apoA-I

Renal catabolism of apoA-I

TG-enriched cholesterol-depleted

HDL particles

Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014



► Insulin resistance leads to hepatic VLDL overproduc tion► Elevated TG, VLDL-C, non-HDL-C, VLDL-TG ► Elevated VLDL-P and large VLDL-P► Increased VLDL size► Increased remnants and remnant-cholesterol► Increased apoC-III

► Abnormal Remodeling of apoB particles►Variable LDL-C► Increased small and total LDL-P► Increased sd-LDL-C► Increased LDL-TG

► Abnormal remodeling of apoA-I particles►Low HDL-C►Decreased large and total HDL-P►Decreased HDL2-C

Lipoprotein Biomarkers: Insulin Resistance25

Dayspring T. Chapter 4 Lipoproteins in Diabetes Me llitus Jenkins, Toth, Lyons. Humana Press 2014

Incident Diabetes Biomarkers

Insulin Resistance

Pancreatic Beta-Cell DysfunctionInitial hyperinsulinemia

Later hypoinsulinemia

Hyperglycemia Dyslipidemia

Alpha-

hydroxybutyrateOleic Acid

Linoleoyl-

glycerophosphocholine

Ferritin

Proinsulin: C-peptide Ratio

C-peptide InsulinProinsulin

LeptinAdiponectin Leptin/BMI

Glucose HbA1c Fructosamine

1,5-Anhydroglucitol

Trigs HDL-C

LDL-PApo B

HDL-P

Proinsulin

Proinsulin

C-Peptide and

Insulin

Incident Diabetes and Beta-Cell Function

Enzymes cleave proinsulin into

With increasing demand for insulin (insulin resistance),

cleavage capacity becomes exhausted, resulting in

increased levels of proinsulin

Pre-Insulin

Proinsulin

Insulin

A-chain C-Peptide B-chain

A-chain

B-chainC-Peptide

Mature insulin 51 amino acids

An elevated

proinsulin/C-peptide

ratio is a marker related

to beta-cell strain*

inactive insulin precursor

(110 amino acids)

70 amino acids

*Diabetologica 2011;54(12):3047-54 Holt R. Essential Endocrinology & Diabetes 6 th Ed 2012 Swiley Blackwell



Biomarker testing 19 blood-based biomarkers and derived factors organized into three functional categories:

(1) glycemic control, (2) insulin resistance, and (3) pancreatic beta cell function can identify IR early, inform

treatment, and improve glycemic control in a enable andhigh proportion of patients

Biomarker Testing for Prediabetes

Evidence of insulin resistance and beta cell dysfunction in the normoglycemic patients is prevalent and heterogeneous

Of those patients classified as normoglycemic (glucose < 100 mg/dL and HbA1c <5.7, n=929), 82% demonstrated at least one high range biomarker of insulin resistance or beta cell function

Proportion of normoglycemic patients demonstrating high range values of each biomarker

40

30

20

10

0

J Cardiovasc Trans Res 2014;7(6):597-606

Biomarker Associated with Prediabetes

Varvel SA et al. J Cardiovasc Trans Res 2014;7(6):597 -606

Distribution of the total number of high range biomarker values observed

in normoglycemic patients

20

15

10

5

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Number of IR and beta cell biomarkers in high range per patient



Urinary Microalbumin and hs-CRP in Predicting T2DM O nset

Brantsma AH, et al. Diabetes Care 28:2525–2530, 2005

Prevention of REnal and Vascular ENd Stage

Disease (PREVEND)

> 3

1-3

< 3< 1515-30

> 30

0

2

5

6

8

10

Inci

denc

e of

T2D

M (

%)

UAE (mg/24/hr)

CRP (mg/24/hr)

Incidence of T2DM after 4.2 years of follow

up by category of Urinary Albumin

Excretion (UAE) and CRP at baseline

LIFESTYLE THERAPY RISK STRATIFICATION FOR DIABETES COMPLICATIONS

1993

ACEEndocrinology

• Maintain optimal weight

• Calorie restriction

• Plant-based diet: high polyunsaturated and monounsaturated fatty acids

• Avoid trans fatty acids; limit saturated fatty acids

• 150 min/week moderate exertion (eg. walking, stair climbing)

• Strength training

• Increase as tolerated

• About 7 hours per night

• Community engagement

• Screen for mood disorders

• No tobacco products

Nutrition

Physical Activity

Sleep

Behavioral Support

Smoking Cessation

+

+

+

+

+

+

• Structured counseling

• Meal replacement

• Structured program

• Medical evaluation/ clearance

• Medical supervision

• Screen for sleep apnea

• Refer to mental healthcare professional

• Behavioral therapy

• Structured programs

INTENSITY STRATIFIED BY BURDEN OF DISEASE AND RELATED COMPLICATIONS

Endocrine Practice 2016;22(1):103-113

1993

ACEEndocrinology

PREDIABETES ALGORITHMIFG (100-125) IGT (140-199) METABOLIC SYNDRO ME (NCEP 2001)

TREAT ASCVD RISK FACTORS

LIFESTYLE THERAPY(including Medically Assisted Weight Loss)

WEIGHT LOSS THERAPIES

ANTIHYPERGLYCEMIC THERAPIESFPG > 100 2 Hour PG > 140

1 PRE-DM CRITERION

MULTIPLE PRE-DM CRITERIA

If glycemia not normalized

GLP-1 RA

TZD

PROCEED TO HYPOGLYCEMIA

ALGORITHM

DYSLIPIDEMIA ROUTE

HYPERTENSION ROUTE

CVD RISK FACTOR MODIFICATIONS ALGORITHM

NORMAL GLYCEMIA

PROGRESSION

OVERT DIABETES

LEGEND

Orlistat, lorcaserin, phentermine/topiramate ER, naltrexone/bupropion, liraglutide 3 mg, or bariatric surgery as indicated for obesity treatment

Intensify Weight Loss

Therapies

Low-risk Medications

Consider with Caution

Metformin

Acarbose




GLYCEMIC CONTROL ALGORITHM 1993

ACEEndocrinology

LIFESTYLE THERAPY (including Medically Assisted Weight Loss)

Entry A1c < 7.5% Entry A1c ≥ 7.5% Entry A1c ≥ 9.0%

Dual Therapy

NO

ADD OR INTENSIFY INSULLIN

MONOTHERAPY*DUAL THERAPY*

TRIPLE THERAPY*

√

√

√

√

√

√

METor other 1st-line agent

METor other 1st-line agent + 2nd-line agent

GLP-1 RA

DPP4i

SGLT-2i

Colesevelam

Bromocriptine QR

TZD

Basal Insulin

SU/GLN

AGi

If not at goal in 3 months proceed

to or intensify insulin therapy

If not at goal in 3 months proceed

to or intensify triple therapy

If not at goal in 3 months proceed to or

intensify double therapy

Bromocriptine QR

SYMPTOMS

Triple Therapy

YES

OR

Insulin ±

Other Agents

Refer to Insulin Algorithm

√Few adverse events and/or possible benefits

Use with caution

LEGEND

√ GLP-1 RA

√

√

√

√

√

Basal Insulin

Colesevelam

AGi

SU/GLN

TZD

SGLT-2i

DPP-4i

GLP-1 RA

SU/GLND

SGLT-2i

DPP-4i

AGi√

√

√

√

√ Metformin

!TZD

* Order of medications listed represents a suggested hierarchy of usage: length of line reflects strength of recommendation

PROGRESSION OF DISEASE

!

!

!

!

!

!

!

!


1993

ACEEndocrinology

ASCVD RISK FACTOR MODIFICATIONS ALGORITHM

DYSLIPIDEMIA HYPERTENSION

Lifestyle Therapy (Including Medically Assisted Weight Loss)

STATIN THERAPY If TG > 500 mg/dL, fibrates, omega 3 ethyl esters, niacin

ACEior

ARB

For initial blood pressure > 150/100 mm Hg: DUAL THERAPY

Try alternate statin, lower statin dose or frequency, or add non-statin LDL-C lowering therapies

Repeat lipid panel; assess adequacy, tolerance of therapy

LIPID PANEL; Assess ASCVD Risk

HIGHRISK LEVELS

√

+Thiazide

Calcium Channel Blockerβ-blocker

ACEior

ARB

If not at goal (2-3 months)


If statin-intolerant

Add calcium channel blocker , β-blocker or or thiazide diuretic

Add next agent from above group, repeat

Additional choices (α-blockers, central agents, vasodilators,

aldosterone antagonists)

Achievement of target blood pressure is critical


GOAL: SYSTOLIC ~ 130, DIASTOLIC ~ 80 mm Hg

DESIRABLE LEVELS DESIRABLE LEVELS

LDL-C (mg/dL)Non-HL-C (mg/dL)TG (mg/dL)

TC/HDL-C (mg/dL)

ApoB(mg/dL)

LDL-P (nmol/L)

< 100

< 130< 150< 3.5

< 90

< 1200

< 70< 100< 150< 3.0< 80

< 1000

Intensify lifestyle therapy (weight loss, physical activity, dietary changes) and glycemic control; consider additional therapy

IF NOT AT DESIRABLE LEVELS

TO LOWER LDL-C:

TO LOWER Non-HDL-C, TG:

TO LOWER ApoB, LDL-P:

Intensify statin, add ezetimibe, PCSK9i, &/or colesevelam or niacin Intensify statin and/or add Rx-grade OM3 fatty acid, fibrate and/or niacin Intensify statin and/or add ezetimibe, PCSK9i, colesevelam and/or niacin

Assess adequacy & tolerance of therapy with focused laboratory evaluations and patient follow-up

* EVEN MORE INTENSIVE THERAPY MIGHT BE WARRANTED

√

√

Intensify therapies to attain goals according to risk levels

VERY HIGHDM but no other major risk and/or age <40

DM + major CVD risk(s) (HTN, Fam Hx, low HDL-C, smoking) or ASCVD*

* EVEN MORE INTENSIVE THERAPY MIGHT BE WARRANTED ** FAMILIAL HYPERCHOLESTEROLEMIA


http://www.medpagetoday.com/Cardiology/Prevention/6 2307 accessed 1/26/2017

► Liraglutide (LEADER) and empagliflozin (EMPA-REG) and the novel drug semaglutide (SUSTAIN) reduced CV events

► Bernard Zinman: “who ever thought we'd have a diabetes therapy that reduces cardiovascular death?”

► Christopher Cannon: "that new diabetes mellitus drugs can actually improve cardiovascular outcomes" the top advance of 2016 in cardiology”

► The cardiology, unlike the endocrine community has rapidly embraced the idea of using diabetes drugs for cardiovascular risk reduction

► Steve Nissen: Greater involvement by cardiologists is essential to translating the benefits observed in clinical trials to the care of individual patients.



Summary Slide

Glycemic indices are the main target goal of insulin resistance therapy

Other biomarkers can be used to assess insulin resistance before glycemic abnormalities appear

Several lipid/lipoprotein biomarkers associate with IR

There is a beneficial legacy effect even with short term treatments

AACE guidelines stress lifestyle and pharmacologic algorithms to control weight, glycemia, dyslipidemia and hypertension

Documents

Smoldering Insulin Resistance: Strategies to Optimize ... · Smoldering Insulin Resistance: Strategies to Optimize Cardiometabolic Health Thomas Dayspring, MD, FACP, FNLA, NCMP Chief