Diabetes: An Update for Subspecialistsbeyondprinting.com/gims20course/uploads/1/3/0/4/...GI- maldigestion, autonomic neuropathy, sprue – Infectious diseases- increased risk + specific

David M. Nathan, M.D. January, 2020

Diabetes: An Update for Subspecialists

David M. Nathan, M.D. has no conflicts of interest.

Dualities of Interest

Prevalence of Diabetes in the U.S.

Prevalence of all diabetes 29.1 million (9.3%) Type 1 1+ million (0.4%) Type 2 28 Diagnosed 21 Undiagnosed 6 GDM >150,000 (~5-10% of all

pregnancies) Prediabetes 86 million (20%)

1,500,000 new cases per year

CDC 2015

©2015 David M. Nathan

>100,000,000 with diabetes and pre-diabetes

Consequences of Diabetes in the U.S. CDC 2015


• Most common cause of ESRD in adults • Most common cause of blindness • Most common cause of amputations • 2-5 fold increased risk for CVD • >$327 billon per year in US (ADA, 2017)

Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO, Steroids, GH Impaired glucose tolerance

G L U C O T O X I C I T Y

Glucotoxicity

Type 2 Diabetes

Decreased insulin secretion Genes, fetal environment

Fasting Hyperglycemia

“Environmental” factors responsible

for epidemic

Obesity

Sedentary


The current-day care of type 2 DM is largely directed at lowering glucotoxicity, allowing beta-cells to function better and more effectively.

Pathophysiology of Type 2 Diabetes

The best example of the potential beneficial effects of weight loss derive from bariatric

surgery where loss of 35-50% of excess weight ameliorates the majority of diabetes,

including remissions in 30-65%.

Solving- treating more effectively- the obesity “problem” is the single greatest

challenge and would be the most effective means of preventing and treating diabetes.


Risk for Development of Type 2 Diabetes

0 10 20 30 40 50 60 70 80 90

100

Effect of BMI in Women

Attained BMI

35 23 24 25 27 29 31 33 35

NHS. Ann Int Med 1995;122:481

Age-adjusted RR(%) of Developing DM over 14 yr In women aged 30-55 in 1976


Overweight 32%

Obese 38%

US 2015

Complications of Diabetes Result of Level of

Glycemia x duration Plus

other risk factors: Hypertension

Lipids Smoking

The outpatient and inpatient management of diabetes interfaces with virtually every area of

medical care

Diabetes and Subspecialties Special issues

– Cardiovascular/peripheral vascular • MI- intensive management • Foot care, ulcers, wound healing

– Renal- CKD – Neurology- peripheral, autonomic, stroke – Anesthesiology- perioperative management – Oncology- nutrition, chemotherapy, steroids – Rheumatology- steroid management – Psychiatry- atypical antipsychotics, depression,

behavior/self-care ©2017 David M. Nathan

Diabetes and Subspecialties Special issues

– GI- maldigestion, autonomic neuropathy, sprue – Infectious diseases- increased risk + specific infections – Surgery- management

• Vascular-Peripheral, cardiac, neuro • Transplantation- kidney, pancreas, heart, liver • Orthopedic- cheiropathy (adhesive capsulitis, trigger

fingers, carpal tunnel), amputations, corrective foot • Urology- bladder dysfunction, ED

– Ophthalmology- retina, cataract, glaucoma


Topics • Prevention • Management

– Outpatient • Metabolic treatment goals • Algorithm

– Inpatient – Other “special cases”


Response to an Epidemic: Prevention

IGT Type 2 DM Early Complications Morbidity/Mortality

10 20 Current 3o Prevention Intervention Diagnosis Intervention

ETDRS DRS BP Lipids Recent CVD studies

UKPDS Kumamoto

FDPS DaQing STOPNIDDM DREAM IND-DPP


Mean Weight Change from Baseline

0 6 12 18 24 30 36 42 48 Months

Lifestyle (behavioral modification)

Metformin 850 mg bid

+ Placebo

~220 min/wk ~190 min/wk

7.2%

4.2%

NEJM 2002;346: 393

DPP high risk cohort = BMI 34, IGT + IFG

Tested a behavioral lifestyle intervention that achieved a 7% weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes

Chart1

000

666

121212

181818

242424

303030

363636

424242

484848

PL

MET

LS

Weight Change (Kg)

0

0

0

-0.11

-2.26

-6.75

-0.25

-2.71

-6.67

-0.15

-2.3

-6.06

0.09

-2.05

-5.41

0.06

-1.66

-4.1

0.37

-1.2

-3.98

0.4

-1.52

-3.35

-0.11

-1.28

-3.48

Sheet1

0612182430364248

PL0-0.11-0.25-0.150.090.060.370.4-0.11

MET0-2.26-2.71-2.3-2.05-1.66-1.2-1.52-1.28

LS0-6.75-6.67-6.06-5.41-4.1-3.98-3.35-3.48

0 1 2 3 4

0

10

20

30

40

Placebo (n=1082) Metformin (n=1073, p

-15 -10 -5 0 +5

0 5

10

15

20

Haz

ard

rate

per

100

/yr

Mean weight change from baseline (kg)

Diabetes Care 2006;29:2102-2017

Effect of Weight Loss on Diabetes Prevention

Ann

ual D

iabe

tes

Inci

denc

e In the lifestyle group, every kg of weight loss was associated with a 16% reduction in risk of diabetes.

1 kg

16%

After 2.8 y of DPP ILS v PLBO 58% MET v PLBO 31%

After 10 y DPP/DPPOS 34% 18%

Other Benefits over Time with ILS (compared with placebo)

• Lower HbA1c with fewer meds • Lower BP and lipid levels with fewer meds

Lancet 2009;374:1677 NEJM 2002;346:393

Long-term Diabetes Prevention Risk Reduction

After 15 y DPP/DPPOS 27% 18% Lancet D&E 2015; 3: 866

CMS support for DPP programs effective 1/18

Treatment: Standards of Care A1c BP+ LDL* HDL TRI ADA

Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD 40 Moderate High Moderate intensity statin can also be considered for patients w/o CVD but with risk factors (LDL >100, hypertension, smoking, CKD, albuminuria, family history or premature CVD) Moderate = atorva 10-20, rosuva 5-10, simva 20-40 High intensity = atorva 40-80, rosuva 20-40, add PCSK-9 or ezetemibe if LDL > 70 mg/dl


DCCT Retinopathy Results

DCCT Research Group NEJM 1993;342:381

Primary Prevention Secondary Intervention

76% 54%

2%

Metabolic Therapy and Type 1 Diabetes

“Intensive” therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible.

Long-term follow-up of DCCT showed: ~ 50% reduction of late-stage, severe complications (e.g. need for eye surgery, CKD-3 or worse, CVD events).

Mortality reduced by 33%.

Setting Treatment Goals: Glycemia & Microvascular

Risk Reduction with Intensive vs conventional therapy (%)

DCCT(6.5y) M I c r o a l b u m I n N e u r o p a t h y

R e t i n o p a t h y

T Y P E

2

T Y P E

1

UKPDS (10y) Sev. Microvasc

ACCORD (4y)

VADT(5.6y) A l b u m I n u r I a

R e t I n o p a t h y

Kumamoto(6y)

ADVANCE (5y) Microva

R e t i n o p a t h y M I c r o a l b u m I n

-30 -20 -10 0 10 20 30 40 50 60 70 80


2.0%

A1C difference

0.9%

1.1%

1.5%

0.7%

2.3%

Reduction in microvascular complications roughly proportional to A1c reduction.

UKPDS

Lancet 1998; 352: 837

Intensive Therapy and Type 2 Diabetes 7.9%

7.0% 0.9% 5102

Age 53 “New-onset” No prior CVD 10-yr median f/u 25% reduction in advanced complications during UKPDS. Continued benefit with 10 more years follow-up.

:laser, vitreous hem., renal failure

10-yr further f/u “Legacy” Effect

UKPDS

First 10 years of UKPDS

Relationship between Glycemia and Complications

DCCT and UKPDS

Current Mean HbA1c (%)

Event Rate per

1000 Pt-Y DCCT

UKPDS

43% reduction in risk for every 10%

decrease in HbA1c

37% reduction in risk for every 1%

decrease in HbA1c


?

Chart1

55

5.55.5

66

6.56.5

77

7.57.5

88

8.58.5

99

9.59.5

1010

10.510.5

1111

11.511.5

1212

DCCT

UKPDS

8

5

10

10

18

15

38

23

60

40

105

58

160

Sheet1

55.566.577.588.599.51010.51111.512

DCCT810183860105160

UKPDS51015234058

Selecting Metabolic Goals • HbA1c ~7% substantially reduces microvascular

complications; limited data in HbA1c range

ADA Standards of Care Diabetes Care 2019;42 (Suppl 1)

Two major premises: 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease, use specific drugs demonstrated in recent CVOTs (SGLT-inhib, GLP-agonists).

Diabetologia 2009; 52:17-30 Diabetes Care 2009;32:193-203

How to Achieve Metabolic Goals

Development of Medications Used in the Treatment of Type 2 Diabetes

1922 1936 1942 1950 1995 1997 2000 2004 2005 2006 20072009 2013

INSULIN

S U L F O N Y L U R E A

M O D I F I E D

I N S U L I N

B I G U A N I D E S

73 YEARS

I N S

A N A L O G S

A G I

T Z D S

G L P

A G O N I S T S

D P P 4 I N H I B

P R A M L I N T I D E

W E L C H O L

C Y C L O S E T

M E T F O R M I N

US

18 YEARS

2

8 7 4

S G L T 2 I N H 4

Major Premises

• Effectiveness in lowering A1c – Use more effective drugs if initial A1c higher – Can use less effective medications if A1c < 8.5

• Safety • Side-effects, tolerability/acceptance • Other characteristics, effect (s) on

– Weight – CVD risk factors – Beta-cell preservation

• Cost

Selection of Interventions


Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c: Potency of Monotherapy

HbA1c %


21st Century 20th Century

Chart1

AGIs

SGLT-2 inh

DPP-4 inh

Pramlintide

GLP-agonist

TZD

Sulfonylurea

Metformin

Insulin

-0.5

-0.6

-0.7

-0.7

-1

-1

-1.5

-1.5

-2.5

Sheet1

SymilinAGIsSGLT-2 inhDPP-4 inhPramlintideGLP-agonistTZDSulfonylureaMetforminInsulin

-0.5-0.6-0.7-0.7-1-1-1.5-1.5-2.5

Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms

Class Primary Mechanism Insulin

Sulfonylureas

“Glinides”

Biguanides (metformin)

Thiazolidinediones

Alpha-glucosidase inhibitors Amylin-mimetics

(pramlintide)

Incretin agonists

DPP-IV inhibitors

SGLT-2 inhibitors

Insulin Supply

Liver sensitivity(HGO) Peripheral sensitivity

GI absorption rate

GI motility

Glycosuria ©2019 David M. Nathan

Insulin Supply

Insulin Supply

Insulin Supply Insulin Supply


DPP4 Inh, SGLT2-Inh

Therapy of Type 2 Diabetes

• Highly effective in short term • 5-10 lb weight loss usually sufficient to ameliorate

hyperglycemia • Long-term benefit parallels results of obesity therapy • More effective lifestyle interventions (such as those used

in DPP or LookAHEAD) are available, but require more effort than the usual “diet”

Lifestyle: Diet and Exercise


% W

eigh

t cha

nge

from

bas

elin

e

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4Year

DSE

ILI19 lb

8.5 lb

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0 1 2 3 4Year

DSE

ILI

% A

1c c

hang

e fr

om b

asel

ine

Effects of Behavioral Intervention 7.3%

6.6%

7.0%

Fewer diabetes medications

Weight HbA1c

Chart11

000000

110.290.280.280.28

220.290.280.290.28

330.280.290.280.28

440.290.290.280

DSE

ILI

Year

0

0

-0.63

-8.5

-0.93

-6.35

-0.92

-5.04

-1.01

-4.66

HDL

HDL

DSEILI

000

1.35Year 13.381

1.93Year 23.792

2.05Year 33.583

2.58Year 43.954

DSE -DSE +

00

0.270.28

0.310.31

0.320.31

0.330.33

ILI -ILI +

00

0.280.27

0.310.3

0.320.32

0.340.33

HDL

0000

0.280.270.270.28

0.310.310.30.31

0.320.320.320.32

0.340.330.330.34

DSE

ILI

Year

DBP

DBP

DSEILIYear

000

-1.66-3.11

-2.21-2.722

-2.73-2.783

-3.44-3.194

DSE -DSE +

00

0.30.31

0.320.32

0.320.33

0.330.33

ILI -ILI +

00

0.30.3

0.320.32

0.320.33

0.330.33

DBP

0000

0.310.30.30.3

0.320.320.320.32

0.330.320.330.32

0.330.330.330.33

DSE

ILI

Year

A1c

A1c

DSEILIYear

000

-0.12-0.641

-0.09-0.372

-0.1-0.263

-0.08-0.24

DSE -DSE +

00

0.030.04

0.050.04

0.050.04

0.050.05

ILI -ILI +

00

0.030.04

0.040.05

0.040.05

0.050.05

A1c

0000

0.040.030.040.03

0.040.050.050.04

0.040.050.050.04

0.050.050.050.05

DSE

ILI

Year

SBP

SBP

DSEILIYear

000

-2.36-7.081

-3.11-5.012

-3.17-4.753

-3.41-4.664

DSE -DSE +

00

0.590.59

0.620.63

0.660.66

0.670.68

ILI -ILI +

00

0.590.58

0.620.62

0.660.66

0.670.67

SBP

0000

0.590.590.580.59

0.630.620.620.62

0.660.660.660.66

0.680.670.670.67

DSE

ILI

Year

Non-HDL

Non-HDL

DSEILIYear

000

-8.12-10.761

-14.15-14.12

-19.86-18.743

-23.77-21.324

DSE -DSE +

00

1.211.21

1.381.37

1.41.39

1.411.41

ILI -ILI +

00

1.211.2

1.361.36

1.391.39

1.391.4

Non-HDL

0000

1.211.211.21.21

1.371.381.361.36

1.391.41.391.39

1.411.411.41.39

DSE

ILI

Year

LDL

LDL

DSEILIYear

000

-5.64-5.251

-11.24-9.572

-16.14-14.023

-18.88-16.774

DSE -DSE +

00

1.051.05

1.181.17

1.191.18

1.191.2

ILI -ILI +

00

1.041.04

1.161.16

1.171.17

1.181.19

LDL

0000

1.051.051.041.04

1.171.181.161.16

1.181.191.171.17

1.21.191.191.18

DSE

ILI

Trig

Trig

DSEILIYear

000

-15.25-29.631

-17.14-24.912

-19.73-25.73

-27.51-22.94

DSE -DSE +

00

2.982.97

3.283.27

3.63.6

4.224.22

ILI -ILI +

00

2.972.97

3.243.25

3.583.57

4.184.18

Trig

0000

2.972.982.972.97

3.273.283.253.24

3.63.63.573.58

4.224.224.184.18

DSE

ILI

Weight Chg

Weight Change

DSEILIYear

000

-0.63-8.51

-0.93-6.352

-0.92-5.043

-1.01-4.664

DSE -DSE +

00

0.280.29

0.280.29

0.290.28

0.290.29

ILI -ILI +

00

0.280.28

0.280.29

0.280.28

00.28

Weight Chg

0000

0.290.280.280.28

0.290.280.290.28

0.280.290.280.28

0.290.290.280

DSE

ILI

Chart8

000000

110.040.030.040.03

220.040.050.050.04

330.040.050.050.04

440.050.050.050.05

DSE

ILI

Year

0

0

-0.12

-0.64

-0.09

-0.37

-0.1

-0.26

-0.08

-0.2

HDL

HDL

DSEILI

000

1.35Year 13.381

1.93Year 23.792

2.05Year 33.583

2.58Year 43.954

DSE -DSE +

00

0.270.28

0.310.31

0.320.31

0.330.33

ILI -ILI +

00

0.280.27

0.310.3

0.320.32

0.340.33

HDL

0000

0.280.270.270.28

0.310.310.30.31

0.320.320.320.32

0.340.330.330.34

DSE

ILI

Year

DBP

DBP

DSEILIYear

000

-1.66-3.11

-2.21-2.722

-2.73-2.783

-3.44-3.194

DSE -DSE +

00

0.30.31

0.320.32

0.320.33

0.330.33

ILI -ILI +

00

0.30.3

0.320.32

0.320.33

0.330.33

DBP

0000

0.310.30.30.3

0.320.320.320.32

0.330.320.330.32

0.330.330.330.33

DSE

ILI

Year

A1c

A1c

DSEILIYear

000

-0.12-0.641

-0.09-0.372

-0.1-0.263

-0.08-0.24

DSE -DSE +

00

0.030.04

0.050.04

0.050.04

0.050.05

ILI -ILI +

00

0.030.04

0.040.05

0.040.05

0.050.05

A1c

0000

0.040.030.040.03

0.040.050.050.04

0.040.050.050.04

0.050.050.050.05

DSE

ILI

Year

SBP

SBP

DSEILIYear

000

-2.36-7.081

-3.11-5.012

-3.17-4.753

-3.41-4.664

DSE -DSE +

00

0.590.59

0.620.63

0.660.66

0.670.68

ILI -ILI +

00

0.590.58

0.620.62

0.660.66

0.670.67

SBP

0000

0.590.590.580.59

0.630.620.620.62

0.660.660.660.66

0.680.670.670.67

DSE

ILI

Year

Non-HDL

Non-HDL

DSEILIYear

000

-8.12-10.761

-14.15-14.12

-19.86-18.743

-23.77-21.324

DSE -DSE +

00

1.211.21

1.381.37

1.41.39

1.411.41

ILI -ILI +

00

1.211.2

1.361.36

1.391.39

1.391.4

Non-HDL

0000

1.211.211.21.21

1.371.381.361.36

1.391.41.391.39

1.411.411.41.39

DSE

ILI

Year

LDL

LDL

DSEILIYear

000

-5.64-5.251

-11.24-9.572

-16.14-14.023

-18.88-16.774

DSE -DSE +

00

1.051.05

1.181.17

1.191.18

1.191.2

ILI -ILI +

00

1.041.04

1.161.16

1.171.17

1.181.19

LDL

0000

1.051.051.041.04

1.171.181.161.16

1.181.191.171.17

1.21.191.191.18

DSE

ILI

First Step- Metformin + Lifestyle • Recognizes failure of life-style alone • Inhibits hepatic glucose output- predominantly lowers

fasting glycemia • Lowers HbA1c by ~1.5% • Effective in obese and non-obese patients and in

preventing diabetes in pre-diabetics (DPP) • Extremely safe, generally well-tolerated including

down to eGFR as low as 45 ml/min • Glucophage off-patent, very inexpensive



DPP4 Inh, SGLT2-Inh

A1c >7% or not at goal

“Intensive” usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin



DPP4 Inh, SGLT2-Inh


GLP and DPP4 Inhibitors • Stimulate insulin

secretion • Suppress glucagon • Slow motility • Lower A1c by ~1.0% • Injections twice per

day • Weight loss of ~ 6 lb • Associated with

nausea, vomiting, diarrhea- ~40%

• CVD benefit with lira- and semaglutide

• Expensive

• Inhibit breakdown of endogenous GLP, raising levels by ~2-fold

• Decrease A1c by ~0.6% • Oral medication • No weight loss • No GI side-effects • Neutral for CVD • Expensive

GLP and its Analogues DPP 4 Inhibitors


GLP and DPP4 Inhibitors


• SAVOR (saxagliptin): increased CHF hospitalizations • EXAMINE (alogliptin): no risk • TECOS (sitagliptin): no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists • LEADER: CVD Benefit with liraglutide • SUSTAIN: CVD Benefit with semaglutide • ELIXA: NO Benefit with lixisenatide • EXCSEL: NO Benefit with Exenatide-LAR.

Results of CVOTs DPP-4 inhibitors


Newest Medication: SGLT-2 inhibitors


– Inhibits re-absorption of glucose in proximal tubule – Limited lowering of BG on basis of glycosuria – Lowers A1c by ~0.6 – ? Added benefit- +/- lower BP, minor weight loss – Added risk- vaginitis, UTIs – Dapagliflozin, canagliflozin, empagliflozin – CVD benefit with empagliflozin and canagliflozin – Increased risk of amputations with canagliflozin

Newest Medication: SGLT-2 inhibitors

Glycemic Potency vs Costs Decrease in HbA1c: Potency of Monotherapy vs Cost

HbA1c %


21st Century 20th Century

$ $ $$

$$ $$

$$ $$

$$ $$

$$ $$

$$ $$

$$ $

$88 411 400 300 770 322 4 4 130/300 Average cost/mo

NPH-Relion $25

Are the new drugs “worth it”?

Chart1

AGIs

SGLT-2 inh

DPP-4 inh

Pramlintide

GLP-agonist

TZD

Sulfonylurea

Metformin

Insulin

-0.5

-0.6

-0.7

-0.7

-1

-1

-1.5

-1.5

-2.5

Sheet1

SymilinAGIsSGLT-2 inhDPP-4 inhPramlintideGLP-agonistTZDSulfonylureaMetforminInsulin

-0.5-0.6-0.7-0.7-1-1-1.5-1.5-2.5

Treat to Target Trial, Riddle et al. Diabetes Care 2003; 26:30380

756 T2DM with A1c >7.5% (baseline A1c 8.6%) on OA

Is Glargine better than NPH? FPG (mg/dl)

A1c (%) PG < 56 mg/dl

PG < 72 mg/dl

Singh, SR CMAJ 2009;180:385

Updated Meta-analysis Long-acting Analogues vs Non-analogues: 49 RCTs


The consensus for T2DM is that compared with NPH, long-acting analogues: • Don’t reduce HbA1c (nominally higher) • Reduce the frequency of nocturnal hypoglycemia modestly • The frequency of total hypoglycemia is about the same • Severe hypoglycemia is very rare and generally no

different

If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue. Advanced CVD. TZDs No hypos Edema, CHF, Never? NASH CVD risk, Expensive SGLT- No hypos. Weak, DKA Mild DM Inhib. Dec. BP UTIs, yeast Advanced CVD, Expensive CHF, CKD


• Almost 20% of MGH inpatients have diagnosis of diabetes

• An additional 9% have undiagnosed diabetes • Average stay is 20% longer than non-diabetics

Inpatients with Diabetes Background

Wexler, Nathan, Cagliero JCEM 2008;93: 4238 ©2005 David M. Nathan

Adversely affects: • Schedule- late, missed meals • Diet- different • Medications- changed, delayed, held • Activity- less • Monitoring- different • Stress- more • Self-care- gone

Barriers to Good Care for Inpatients with Diabetes

Impact of Hospitalization


Principles of Inpatient Care for Persons with Diabetes

• Maintain metabolic control in a safe, acceptable range- probably 80-200 mg/dl – Avoid large fluctuations in blood glucose that would

lead to dehydration, hypoglycemia; prevent DKA – Never stop insulin in type 1 – Usually stop oral agents in type 2, cover with insulin – Basal insulin recommended

• Protect feet • Decrease risk of macrovascular and

microvascular “events”- heart, kidney ©2019 David M. Nathan

Effect of Intensive Insulin Therapy in Critically Ill SICU Patients • 1548 ventilated

surgical ICU patients • 63% s/p cardiac surgery • Randomized to:

-Conventional therapy goal 180-200 mg/dL - Intensive therapy with insulin infusions if BG > 110 mg/dL to keep bg 80-110 All patients received ~9 g IV glucose/hr followed by enteral or parenteral feeding.

• After discharge from ICU, target 180-200 mg/dL for all.

Van den Berghe Crit Care Med 2003;31:359

van den Berghe G N Engl J Med. 2001;345:1359–1367.

Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival

van den Berghe G N Engl J Med. 2001;345:1359–1367.

Survival in ICU (%)

100

96

92

88

80

84

0 20 40 60 80 100 120 140 160

Intensive treatment

Conventional treatment

Days After Admission

• Intensive therapy reduced mortality by 43% (4.6 vs 8%) • Bacteremia, antibiotic use,

polyneuropathy, duration of ventilation, and multi-organ failure reduced .

Subsequent Studies: No benefit of intensive insulin in sepsis • Mean am glucose 112

vs 151 mg/dl • No difference in death or

organ failure at 28 days • Stopped early for

increased hypoglycemia (17% vs 4%) in intensive group

Goal 80-110 mg/dl

Goal 180-200 mg/dl

Brunkhorst, NEJM 2008.

Subsequent Studies: NICE-SUGAR Study

• Multicenter trial in Canada and Australia

• 6104 patients • Mean glucose of 115

versus 144 mg/dl • Increased mortality (2.6%)

in intensive control group • Severe hypoglycemia in

6.8% versus 0.5%

N Engl J Med 2009; 360:1283-97

MBG 144 mg/dl

MBG 115 mg/dl

Prob

abili

ty o

f sur

viva

l

Medical and Surgical ICU Patients

Summary of Current Evidence

• Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- ?causal, ?marker of disease severity

• Normalizing glycemia in intensive care units with inconsistent results; several meta-analyses have shown no mortality benefit, a decrease in post-op infections but with more hypoglycemia

• Almost no data to demonstrate role of tight glucose control in non-critically ill patients

Inpatient Management of Glycemia


American College of Physician 2011: “not using intensive insulin therapy to strictly control blood glucose”

Target glucose levels of 80-110 mg/dl

ADA 2019

140-180 mg/dl ICU & Non-ICU


Special “Cases”

• Glucocorticoids used in pharmacologic doses (e.g. prednisone > 10 mg/day, dexamethasone > 1mg/day) can precipitate diabetes or raise BG

• The hyperglycemic effect of prednisone has the same time course as NPH insulin

• NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy

Glucocorticoids


Special “Cases”

• Mechanisms unclear, but associated with weight gain, insulin resistance and β-cell failure

• May precipitate, worsen DM, cause DKA • Advisable to check a HbA1c prior to initiation and follow BG carefully • Insulin may be necessary if psych medications can’t be changed

Atypical Antipsychotics: olanzapine, clozapine, quetiapine and others


Conclusions • Diabetes, and especially type 2, affects a substantial

minority of the inpatient and outpatient population • Owing to its frequency and effects on virtually every

aspect of clinical medicine, practitioners should be familiar with its prevention, diagnosis, and treatment

• Endocrinologists can’t do it all on our own


Diabetes: An Update for SubspecialistsSlide Number 2Prevalence of Diabetes in the U.S.Slide Number 4Pathophysiology of Type 2 DiabetesSlide Number 6Slide Number 7Slide Number 8Diabetes and SubspecialtiesDiabetes and SubspecialtiesTopicsSlide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Treatment: Standards of CareTreatment with StatinsSlide Number 21Slide Number 22Slide Number 23Slide Number 24Selecting Metabolic GoalsSlide Number 26Slide Number 27Development of Medications Used in the Treatment of Type 2 DiabetesMajor PremisesSlide Number 30Anti-Hyperglycemic Agents in Type 2 DiabetesSlide Number 32Slide Number 33Effects of Behavioral InterventionFirst Step- Metformin + LifestyleSlide Number 36Slide Number 37GLP and DPP4 InhibitorsGLP and DPP4 InhibitorsNewest Medication: SGLT-2 inhibitorsNewest Medication: SGLT-2 inhibitorsSlide Number 42Slide Number 43Slide Number 44Slide Number 45If you Use a New DrugInpatients with Diabetes Barriers to Good Care for Inpatients with Diabetes Principles of Inpatient Care for Persons with DiabetesSlide Number 50Slide Number 51Subsequent Studies:�No benefit of intensive insulin in sepsisSubsequent Studies: NICE-SUGAR StudySummary of Current EvidenceSlide Number 55Special “Cases”Special “Cases”Conclusions

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