What’s New in Diabetes 2019

What’s New in Diabetes 2019

Egils Bogdanovics M.D.

Marjorie

Case 1: January 11, 1922

• 12 year old Leonard Thompson, on a

starvation diet for 2 years received his first

insulin injection

• A “thick brown muck” prepared by Banting

and Best – 7.5cc in each buttock lowered

glucose from 440 to 320 and resulted in an

abscess at each injection site

Discovery of Insulin

Patient J.L., December 15, 1922 February 15, 1923

The Miracle of Insulin

• 30.3 million Americans have

diabetes (9.4% of population)

• 7.2 million are undiagnosed

• 84.1 million have prediabetes

• Cost in 2002: $132 billion total

• Cost in 2007: $174 billion total

• Cost in 2012: $245 billion total

• Cost in 2020: $490 billion total

• One out of every three Americans

born today will develop Diabetes

Diabetes 2019: An Epidemic

Diabetes in Connecticut

• 420,000 people have diabetes (11%)

• 120,000 of them don’t know it

• 1,051,000 have Prediabetes

• $ 5.3 Billion/ year cost

Case 2: T2 Metformin Failure

• 54 year old JT on MNT and metformin for

3 years

• HbA1c 7.7

• BMI 33

• Refuses injectable

2019: 12 Classes of Drugs for Type 2

Medication Route of

Administration

Year of approval HbA1c reduction

with monotherapy

Insulin Parenteral 1921 >2.5

Sulfonylureas Oral 1946 1.5

Metformin Oral 1995 1.5

Alpha-glucosidase

inhibitors

Oral 1995 0.5-0.8

Thiazoladenediones Oral 1997 0.8-1.0

Metiglinides Oral 1997 1.0-1.5

GLP-1 analogs Parenteral 2005 0.6-1.5

Amylin Analogs Parenteral 2005 0.6

DPP-IV inhibitors Oral 2006 0.5-0.9

Colesevelam Oral 2008 0.5

Bromocriptine Oral 2009 0.7

SGLT2 inhibitors Oral 2013 0.9

Guidelines

Glucose-lowering medication in type 2 diabetes: overall approach

American Diabetes Association Dia Care 2019;42:S90-S102

Glucose-lowering medication in type 2 diabetes: without established ASCVD or CKD

American Diabetes Association Dia Care 2019;42:S90-S102

Phlorizin 1835

SGLT2 Inhibition Lowers Renal Threshold

for Glucose Excretion

Case 3: T2 with CV Disease

• 62 year old male RM with T2DM x 12

years, CABG x 4, BMI 34.

• Meds: metformin, atorvastatin, lisinopril,

metoprolol, CoQ10, and ASA

• HbA1c 7.9

• UMA 1020

Diabetes and Heart Disease: Residual Risk

Cardiovascular Outcome Trials

December 2008

Completed and Ongoing CVOT

William T. Cefalu et al. Dia Care 2018;41:14-31

Glucose-lowering medication in type 2 diabetes: overall approach

American Diabetes Association Dia Care 2019;42:S90-S102

Glucose-lowering medication in type 2 diabetes: with ASCVD or CKD

American Diabetes Association Dia Care 2019;42:S90-S102

SGLT2i CVOT: Primary Endpoints

Five-year Kaplan-Meier survival estimates for 115,803 adults age ≥65 years in fee-for-service

Medicare with diabetes by incident heart failure status.

Alain G. Bertoni et al. Dia Care 2004;27:699-703

SGLT2i CVOT: CHF

Zelniker TA Lancet 2019 393:31

JJ McMurray et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1911303/ EASD September 2019

DAPA-HF

V Perkovic et al. N Engl J Med 2019;380:2295-2306/ EASD September 2019

• Primary Composite Endpoint: worsening heart failure

(hospitalization or an urgent visit resulting in intravenous

therapy for heart failure) or cardiovascular death.

• HFrEF: NYHA II,II,IV and EF <40 (ave 31)

• Non-DM n=2651 and DM n=2137

• ACE/ARB 94%

• Beta Blocker 96%

• MRA 71%

• Follow up 18.2 months

JJ McMurray et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1911303/ EASD September 2019

DAPA-HF Cardiovascular Outcomes

NNT=21

JJ McMurray et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1911303/ EASD September 2019

No Diabetes/ Diabetes Subgroup: Primary

Endpoint

No Diabetes/ Diabetes Subgroup: Primary

Endpoint

No Diabetes/ Diabetes Subgroup: Primary

Endpoint

No Diabetes/ Diabetes Subgroup:

Primary Endpoint

SGLT2i

Afferentarteriole

vasoconstriction

↓ Glomerular pressure

Early clinical markers

- initial dip in GFR

- reduction of

albuminuria

SGLT2i Exert a Hemodynamic EffectWithin the Kidney

GFR, glomerular filtration rate.Adapted from Cherney D et al. Circulation 2014;129:587-97; Skrtic M et al. Diabetologia 2014;57:2599-602.

SGLT2i

Afferentarteriole

vasoconstriction

↓ Glomerular pressure

Early clinical markers

- initial dip in GFR

- reduction of

albuminuria

By restoring tubulo-glomerular feedback, SGLT2i may

induce afferent arteriole vasoconstriction thereby

lowering glomerular hypertension with potential

nephroprotection

V Perkovic et al. N Engl J Med 2019;380:2295-2306.

CREDENCE Canagliflozin and Renal Events in Diabetes with

Established Nephropathy Clinical Evaluation

V Perkovic et al. N Engl J Med 2019;380:2295-2306.

• Primary Composite Endpoint: ESKD, Doubling

Creatinine, or Renal or CV Death

• HbA1c 8.3, eGFR 56, UMA 927

• All on RAS blockade

• Canagliflozin 100 mg daily

• Follow up 2.6 years. Stopped at planned interim

analysis

V Perkovic et al. N Engl J Med 2019;380:2295-2306.

CREDENCE: ESKD, doubling creatinine, or renal or CV death

V Perkovic et al. N Engl J Med 2019;380:2295-2306.

Subgroup Analysis, According to eGFR at Screening and

Albuminuria at Baseline

V Perkovic et al. N Engl J Med 2019;380:2295-2306.

Effects on Albuminuria and Estimated GFR

Possible Mechanisms Responsible for Cardiorenal

Protection with SGLT2 Inhibition

Rajasekeran H et al KI 2016; 89:524-6

GLP1 Receptor Analogs

1932: La Barre proposed the name “Incretin”

for an intestinal derived factor which lowered

glucose

La Barre J. Sur les possibilites d'un traitement du diabete

par l'incretine. Bull Acad R Med Belg 1932;12:620-634

Exendin-4: Exocrine gland

Endocrine function

Heloderma suspectum

GLP1RA CVOT 3pt MACE

• LEADER liraglutide HR 0.87

• SUSTAIN-6 semaglutide (inj) HR 0.74

• HARMONY albiglutide HR 0.78

LANCET 2019; 394: 121-130

REWINDResearching CV Events with a Weekly Incretin in Diabetes

• Primary Composite Endpoint: CV Death,

non-fatal MI, and non-fatal CVA

• N=9901

• 31% with established CAD

• Mean follow up 5.4 years

LANCET 2019; 394: 121-130

REWIND: 3 point MACE

LANCET 2019; 394:121-130

Rybelsus (oral semaglutide)

M Husain et al. N Engl J Med 2019;381:841-851.

Oral Semaglutide Pioneer 6

Peptide InnOvatioN for Early DiabEtEs tReatment:

Cardiovascular Outcomes

LANCET 2019; 394: 39-50

2019 SGLT2i and GLP1RA

• Glucose control

• Favorable weight effect

• Favorable hypoglycemia risk

• Cardiorenal protection

Case 4: Basal Failure

• 58 year old KL with T2DM x 11 years.

• On MNT, metformin, canagliflozin, and

insulin detemir 32 units daily

• HbA1c 8.5

• BMI 31

Xultophy: liraglutide/degludec

• In patients naïve to insulin or GLP-1RA:

begin at 10 units daily (liraglutide 0.36 mg and

degludec 10 units)

• In patients on basal insulin or GLP1RA:

begin at 16 units daily (liraglutide 0.58 mg and

degludec 16 units)

• Titrate by 2 units every 3 to 4 days. Max 50

units (1.8 mg liraglutide)

Soliqua: lixisenatide/glargine

• In patients naïve to basal insulin or to a

GLP1RA, on a GLP1RA, or currently on <30

units insulin: begin 15 units daily

• Inadequately controlled 30 to 60 units insulin:

begin 30 units daily

• Titrate by 2 to 4 units weekly. Max 60 units (20

ug lixisenatide)

Case 5: Hypo Unawareness

• 58 year old male with T1DM x 38 years.

• On MDII Tresiba and Humalog.

• HbA1c 6.8

• Hypoglycemia symptom: yawn

• Professional CGM obtained.

“Sensor Modal Day” Report

Hypoglycemia Unawareness

“with Freddie, no reaction occurred after a

blood sugar of 60 mg/dl and with Alice S.,

none occurred when the blood sugar was as

low as 40 … Dangerous hypoglycemia may

occur without warning symptoms.”

Joslin, E 1924

Hyperglycaemia

Glycaemic control: variability

BG, blood glucose

Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12

Hypoglycaemia

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24

0

6

2

4

10

12

14

16

18

22Time (hours)

BG

(m

mo

l/L

)

Patient A

36

72

108

144

180

216

252

288

324

BG

(mg/d

L)

Mean BG ≈ HbA1c 7.8%

(61.7 mmol/mol)

Patient B

Low

variability

High

variability

8

0

Hyperglycaemia

Glycaemic control: similar HbA1c, different profile

Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12

Hypoglycaemia

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 2422Time (hours)

Mean BG ≈ HbA1c 7.8%

(61.7 mmol/mol)

Low

variability

High

variability

36

72

108

144

180

216

252

288

324

BG

(mg/d

L)

00

6

2

4

10

12

14

16

18

BG

(m

mo

l/L

)

8

Patient A Patient B

Pathophysiological cardiovascular consequences of hypoglycaemia

CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor; Adapted from Desouza et al. Diabetes Care 2010;33:1389; Frier et al. Diabetes Care2011;34 (Suppl. 2):S132; 1. Wright et al. Diabetes Care 2010;33:1591; 2. Chow et al. Diabetologia 2013;56 (Suppl. 1):S243

VEGF IL-6 CRP

Neutrophil

activation

Platelet

activation Factor VIII

Blood

coagulation

abnormalities

Sympathoadrenal response

Epinephrine

Inflammation

Endothelial

dysfunction

Vasodilatation

Heart rate

variability

Rhythm

abnormalities

Haemodynamic changes

Heart workload

Contractility

Output

HYPOGLYCAEMIA

Persists for up to 48 hours1Effects last up to 7 days2

Where is the ball going?

Continuous Glucose

Monitoring (CGM) 2019

Finger Stick Monitoring 1980

The Second Revolution in Diabetes Care:

Home Glucose Monitors• Early ‘Expert’ Reaction,

1970’s:

– Too much information

– Too inaccurate

– Patients will hurt

themselves

• Limitation: point in time

value with no direction or

rate of change

Renard, Eric 2019

Current Continuous Glucose Monitoring Systems 2019

Medtronic

Guardian Connect

Freestyle Libre 14 d

Dexcom G5 and G6

Current Continuous Glucose Monitoring Systems 2019

Sensionics Eversense Implantable CGM

Using a CGM: Change in Time Spent

Within Various Glucose Ranges

100%

125%

Subjects with Baseline

A1C > 9%

Subjects with Baseline A1C

< 7%

-31.1%

27.4%

0.8%

-36.4%

94.6%*

-75%

-50%

-25%

0%

25%

50%

75%

100%

125%

<55 55-80 81-140 141-240 >240

Glucose Range (mg/dL)

Me

dia

n %

Ch

an

ge

*p < 0.05

-75%

-50%

-25%

0%

25%

50%

75%

<55 55-80 81-140 141-240 >240

Glucose Range (mg/dL)

-14.5%

8.8%

-8.5%-14.2%

-46.4%**p < 0.05

<55 141-240 >240<55 141-240

Beyond HbA1c with CGM

• Variability

• Time in Target Range

• Time in Level 1 hypoglycemia (<70 mg/dl )

• Time in Level 2 hypoglycemia (<54 mg/dl)

International Consensus on Time in Range

Battelino T, et al Diabetes Care June 2019

Time in Range

<1 <4 >70 <25 <5

HbA1c 7.2 on CSII

Sir Frederick Banting

Born November 14, 1891