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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