type 2 diabetes update - internal medicine...in type 2 diabetes 17 normal glucose tolerance (n=8)...

10/9/2019

1

Type 2 Diabetes Update

1

• Donald Eagerton M.D., F.A.C.P., F.A.C.E.

• September 2019

Disclosures

• I have served as an investigator for or speaker

for the following: NovoNordisk, Ely Lilly,

Boehringer Engleheim, Aventis, Abbott,

Merck, Sanofi Aventis, BMS,

• I was a site investigator for the LEADER,

DEVOTE, SUSTAIN, LIXI, PIONEER, and

EMPA-REG trials

1

2

10/9/2019

2

The Burden of Diabetes

3

Prevalence of Diabetes and

Prediabetes in the United States

4

1. CDC. National diabetes fact sheet, 2008. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2008.pdf.

2. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.

3. CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf

Prediabetes

37% of US population

Diabetes

9.1% of US population

57

79 86

17.9

18.821.0

5.7

7.8.1

0.

30.

60.

90.

120.

150.

2007 2011 2014

Pers

on

s (

mil

lio

ns

)

Undiagnosed DM

Diagnosed DM

Prediabetes

1 2 3

3

4

10/9/2019

3

6.6 12. 21.37.9

55.571.2

86.6

0.

22.5

45.

67.5

90.

112.5

1990 2000 2010 2020 2030 2040 2050

Nu

mb

er

(mil

lio

ns

)

Diagnosed

Projected Prevalence of Diabetes in

the United States: 1990 to 2050

5

1. National Diabetes Surveillance System. http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. 2. CDC. National diabetes fact

sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. 3. Boyle JP, et al. Popul Health Metr. 2010 Oct 22;8:29.

Year

1 1 2 3 3 3 3

T2D Prevalence Parallels

Prevalence of Obesity

6

0.

15.

30.

45.

60.

75.

1980 1994 2000 2008 2010 2012

BMI, body mass index (in kg/m2); CDC, Centers for Disease Control and Prevention; NHANES, National Health and Nutrition Examination

Survey (x-axis lists last year of each survey); T2D, type 2 diabetes.

*NHANES 1994 data.

Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47. Flegal KM, et al. JAMA. 2002 ;288:1723-1727. Flegal KM, et al. JAMA.

2010;303:235-241. Flegal KM, et al. JAMA. 2012;307:491-497. Ogden CL, et al. JAMA. 2014;311:806-814. Harris MI, et al. Diabetes Care.

1998;21:518-524. CDC. Diabetes data & trends. Available at: http://www.cdc.gov/diabetes/statistics/prev/national/figraceethsex.htm and

http://www.cdc.gov/diabetes/statistics/prev/national/fighispanicthsex.htm.

0.

2.5

5.

7.5

10.

12.5

1980 1994* 2000 2008 2010 2011

White men

White women

Black men

Black women

ObeseNHANES Data,

U.S. Adults ≥20 Years

Diagnosed DiabetesCDC Data,

U.S. Population

Po

pu

lati

on

(%

)

5

6

10/9/2019

4

Increase in Diabetes Parallels the

Increase in Obesity in the United States

7*BMI ≥30 kg/m2.

CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease

Control and Prevention, 2014. Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283;

Ogden CL, et al. JAMA. 2014;311:806-814.

Obesity* Diabetes

17.9

35.1

0.

9.

18.

27.

36.

45.

1998 2012

Po

pu

lati

on

(%

)

96% increase

6.5

9.3

0.

3.

6.

9.

12.

1998 2014

43% increase

Po

pu

lati

on

(%

)

• 7th leading cause of death

in US

• Leading cause of

blindness

• Most frequent cause of

kidney failure

• ~60% of nontraumatic

lower limb amputations

occur in people with

diabetes

• Diabetes also

– Doubles the risk of

periodontal disease

– Doubles the risk of

developing depression

• Depression increases T2D

risk by 60%

– Increases patients’

susceptibility to acute illness

(eg, pneumonia and

influenza)

• Worsens the prognosis of

patients with acute illnesses

Diabetes Morbidity and Mortality

8

CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.

CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.

7

8

10/9/2019

5

Diabetes and Morbidity and Mortality

9

1.5

1.7

1.8

1.5

0. 0.5 0.9 1.4 1.8 2.3

All-cause death

CVD death

Myocardial infarction

Stroke

Risk increase

(relative to individuals without diabetes)

CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-

diabetes-report-web.pdf

Costs of Diabetes

10

$176

$23$44

$244

$69

$9

0.

75.

150.

225.

300.

Diagnosed Undiagnosed Prediabetes Total*

US

Do

llars

(b

illio

ns)

Indirect

Direct

*Includes $1.3 billion in costs from gestational diabetes.

Dall TM, et al. Diabetes Care. 2014;37:3172-3179.

2012 Burden Estimate

9

10

10/9/2019

6

Development of Type 2 Diabetes Depends on Interplay

Between Insulin Resistance and β-Cell Dysfunction

11

Insulin resistance

Insulin resistance

Abnormalβ-Cell

Function

Relative insulin deficiency

Gerich JE. Mayo Clin Proc. 2003;78:447-456.

Type 2 diabetes

Normalβ-Cell

Function

Compensatory hyperinsulinemia

No diabetes

Genes &

environment

Genes &

environment

• Age ≥45 years

• Family history of T2D or

cardiovascular disease

• Overweight or obese

• Sedentary lifestyle

• Non-Caucasian ancestry

• Previously identified IGT, IFG,

and/or metabolic syndrome

• PCOS, acanthosis nigricans, or

NAFLD

• Hypertension (BP >140/90 mmHg)

• Dyslipidemia (HDL-C <35 mg/dL

and/or triglycerides >250 mg/dL)

• History of gestational diabetes

• Delivery of baby weighing

>4 kg (>9 lb)

• Antipsychotic therapy for

schizophrenia or severe bipolar

disease

• Chronic glucocorticoid exposure

• Sleep disorders

– Obstructive sleep apnea

– Chronic sleep deprivation

– Night shift work

Risk Factors for Prediabetes and

Type 2 Diabetes

12

BP, blood pressure; HCL-C, high density lipoprotein cholesterol; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAFLD,

nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes.

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

11

12

10/9/2019

7

Natural History of Type 2 Diabetes

13Figure courtesy of CADRE.

Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349;

UKPDS Group. Diabetes. 1995;44:1249-1258

Fasting glucose

Type 2 diabetes

Years from

diagnosis0 5–10 –5 10 15

Prediabetes

Onset Diagnosis

Postprandial glucose

Macrovascular complications

Microvascular complications

Insulin resistance

Insulin secretion

b-Cell function

Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data.

Data points from obese UKPDS population, determined by HOMA model.

Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.

b-cell Loss Over Time

14

UKPDS

Type 2 Diabetes

b-C

ell

Fu

nc

tio

n (

%)

Years from Diagnosis

25 –

100 –

75 –

0 –

50 –

l

-12

l

-10

l

-6l

-2

l

0

l

2

l

6

l

10

l

14

PostprandialHyperglycemia

Impaired Glucose

Tolerance

13

14

10/9/2019

8

Tissues Involved in T2D

Pathophysiology

16

Organ System Normal Metabolic Function Defect in T2D

Major Role

Pancreatic beta cells Secrete insulin Decreased insulin secretion

Muscle Metabolizes glucose for energy Inefficient glucose uptake

Liver

Secretes glucose during fasting periods to maintain

brain function; main site of gluconeogenesis (glucose

production in the body)

Increased endogenous glucose

secretion

Contributing Role

Adipose tissue (fat)

Stores small amounts of glucose for its own use. When

fat is broken down, glycerol is released, which is used

by the liver to produce glucose

Increased FFA production

Digestive tractDigests and absorbs carbohydrates and secretes

incretin hormonesDecreased incretin effect

Pancreatic alpha cells

Secrete glucagon, which stimulates hepatic glucose

production between meals and also helps suppress

insulin secretion during fasting periods

Increased glucagon secretion

Kidney

Reabsorbs glucose from renal filtrate to maintain

glucose at steady-state levels; also an important site for

gluconeogenesis (glucose production)

Increased glucose reabsorption

BrainUtilizes glucose for brain and nerve function

Regulates appetiteNeurotransmitter dysfunction

T2D, type 2 diabetes.

DeFronzo RA. Diabetes. 2009;58:773-795

15

16

10/9/2019

9

*P≤.05.

Nauck M, et al. Diabetologia. 1986;29:46-52.

The Incretin Effect Is Diminished

in Type 2 Diabetes

17

Normal Glucose Tolerance

(n=8)

Type 2 Diabetes

(n=14)

IV Glucose

Oral Glucose

0 60 120 180

240

Pla

sm

a G

luc

os

e (

mg

/dL

)

180

90

0

0 60 120 180

Pla

sm

a G

luc

os

e (

mg

/dL

) 240

180

90

0

**

* **

* * *

0 60 120 180

C-P

ep

tid

e (

nm

ol/

L)

Time (min)

30

20

10

00 60 120 180

C-p

ep

tid

e (

nm

ol/

L)

Time (min)

30

20

10

0

Acute Insulin Response Is Reduced in

Type 2 Diabetes

18

IRI, immunoreactive insulin.

Pfeifer MA, et al. Am J Med. 1981;70:579-588.

Pla

sm

a I

RI

(µU

/ml)

Time (minutes)

20 g glucose infusion

2nd phase1st

-300

20

40

60

80

100

0 30 60 90 120

120Normal (n=85)

Type 2 diabetes (n=160)

17

18

10/9/2019

10

Müller WA, et al. N Engl J Med. 1970;283:109-115.

Normal Glucose Homeostasis and Pre- and

Postmeal Insulin and Glucagon Dynamics

19

Premeal Postmeal

Insulin Insulin

Glucagon

HGP

Glucagon

HGP

Just enough glucose to meet metabolic

needs between meals

Modest postprandial increase with

prompt return to fasting levels

Glucose (mg %)

Glucagon (pg/mL)

Time (min)

-60 0 60 120 180 240

Meal120

90

60

30

0

140

130

120

110

100

90

Insulin (µU/mL)

360

330

300

270

240

110

80

Normal (n=11)

Hyperglycemia in Type 2 Diabetes Results from

Abnormal Insulin and Glucagon Dynamics

20

Premeal Postmeal

Insulin Insulin

Glucagon

HGP

Glucagon

HGP

FPG PPGGlucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Time (min)

-60 0 60 120 180 240

Meal120

90

60

30

0

140

130

120

110

100

90

360

330

300

270

T2D (n=12)

Normal (n=11)

240

110

80

T2D, type 2 diabetes.

Müller WA, et al. N Engl J Med. 1970;283:109-115.

19

20

10/9/2019

11

Actions of GLP-1 and GIP

GLP-1

• Released from L cells in ileum and colon

• Stimulates insulin release from b-cell in a glucose-dependent manner

• Potent inhibition of gastric emptying

• Potent inhibition of glucagon secretion

• Reduction of food intake and body weight

• Significant effects on b-cell growth and survival

GIP

• Released from K cells in duodenum

• Stimulates insulin release from b-cell in a glucose dependent manner

• Minimal effects on gastric emptying

• No significant inhibition of glucagon secretion

• No significant effects on satiety or body weight

• Potential effects on b-cell growth and survival

21

Drucker DJ. Diabetes Care 2003;26:2929-2940.

21

22

10/9/2019

12

Renal Glucose Reabsorption

in Type 2 Diabetes

• Sodium-glucose cotransporters 1 and 2 (SGLT1

and SGLT2) reabsorb glucose in the proximal

tubule of kidney

– Ensures glucose availability during fasting periods

• Renal glucose reabsorption is increased in type 2

diabetes

– Contributes to fasting and postprandial hyperglycemia

– Hyperglycemia leads to increased SGLT2 levels, which

raises the blood glucose threshold for urinary glucose

excretion

23

Wright EM, et al. J Intern Med. 2007;261:32-43.

90% of glucose

SGLT1

(180 L/day) (90 mg/dL) = 162 g glucose per day

10% of glucose

Glucose

No Glucose

S1

S3

Normal Renal Handling of Glucose

24

SGLT2

Abdul-Ghani MA, et al. Endocr Pract. 2008;14:782-790.

23

24

10/9/2019

13

Increased SGLT2 Protein Levels Change

Glucose Reabsorption and Excretion Thresholds

25

TmG, glucose transport maximum.

Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.

27090

Ren

al

Glu

co

se R

eab

so

rpti

on

TmG

180

TmG

Blood Glucose Concentration (mg/dL)

Reabsorption

increases

27090 180

Blood Glucose Concentration (mg/dL)

Excretion

threshold

increases

Ren

al

Glu

co

se E

xcre

tio

n

Reabsorption Excretion

Hypothalamic Dopaminergic Tone

and Autonomic Imbalance

26

In diabetes:

Low dopaminergic tone in

hypothalamus in early morning

Sympathetic tone

HPA axis tone

Hepatic gluconeogenesis

FFA and TG

Insulin resistance

Inflammation/hypercoagulation

Impaired glucose metabolism

Hyperglycemia

Insulin resistance

Adverse cardiovascular pathology

20Fonseca V. Dopamine Agonists in Type 2 Diabetes. New York, NY: Oxford University Press; 2010.

Cincotta AH. In: Hansen B, Shafrir E, eds. Insulin Resistance and Insulin Resistance Syndrome. New York, NY: Taylor &

Francis; 2002:271-312.

25

26

10/9/2019

14

AACE Comprehensive Care PlanComprehensive Care Plan

Disease

managemen

t from a

multidisciplin

ary team

Antihypergly

cemic

pharmacoth

erapy

Comprehen

sive

diabetes

self-

education

for the

patient

Therapeutic

lifestyle

change


27

THERAPEUTIC LIFESTYLE

CHANGE

Glycemic Management of Type 2 Diabetes

28

27

28

10/9/2019

15

Components of Therapeutic Lifestyle

Change

• Healthful eating

• Sufficient physical activity

• Sufficient sleep

• Avoidance of tobacco products

• Limited alcohol consumption

• Stress reduction


29

AACE Recommendations:

Therapeutic Lifestyle Changes

Parameter Treatment Goal

Weight loss(for

overweight and

obese patients)

Reduce by 5% to 10%

Physical activity150 min/week of moderate-intensity exercise (eg, brisk

walking) plus flexibility and strength training

Diet

• Eat regular meals and snacks; avoid fasting to lose

weight

• Consume plant-based diet (high in fiber, low

calories/glycemic index, and high in

phytochemicals/antioxidants)

• Understand Nutrition Facts Label information

• Incorporate beliefs and culture into discussions

• Use mild cooking techniques instead of high-heat

cooking

• Keep physician-patient discussions informal30


29

30

10/9/2019

16

AACE Recommendations: Medical

Nutritional Therapy

• Consistency in day-to-day carbohydrate intake

• Adjusting insulin doses to match carbohydrate intake (eg, use of carbohydrate counting)

• Limitation of sucrose-containing or high-glycemic index foods

• Adequate protein intake

• “Heart-healthy” diets

• Weight management

• Exercise

• Increased glucose monitoring


31

ANTIHYPERGLYCEMIC

THERAPY

Glycemic Management of Type 2 Diabetes

32

31

32

10/9/2019

17

33

34

10/9/2019

18

Noninsulin Agents for DM2Class Primary Mechanism of Action Agent(s) Available as

a-Glucosidase

inhibitors

• Delay carbohydrate absorption

from intestine

Acarbose

Miglitol

Precose or generic

Glyset

Amylin analogue

• Decrease glucagon secretion

• Slow gastric emptying

• Increase satiety

Pramlintide Symlin

Biguanide• Decrease HGP

• Increase glucose uptake in muscleMetformin

Glucophage or

generic

Bile acid

sequestrant

• Decrease HGP?

• Increase incretin levels?Colesevelam WelChol

DPP-4 inhibitors

• Increase glucose-dependent

insulin secretion


Alogliptin

Linagliptin

Saxagliptin

Sitagliptin

Nesina

Tradjenta

Onglyza

Januvia

Dopamine-2 agonist • Activates dopaminergic receptors Bromocriptine Cycloset

Glinides • Increase insulin secretionNateglinide

Repaglinide

Starlix or generic

Prandin

36

DPP-4, dipeptidyl peptidase; HGP, hepatic glucose production.

Garber AJ, et al. Endocr Pract. 2015;21:438-447.

Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. Continued on next slide

35

36

10/9/2019

19

Noninsulin Agents

Available for T2D

Class Primary Mechanism of Action Agent(s) Available as

GLP-1 receptor

agonists

• Increase glucose-dependent

insulin secretion


• Slow gastric emptying

• Increase satiety

Albiglutide

Dulaglutide

Exenatide

Exenatide XR

Liraglutide

Tanzeum

Trulicity

Byetta

Bydureon

Victoza

SGLT2 inhibitors• Increase urinary excretion of

glucose

Canagliflozin

Dapagliflozin

Empagliflozin

Invokana

Farxiga

Jardiance

Sulfonylureas • Increase insulin secretion

Glimepiride

Glipizide

Glyburide

Amaryl or generic

Glucotrol or generic

Diabeta, Glynase,

Micronase, or generic

Thiazolidinediones

• Increase glucose uptake in muscle

and fat

• Decrease HGP

Pioglitazone

Rosiglitazone

Actos

Avandia

GLP-1, glucagon-like peptide; HGP, hepatic glucose production; SGLT2, sodium glucose cotransporter 2.

Garber AJ, et al. Endocr Pract. 2015;21:438-447.

Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. Continued from previous slide

37

37

38

10/9/2019

20

39

40

10/9/2019

21

Depicted are patient and disease factors used to determine optimal A1C targets.

American Diabetes Association Clin Diabetes 2019;37:11-34

41

42

10/9/2019

22

43

44

10/9/2019

23

• Use GFR in place

of creatinine

• Can initiate

Metformin if GFR is

> 45

• Can remain on it if

GFR is > 30

Metformin Guidelines Have

Changed

45

46

10/9/2019

24

Pharmacologic Therapy for Type 2 Diabetes.9.5 Metformin is the preferred initial pharmacologic agent for

the treatment of type 2 diabetes. A

9.6 Once initiated, metformin should be continued as long as it

is tolerated and not contraindicated; other agents, including

insulin, should be added to metformin. A

9.7 Long-term use of metformin may be associated with

biochemical vitamin B12 deficiency, and periodic

measurement of vitamin B12 levels should be considered

in metformin-treated patients, especially in those with

anemia or peripheral neuropathy. BPharmacologic Approaches to Glycemic Treatment:

Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.

1):S90-S102

Pharmacologic Therapy for Type 2 Diabetes.

9.8 The early introduction of insulin should be considered if

there is evidence of ongoing catabolism (weight loss), if

symptoms of hyperglycemia are present, or when A1C

levels (>10% [86 mmol/mol)] or blood glucose levels (≥300

mg/dL [16.7 mmol/L)] are very high. E

9.9 Consider initiating dual therapy in patients with newly

diagnosed type 2 diabetes who have A1C ≥1.5% (12.5

mmol/mol) above their glycemic target. E

9.10 A patient-centered approach should be used to guide the

choice of pharmacologic agents. Considerations include

comorbidities (atherosclerotic cardiovascular disease, heart

failure, chronic kidney disease), hypoglycemia risk, impact

Pharmacologic Approaches to Glycemic Treatment:


1):S90-S102

47

48

10/9/2019

25

Copyright ADA & EASD 2018


Presence of cardiovascular disease is compelling indication

Step 1: Assess cardiovascular disease

Pharmacologic Therapy for Type 2 Diabetes.9.11 Among patients with type 2 diabetes who have established

atherosclerotic cardiovascular disease, sodium-glucose

cotransporter 2 inhibitors, or glucagon-like peptide 1

receptor agonists with demonstrated cardiovascular disease

benefit (Table 9.1) are recommended as part of the

antihyperglycemic regimen. A

9.12 Among patients with atherosclerotic cardiovascular

disease at high risk of heart failure or in whom heart failure

coexists, sodium-glucose cotransporter 2 inhibitors are

preferred. C

9.13 For patients with type 2 diabetes and chronic kidney

disease, consider use of a sodium-glucose cotransporter 2

inhibitor or glucagon-like peptide 1 receptor agonist shown

Pharmacologic Approaches to Glycemic Treatment:


1):S90-S102

49

50

10/9/2019

26

Pharmacologic Therapy for Type 2 Diabetes.9.14 In most patients who need the greater glucose-lowering

effect of an injectable medication, glucagon-like peptide 1

receptor agonists are preferred to insulin. B

9.15 Intensification of treatment for patients with type 2

diabetes not meeting treatment goals should not be

delayed. B

9.16 The medication regimen should be reevaluated at regular

intervals (every 3-6 months) and adjusted as needed to

incorporate new patient factors (Table 9.1). EPharmacologic Approaches to Glycemic Treatment:


1):S90-S102



Consensus Recommendation—new since 2015

Consider important comorbidities that should influence the choice of a particular glucose-lowering medication

Among patients with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD), sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists with proven cardiovascular benefit are recommended as part of glycaemic management

51

52

10/9/2019

27



Clinical Inertia

Clinical inertia: failure of healthcare providers to initiate or intensify therapy when indicated, due to:

• overestimation of care provided

• use of “soft” reasons to avoid intensification of therapy

• lack of education, training, and practice organzation aimed at achieving therapeutic goals


CHOOSING GLUCOSE-LOWERING MEDICATION IN THOSE WITH ESTABLISHED ASCVD OR CKD

53

54

10/9/2019

28


If ASCVD Predominates:GLP-1 receptor agonist with proven cardiovascular benefit

•Liraglutide > semaglutide > exenatide LAR

SGLT2 inhibitor with proven cardiovascular benefit

•Empagliflozin > canagliflozin


CHOOSING GLUCOSE-LOWERING MEDICATION IN THOSE WITH ESTABLISHED HF OR CKD

55

56

10/9/2019

29



Among patients with ASCVD in whom HF coexists or is of concern, SGLT2 inhibitor are recommended

Rationale: Patients with T2D are at increased risk for heart failure with reduced or preserved ejection fraction

Significant, consistent reductions in hospitalization for heart failure have been seen in SGLT2 inhibitor trials

Caveat: trials were not designed to adjudicate heart failure

Majority of patients did not have clinical heart failure at baseline

57

58

10/9/2019

30

59

60

10/9/2019

31

61

62

10/9/2019

32

63

64

10/9/2019

33

65

66

10/9/2019

34

67

68

10/9/2019

35

69

70

10/9/2019

36

71

72

10/9/2019

37

73

74

10/9/2019

38



Consensus Recommendation:

For patients with type 2 diabetes and CKD, with or without cardiovascular disease, consider the use of an SGLT2 inhibitor shown to reduce CKD progression or, if contraindicated or not preferred, a GLP-1 receptor agonist shown to reduce CKD progression .

Several of these medications have demonstrated renal benefit and cardiovascular benefit and should be considered as part of treatment


CKD ConsiderationsFor SGLT2-i adequate eGFR differs between countries and compounds

SGLT2-i are registered as glucose-lowering agents to be started if eGFR>45-60 ml/min/1.73m2 and stopped at eGFR 45-60, as glucose-lowering effect declines with eGFR

SGLT2-i CVOTs included patients with eGFR>30, and there were no excess adverse events in subjects with eGFR<60

For GLP-1 RA gastrointestinal side effects increase with declining renal function

GLP-1 RA are not recommended in end stage renal disease due to limited experience

75

76

10/9/2019

39


*CI, confidence interval; HR, hazard ratio

Wanner et al. N Engl J Med 2016;375:323-34

HR=0.54*, 95% CI: 0.40;0.75p<0.001

Month

Cum

ula

tive p

robability o

f event

(%)

0 6 12 18 24 30 36 42 48

0

1

2

3

4

5

6

7

8

Empagliflozin

EMPA-REGTime to first renal event (secondary outcome)Doubling of the serum creatinine level, the initiation of renal-replacement therapy, or death from renal disease


LEADER Time to first renal event (secondary outcome)

Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard

regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI:

confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

Marso SP et al. N Engl J Med 2016;375:311–322

77

78

10/9/2019

40



Summary

Consider the presence or absence of ASCVD, CKD and HF

Start with metformin if tolerated, then:

In patients with ASCVD a GLP-1 RA or SGLT2-i is recommended

In patients with ASCVD and HF SGLT2-i is recommended

In patients with CKD, with or without ASCVD consider an SGLT2-i

Agents with proven benefit are preferred

ASCVD, CKD and HF affects choice of additional glucose lowering medication



New Since 2014

MetforminUS and EU Labels were revised in 2016 for use when eGFR is reduced

InsulinsDegludec (long acting) approved in the US (approved earlier in EU)Fast-acting insulin aspart approved in US and EUBiosimilars have become available for glargine and lisproConcentrated forms of several have become availableInhaled insulin (US)

79

80

10/9/2019

41



New Since 2014

SGLT2 InhibitorsErtugliflozin approved in US and EUCombination products approved (with metformin or DPP4 inhibitors)Cardiovascular outcomes trials with empagliflozin, canagliflozin (and dapagliflozin)

complete with broad benefits on cardiorenal outcomes

GLP-1 Receptor AgonistsTwo agents were approved: lixisenatide (in US 2016, EU 2013), semaglutideCombination products approved (with long-acting insulins)Cardiovascular outcomes trials with liraglutide, semaglutide and exenatide

extended-release complete with cardiovascular benefitsNew safety data is reassuring regarding pancreatitis and pancreatic cancer

New ADA Recommendation

In most cases of type 2 Diabetes, the

first injectable agent should be a GLP-1

receptor agonist

81

82

10/9/2019

42

Cardiovascular Risk Reduction with Icosapent Ethyl for HypertriglyceridemiaDeepak L. Bhatt, M.D., M.P.H., P. Gabriel Steg, M.D., Michael Miller, M.D., Eliot A. Brinton, M.D., Terry A. Jacobson, M.D., Steven B. Ketchum, Ph.D., Ralph T. Doyle, Jr., B.A., Rebecca A. Juliano, Ph.D., Lixia Jiao, Ph.D., Craig Granowitz, M.D., Ph.D.

DL Bhatt et al. N Engl J Med 2019;380:11-22.

83

84

10/9/2019

43

In REDUCE-IT, the risk of the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonf

Fatal and nonfatal ischemic events were lower in the icosapent ethyl group than in the placebo group, including a 20% lower r

The benefits were observed against a background of appropriate statin use among patients who had a median LDL cholesterol lev

• The revised standards now recommend that

icosapent ethyl (Vascepa, Amarin) be

considered to reduce CV risk for patients with

diabetes who have atherosclerotic CVD or

other CV risk factors and who are prescribed

a statin and have controlled LDL cholesterol

but persistently elevated triglycerides. The

recommendation is based on findings from the

REDUCE-IT trial, which found that icosapent

ethyl was superior to placebo for reducing risk

for ischemic events in patients with elevated

triglycerides at high CV risk despite statin

therapy.

85

86

10/9/2019

44

• Degludec (Tresiba)

• Glargine U300 (Toujeo)

• Fiasp

• Combination basal insulin

+ GLP1 Xultophy and

Soliqua

• Inhaled insulin (Affreza)

New Insulins

87

88

10/9/2019

45

Summary

• New recommendations for type 2 diabetics

with established cardiovascular disease

• New guidelines for metformin

• New insulins

• New GLP-1s

• GLP-1 are recommended as first injectable

• I did not include everything

• The only hope for diabetes is for technology to

outpace apathy

References

• AACE 2019 Diabetes Management Algorithm

• ADA 2019 Standards of Care

• N Engl J Med 2019; 380:347-357

• DOI: 10.1056/NEJMoa1812389

• June 13, 2019

• N Engl J Med 2019; 380:2295-2306

• DOI: 10.1056/NEJMoa1811744

89

90

10/9/2019

46

Renal Outcomes with Empagliflozin Over

3.2 Years

92

EMPA-REG RENAL

(N=7020)

Arrows = relative risk reduction.

*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.

CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.

Wanner C, et al. N Engl J Med. 2016;375:323-334.

18.8

12.7

0.

4.8

9.5

14.3

19.

23.8

Incident or worsening nephropathy

Pati

en

ts (

%) 39%

P<0.0019.7

5.5

0.

2.5

5.

7.5

10.

12.5

Post-hoc composite outcome*

Pati

en

ts (

%)

44%P<0.001

16.2

11.2

0.

4.3

8.5

12.8

17.

21.3

Progression to macroalbuminuria

Pati

en

ts (

%)

38%P<0.001

91

92

10/9/2019

47

Clinical Outcomes with Liraglutide

93

LEADER

(N=9340)

*CV death, nonfatal MI (including silent MI), or nonfatal stroke.

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Marso SP, et al. N Engl J Med. 2016:375:311-322.

Clinical Outcomes with Liraglutide

94

LEADER Adverse Events Leading to

Discontinuation


Event Liraglutide (%)

(n=4668)

Placebo (%)

(n=4672)

P value

Any adverse event 9.5 7.3 <0.001

Serious adverse event 4.1 5.2 0.01

Nausea 1.6 0.4 <0.001

Vomiting 0.7 <0.1 <0.001

Diarrhea 0.6 0.1 <0.001

Increased lipase level 0.3 0.2 0.43

Abdominal pain 0.2 0.1 0.03

Decreased appetite 0.2 <0.1 0.01

Abdominal discomfort 0.2 0 0.002

93

94

10/9/2019

48

Mann JF et al. N Engl J Med 2017;377:839-848.


95

96

10/9/2019

49


SUSTAIN 6(TRIAL TO EVALUATE CARDIOVASCULAR AND OTHER LONG-TERM

OUTCOMES WITH SEMAGLUTIDE IN SUBJECTS WITH TYPE 2

DIABETES)

Clinical Outcomes with Antihyperglycemic Agents

98

97

98

10/9/2019

50

Marso SP et al. N Engl J Med 2016;375:1834-1844.

Marso SP et al. N Engl J Med 2016;375:1834-1844.

99

100

10/9/2019

51

Clinical Outcomes with Semaglutide

101

SUSTAIN 6 Selected Adverse Events


Event Semaglutide 1 mg (%)

(n=822)

Placebo 1 mg (%)

(n=825)

Any adverse event 89.1 89.2

Serious adverse event 33.6 36.1

Gastrointestinal disorder 52.3 35.2

Diarrhea 18.4 10.5

Nausea 21.9 8.1

Vomiting 14.8 4.1

Acute pancreatitis 0.4 1.1

Gallbladder disorder 3.2 2.8

Cholelithiasis 2.1 1.5

Acute cholecystitis 0 0.2

Severe or symptomatic hypoglycemia 21.7 21.0

Injection site reaction 1.1 1.5

Neoplasm (any) 10.8 8.4

Any malignant 4.9 4.2

Malignant pancreatic 0.1 0.2

• Compared with placebo, the once-

weekly GLP-1 receptor agonist

dulaglutide reduced major adverse

cardiovascular events in adults with

type 2 diabetes with and without

established cardiovascular disease,

making the agent the first type 2

diabetes agent to demonstrate CV

superiority in a broad type 2 diabetes

population.

• In the REWIND CV outcomes trial,

dulaglutide (Trulicity) was associated

with significantly reduced major

adverse cardiovascular events, a

composite endpoint of CV death, non-

fatal myocardial infarction or non-fatal

stroke, meeting the primary efficacy

objective, according to the release.

REWIND: Dulaglutide reduces CV

risk in type 2 diabetes without CVD

101

102

10/9/2019

52

• The REWIND trial is distinct

from other CV outcome trials

due to the limited number of

people with established CV

disease who participated in the

trial, according to Lilly. Of the

9,901 REWIND participants,

only 31% had established CVD.

Additionally, REWIND had a

median follow-up period of

more than 5 years, the longest

for a CV outcome trial in the

GLP-1 receptor agonist class,

according to the release.

REWIND

ORIGINAL ARTICLE

Canagliflozin and Renal Outcomes in

Type 2 Diabetes and Nephropathy• Vlado Perkovic, M.B., B.S., Ph.D., Meg J. Jardine, M.B., B.S., Ph.D., Bruce

Neal, M.B., Ch.B., Ph.D., Severine Bompoint, B.Sc., Hiddo J.L. Heerspink,

Pharm.D., Ph.D., David M. Charytan, M.D., Robert Edwards, M.P.H., Rajiv

Agarwal, M.D., George Bakris, M.D., Scott Bull, Pharm.D., Christopher P.

Cannon, M.D., George Capuano, Ph.D., Pei-Ling Chu, Ph.D., Dick de Zeeuw,

M.D., Ph.D., Tom Greene, Ph.D., Adeera Levin, M.D., Carol Pollock, M.B., B.S.,

Ph.D., David C. Wheeler, M.D., Yshai Yavin, M.B., Ch.B., Hong Zhang, M.D.,

Ph.D., Bernard Zinman, M.D., Gary Meininger, M.D., Barry M. Brenner, M.D.,

and Kenneth W. Mahaffey, M.D.et al., for the CREDENCE Trial Investigators*

June 13, 2019

N Engl J Med 2019; 380:2295-2306

DOI: 10.1056/NEJMoa1811744

103

104

https://www.nejm.org/medical-articles/original-article

https://www.nejm.org/toc/nejm/380/24?query=article_issue_link

10/9/2019

53

SD Wiviott et al. N Engl J Med 2019;380:347-357.


105

106

10/9/2019

54



107

108

10/9/2019

55

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


109

110

10/9/2019

56


Original Article

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

Stephen D. Wiviott, M.D., Itamar Raz, M.D., Marc P. Bonaca, M.D., M.P.H., Ofri Mosenzon, M.D., Eri T. Kato, M.D., M.P.H., Ph.D., Avivit Cahn, M.D., Michael G.

Silverman, M.D., M.P.H., Thomas A. Zelniker, M.D., Julia F. Kuder, M.A., Sabina A. Murphy, M.P.H., Deepak L. Bhatt, M.D., M.P.H., Lawrence A. Leiter, M.D., Darren K. McGuire, M.D., John P.H. Wilding, M.D., Christian T. Ruff, M.D., M.P.H., Ingrid A.M.

Gause-Nilsson, M.D., Ph.D., Martin Fredriksson, M.D., Ph.D., Peter A. Johansson, M.Sc., Anna-Maria Langkilde, M.D., Ph.D., Marc S. Sabatine, M.D.,

M.P.H., for the DECLARE–TIMI 58 Investigators

N Engl J MedVolume 380(4):347-357

January 24, 2019

111

112

10/9/2019

57

Study Overview

• In a randomized trial of patients with type 2 diabetes, treatment with dapagliflozin, an SGLT2 inhibitor that promotes glucosuria, did not result in a higher or lower rate of cardiovascular death, myocardial infarction, or stroke than placebo but did result in a lower rate of hospitalization for heart failure.

Major Cardiovascular and Renal Outcomes and Death from Any Cause.

Wiviott SD et al. N Engl J Med 2019;380:347-357

113

114

10/9/2019

58

Key Efficacy Outcomes and Their Components.


Major Subgroup Analyses of the Primary Efficacy Outcomes.


115

116

10/9/2019

59

Baseline Characteristics of the Patients.


Safety Events.


117

118

10/9/2019

60

Conclusions

• In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure.

• Empagliflozin

• Luraglutide

• Canagliflozin

Three Diabetic Drugs Now Have an

FDA Indication to Decrease Risk of

Cardiovascular Death

119

120

10/9/2019

61

Lipid Management:Other Combination Therapy.

10.28 Combination therapy (statin/fibrate) has not been shown

to improve atherosclerotic cardiovascular disease

outcomes and is generally not recommended. A

10.29 Combination therapy (statin/niacin) has not been shown

to provide additional cardiovascular benefit above statin

therapy alone, may increase the risk of stroke with

additional side effects, and is generally not recommended.

A

Cardiovascular Disease and Risk Management:


1):S103-S123

Comprehensive Medical Evaluation and Assessment of Comorbidities:


1):S34-S45

121

122

10/9/2019

62



Importance of Glycaemic Control

Averting symptomatic hyperglycaemia

Substantial and enduring reduction in microvascular complications• 50-76% reduction DCCT with A1c 7% vs 9%• 25% reduction UKPDS with A1C 7% vs 7.9%• Greatest benefit with reduction from higher levels of A1C

Uncertainty regarding macrovascular benefit of BG control in T2D

Benefits emerge slowly while harms of glucose control medications can be more immediate



Considerations

ASCVD is defined differently across trials• Established CVD (e.g. MI, stroke, revascularization procedure)• Very high cardiovascular risk

Each cardiovascular outcomes trial, while large, is a single experiment

It is not always clear whether differences in trial findings within a drug class are related to trial design or to true differences in the individual medications

• Where evidence suggests a hierarchy, this is noted

123

124

10/9/2019

63



Conclusions

Hospitalization for heart failure was reduced consistently with SGLT2-i in two trials but was a secondary outcome

For patients with type 2 diabetes and CKD, with or without cardiovascular disease, consider the use of an SGLT2 inhibitor shown to reduce CKD progression or, if contraindicated or not preferred, a GLP-1 receptor agonist shown to reduce CKD progression

• Studies of HF or CKD as primary outcome are ongoing with SGLT2-i.



Conclusions

Given the new evidence of outcomes benefit with the use of specific glucose lowering medications in patients with established ASCVD, an important early step in this new approach is to consider the presence or absence of ASCVD, CKD and heart failure.

In patients with ASCVD, studies have demonstrated benefit on cardiovascular outcomes, and some GLP-1 RA and SGLT2-i are recommended in these patients

125

126

type 2 diabetes update - internal medicine...in type 2 diabetes 17 normal glucose tolerance (n=8)...

Documents