Management of Type Diabetes(T2DM):Getting to Goal Safely

Martin J. Abrahamson, MD FACP

Associate Professor of Medicine, Harvard Medical School

Learning objectives

Develop an approach to intensifying treatment of people with T2DM using medications that have weight benefit, reduce risk for hypoglycemia and are ”simpler” and ”safer” to use

Understand the importance of individualizing goals of treatment

Understand cardiovascular risk associated with T2DM and the cardiovascular outcomes studies using drugs to treat T2DM

Understand the pathophysiology and natural history of type 2 DM (T2DM)

Prevalence of diabetes

IDF Atlas 8th edition

3

Diabetes in Kuwait

IDF Atlas, 8th edition

• Total adult population : 2,922,000

• Prevalence of diabetes in adults : 15.1%

• Total cases of diabetes in adults : 441,000

Diabetes in Middle East and North Africa:

• Projected increase of 72% between 2017 and 2045

• 39 million to 67 million

Pathogenesis of T2D: The Ominous Octet

GI, gastrointestinal; HGP, hepatic glucose production; SU, sulphonylurea; T2D, type 2 diabetesDeFronzo RA. Diabetes 2009;58:773–795

Adipose tissue

Increased lipolysis

Skeletal muscle

Decreased glucose uptake

Liver

Insulin resistance

Increased HGP

Brain

Neurotransmitter dysfunction

PancreasImpaired insulin

secretion (β-cell decline)

GI tractDecreased incretin effect

KidneysIncreased glucose

reabsorption

Islet α-cellsIncreased glucagon

secretion

HyperglycemiaEnergy homeostasis

AGi, α-glucosidase inhibitors; DPP4i, DPP-4 inhibitors; GLP-1Ra, GLP-1 receptor agonists; HGP, hepatic glucose production; SU, sulphonylureas; TZDs, thiazolidinediones

Ferrannini E, DeFronzo RA. Eur Heart J 2015;36:2288–2296.

Sites of action of non-insulin therapeutic agents

SU and meglitinidesGLP-1 RA

DPP4i

GLP-1 RAAGi

colesevelam

TZD

SGLT2i

TZDGLP-1 RA

bromocriptine

TZDMET

GLP-1 RADPP4i

GLP-1 RADPP4i

Hyperglycemia

Incretin effectInsulin release

Glucagon secretion

HGPNeurotransmitter

dysfunction

Glucose uptake

Glucose reabsorption

Lipolysis

α-cells

β-cells

Elevated glucose levels are associated with increased CV risk in people with diabetes

1. Green JB. Postgrad Med 2014;126:190‒204; 2. Iribarren C et al. Circulation 2001;103:2668–2673; 3. Khaw KT et al. Ann Intern Med 2004;141:413–420; 4. Stratton IM et al. BMJ 2000;321:405–412;

5. Basa AL & Garber AJ. Ochsner J 2001;3:132–137; 6. Stamler J et al. Diabetes Care 1993;16:434–444.

• Over three-quarters of all hospitalizations for diabetes complications are due to macrovascular disease5

• Macrovascular complications of diabetes affect:‒ Heart (coronary artery disease)‒ Brain (cerebrovascular disease)‒ Extremities (peripheral vascular disease)

• CV mortality is increased in people with diabetes and rises further with additional CV risk factors6

• CV risk, which is increased 2-fold in people with T2DM,1

rises with escalating HbA1c levels2-4

Dia

bete

s

2x CV risk

>75%due to CV

↑BP

↑BMI AgeSmoking

Dyslipidemia

CV

↑HbA1c

Key trials have shown that good glycemic control reduces macrovascular complications

• The more advanced the disease and the longer the duration of diabetes, the more difficult it becomes to reduce CV events and mortality3-7

• Good glycemic control reduces CV risk in people with T1DM‒ Significantly ↓ non-fatal MI, stroke or death from CVD1

‒ Significantly ↓ CV events1

• Multifactorial treatment is key to reducing the risk of CVD• Diabetes management should include management of lipids and blood

pressure plus aspirin use in addition to glucose control, leading to ↓ CV events and mortality8

• Good glycemic control reduces CV risk in people with T2DM‒ Significantly ↓ MI (after 10 years follow-up)2

DCCT/EDIC

UKPDS

ADVANCEACCORD

VADT

Steno-2

1. DCCT/EDIC. N Engl J Med 2005;353:2643–2653; 2. Holman RR et al. New Engl J Med 2008;359:1577–1589; 3. Gerstein HC et al. N Engl J Med 2008; 358:2545–2559; 4. Patel A et al. N Engl J Med 2008;358:2560–2572; 5. Zoungas S et al. N Engl J Med 2014; 371:1392–1406; 6. Duckworth W et al.

N Engl J Med 2009;360:129–139; 7. Hayward RA et al. N Engl J Med 2015;372:2197–2206; 8. Gaede P et al. N Engl J Med 2008;358:580–591.

Case number 1

• Daniel

• Aged 53 years

• Newly diagnosed with type 2 DM

• BMI 30 kg/m2

• A1c 7.3%

• Fasting glucose 146 mg/dL (8.1 mmol/l) (repeat 138 mg/dL [7.7 mmol/l])

• Normal renal and liver function

• No complications of diabetes

What is your HbA1c target for this patient?

A. 7.5 - 8.0%

B. 7.0 - 7.5%

C. 6.5 - 7.0%

D. <6.5%

In addition to lifestyle modification how would you treat him?

1. Metformin

2. Sulfonylurea

3. DPP 4 inhibitor

4. GLP 1 receptor agonist

5. SGLT2 inhibitor

Copyright ADA & EASD 2018

Foundational therapy is metformin and comprehensive lifestyle

management (including weight management and physical activity)

General Treatment Considerations

• Glycemic targets: Individualization is key!

• Tighter targets (<6.5%) - younger, healthier, long life expectancy

• Looser targets (7.0 - 8.0% +) - older, comorbidities (e.g. coronary heart disease, multiple microvascular complications), hypoglycemia prone, shorter life expectancy etc

• Aim for best possible control that can be achieved safely

What do we mean by ”safely”?

• Reduce risk of hypoglycemia

• Reduce weight gain

• Reduce cardiovascular risk

Hypoglycemic risk with antihyperglycemicagents added to metformin

0

5

10

15

20

Biphasic insulin Glinides SU Basal insulin DPP-4i GLP-1RA TZD AGI

Odds r

atio v

s.

pla

cebo

AGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium glucose co-

transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedioneLiu et al. Diabetes Obes Metab 2012;14:810–20; Liu et al. J Diabetes Complications 2015;29:1295–303

SGLT2-i

Increased risk vs. placebo

No increased risk vs. placebo

The consequences of hypoglycemia

Desouza et al. Diabetes Care 2010;33:1389–94; Frier et al. Diabetes Care 2011;34(Suppl. 2):S132–7; Frier. Nat Rev Endocrinol

2014;10:711–22; Gjedde et al. Diabetes 2015;64(Suppl. 1):A91

Brain

HeartCognitive dysfunctionBlackouts, seizures, comasPsychological effects

Increased risk of myocardial ischemiaCardiac arrhythmias

Circulation

InflammationBlood coagulation abnormalities

Hemodynamic changesEndothelial dysfunction

Falls, accidents, driving accidentsFracturesDislocations

Musculoskeletal

Impact of different treatments on body weight

SGLT2i

0

–2

8

2

6

–6

4

–4

10

Range o

f w

eig

ht

change (

kg)

SUs Glinides TZDs Insulin DPP-4 inhibitor

Metformin GLP-1 analogue

Diabetes medication

Insulin detemir

DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1; SGLT2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione

Adapted from Mitri & Hamdy. Expert Opin Drug Saf 2009;8:573–84; Liu et al. J Diabetes Complications 2015;29:1295–303

• Daniel responds well to lifestyle management and metformin

• He loses 10 lb and maintains this weight loss

• He tolerates metformin at it’s maximum dose of 1000 mg twice daily

• Fasting glucose drops below 120 mg/dL (6.6 mmol/l)

• A1c decreases to 6.6%

• He is exercising 5 times per week for 30 mins each time and has reduced his caloric and carbohydrate intake

• 3 years later his weight has increased by 5 lb, fasting glucose is up to 145 mg/dL (8 mmol/l), and the A1c is now 7.6%

Case number 1 contd

1. He is not paying attention to diet and exercise

2. Metformin is not working any longer

3. He has worse insulin resistance

4. His β cell function has deteriorated

Why do you think glucose control has deteriorated?

Decline of -Cell Function in the UKPDS Illustrates Progressive Nature of Type 2 Diabetes

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

Years

-cell function(% of normal by HOMA)

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6

Time of diagnosis

HOMA=homeostasis model assessment

A. Add a sulfonylurea

B. Add an SGLT2 inhibitor

C. Add basal insulin

D. Add a DPP-4 inhibitor

E. Add a GLP-1RA

How would you next treat this patient?

Cardiovascular outcomes trials (CVOT) in diabetes

Results of CVOT for Newer Diabetes TherapiesDPP-4 Is GLP-1 RAs SGLT2-Is

Saxa Alo Sita Lixi Lira Exena

QW

Sema Dula Albi Empa Cana

*MACENeutral Neutral Neutral Neutral

(13%) Neutral

(26%)

(22%)

(14%)

(14%)

CV

Death

(22%)

(38%)

(13%)

Death

(Any

Cause)

(15%) Neutral

Non-

Fatal

Stroke

(39%)

Hosp

for HF

NS

Neutral

(35%)

(33%)

*MACE = Death From CV Causes, Nonfatal MI, or Nonfatal Stroke (+/- hospitalization for unstable angina) NS = non-statistically significant

Cefalu W, et al. Diabetes Care. 2018;41(1):14-31; Hernandez AF, et al. Lancet. 2018;392(10157):1519-1529; https://www.healio.com/endocrinology/diabetes/news/online/%7B6a15d82b-f25b-4e5f-b14b-857ddc955fd8%7D/rewind-dulaglutide-reduces-cv-risk-in-type-2-diabetes-without-cvd

Copyright ADA & EASD 2018Copyright ADA & EASD 2018

Presence of cardiovascular disease is compelling indication

Step 1: Assess cardiovascular disease

Copyright ADA & EASD 2018

If ASCVD Predominates:

GLP-1 receptor agonist with proven cardiovascular benefit

• Liraglutide > semaglutide > exenatide LAR

SGLT2 inhibitor with proven cardiovascular

benefit• Empagliflozin > canagliflozin

Copyright ADA & EASD 2018Copyright ADA & EASD 2018

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

A. Add a sulfonylurea

B. Add an SGLT2 inhibitor

C. Add basal insulin

D. Add a DPP-4 inhibitor

E. Add a GLP-1RA

Now that we have reviewed the data how would you treat this patient?

What should be the target levels for BP?

A. <120/80 mmHg

B. <130/80 mmHg

C. <140/85 mmHg

D. <140/90 mmHg

E. <150/90 mmHg

What should be the target levels for LDL?

A. <30 mg/dL

B. 30-50 mg/dL

C. 50-70 mg/dL

D. 70 to 100 mg/dL

Copyright ADA & EASD 2018

Copyright ADA & EASD 2018

Copyright ADA & EASD 2018

Copyright ADA & EASD 2018

Once Weekly Exenatide Plus Dapaglaflozin Daily Alone or in Combination as Add on to Metformin

Frias JP et al. Lancet Diabetes Endocrinol published online September 16 2016

Mean HbA1c at baseline 9.3%

Weight Change – GLP1 RA or SGLT2 I or Both

Frias JP et al. Lancet Diabetes Endocrinol published online September 16 2016

Dapaglaflozin

Exenatide weekly

Both drugs

DPP-4 inhibitors: key points

• Delay breakdown of endogenous GLP-1 to increase insulin secretion and reduce glucagon secretion

• Moderate HbA1c reduction

• Good safety profile

• Hypoglycemia rare

• Dose adjustment of some DPP4i required in renal dysfunction

Glucagon-like peptide-1 RAs: key points

• Injectable non insulin agents that increase insulin and reduce glucagon secretion

• Delay gastric emptying; increase satiety

• Robust HbA1c reduction

• Hypoglycemia rare

• Good weight reduction

• Some have positive effect on CV outcomes

SGLT2 inhibitors: key points

• Inhibit renal reabsorption of glucose

• Moderate HbA1c reduction

• Good weight reduction

• Hypoglycemia rare

• Contraindicated if eGFR 45 ml/min/1.73 m2

• Some have positive effect on CV outcomes

Patients with T2D are diverse and complex

Hypogly

cem

iarisk

Com

orb

iditie

s? ?

T2D, type 2 diabetes

Key points

There are multiple pathophysiologic

abnormalities that contribute to the development of

T2DM

“Ominous octet”

T2DM is a progressive disease

characterised by progressive loss of beta cell function

People with T2DM are at increased risk for cardiovascular

disease

Key points

The goal of care is the best possible

glycemic control that you can achieve

safely

“Do no harm”

Goals should be individualised based

on the characteristics of the

patient

“One size does not fit all”

We can optimise care using therapies that are safer and

associated with less risk of

hypoglycemia, lower weight gain, lower cardiovascular risk and are simpler to

use