Diabetes Management Guideline 2018

Dr. Mohamed Farghaly

FRCGP(UK).MRCGPI(UK).DIH(IRELAND)
DMSc(UK).MBChB(ALEX)
A.Professor Dubai Medical College
Consultant DHIC ,Head Of Insurance Medical Regulation
Dubai Health Authority
 Presentation Outlines
• Burden and prediabetes

• Cardiovascular disease is the leading cause of mortality and morbidity among diabetic
patients.

• Lowering blood glucose levels in patients with diabetes mellitus is a too simplistic goal. The
key component being how to lower blood sugar and how much.

• Lower Cardiovascular Risk with Diabetic Drugs: A Paradigm Shift from Glucocentricity to
Cardio Protectiveness

• FDA (Food and Drug Administration) and European medicine agency (EMA) made it
mandatory to have CVOT (Cardiovascular outcome trial) as an integral part of drug approval
process.

Diabetes Case Rep 2017,2:2

3
Diabetes: A Global Emergency
Number of people with diabetes worldwide and per region in 2017 and 2045 (20-
79 years)

International Diabetes Federation. IDF Diabetes Atlas, 8ed. Brussels, Belgium: International Diabetes Federation, http://www.diabetesatlas.org
 What is Prediabetes?
Fasting Plasma 2-hour Plasma Hemoglobin A1C
Glucose Glucose On OGTT

Diabetes Diabetes Diabetes

Mellitus Mellitus Mellitus
126 mg/dL 200 mg/dL 6.5%
Prediabetes Prediabetes
Impaired Fasting Impaired Glucose Prediabetes
Glucose Tolerance
100 mg/dL 140 mg/dL 5.7%

Normal Normal Normal

Any abnormality must be repeated and confirmed on a separate day

The diagnosis of diabetes can also be made based on unequivocal symptoms and a random glucose >200 mg/dL

Adapted from:
American Diabetes Association. Diabetes Care. 2014;37 Suppl 1:S81-90.
 Does Prediabetes Predict Diabetes?
Progression of IGT/IFG to DM in11year follow up

Persons with IGT Persons with IFG

Stephen Twigg. Pre diabetes Symposium ADS & ADEA Annual Scientific Meeting Sydney 2004
 What are the Health Risks
Associated with Prediabetes?
• Progression to diabetes: 11% of people with pre-diabetes develop T2DM
each year (DPP)

• Other studies: majority with Prediabetes develop T2DM in 10 years

• Microvascular complications at onset of DM

• 50% higher risk of CVD, CAD and Stroke

 Prevention Studies in People with IGT
Downstream strategies
• Lifestyle interventions
– Da Qing : Diet and Exercise
– Malmo study : Diet and exercise
– Finish Diabetes Prevention Study Lifestyle
– DPP (Diabetes Prevention Study) Lifestyle, MF (Glitazone)
• Lifestyle interventions with pharmacological agents
– FHS (Fasting Hyperglycaemia Study) Healthy Living & SU
– EDIT (Early Diabetes Intervention Study): Acarbose and MF
– STOP NIDDM : Acarbose
 Metformin in Prediabetes
• Glucophage XR is approved by UAE MOH in prediabetes to be used up to 2000 mg.

• Publication that reviews the therapeutic use of Metformin in pre-diabetes based on all the evidence
available. Nevertheless, the guidelines reviewed are not the most updated (ADA/IDF)

• Metformin in the DPPOS, Metformin was used in a dose of 850mg once, increased in one month to
1700 (850 twice) depending on tolerability. 84% of subjects were taking 1700mg.
• In other trials from 1000-2000mg/day

• IDF 2017: "Now all the guidelines recommend metformin as the first choice for initiating
pharmacologic treatment in people with T2D. Titration from 500 to 2000 mg per day,

• administration with or after meals and use of extended-release (XR) preparations can maximize
tolerance. Metformin dose should be reduced to 1000 mg per day when renal function is in stage 3A
and contraindicated when renal function is in stage 3B or above.

10
 DPP: Managing Prediabetes

For those found to have prediabetes, provide support or referral to

encourage
❑Weight loss of at least 7%
❑Moderate exercise of at least 150 minutes per week

Consider metformin for certain patients

❑Obese (BMI ≥35 kg/m2)
❑<60 years (most effective, 25-44 years)
❑Patient with both IFG and IGT
❑A1C in the high Range
American Diabetes Association, 2012.
Ominous Octet

Decreased
Incretin Effect
Decreased Insulin
Increased
Secretion
Lipolysis

Islet– cell

ETIOLOGY OF T2DM
Impaired Insulin Increased Lipolysis
Secretion

Hyperglycemia

Increased Decreased Glucose

HGP Uptake
DEFN75-3/99

HYPERGLYCEMIA Increased
Glucose
Reabsorption

Increased
Glucagon
Secretion Increased
Hepatic Glucose
Production Decreased Glucose
Uptake

Neurotransmitter
Dysfunction
Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58:773-795. Copyright © 2009 American Diabetes Association. All rights reserved.
 Consider Therapies Targeting Different
Pathophysiologic Abnormalities

1. Ferrannini E, et al. Eur Heart J. 2015;36:2288-96. 2. ADA. Diabetes Care. 2017;40(Suppl 1):S1-135
Natural History: Insulin Secretion and Blood Glucose Control

Obesity IFG Diabetes Uncontrolled hyperglycaemia

250
function (%)

Insulin resistance
Relative

200
150 Normal
100 Insulin level
Beta-cell failure
50
350
Glucose level

300 Postprandial glucose

(mg/dL)

250
200 Fasting glucose
150
100 Normal
50
–10 –5 0 5 10 15 20 25 30
Years of diabetes

IFG, impaired fasting glucose

Adapted from Bergenstal et al. In: Degroot & Jameson (eds). Endocrinology 2001;821–35
16
Effective control of DM reduces risk of complications –
UKPDS 35

1% decrease in HbA1c correlates with reduction in risk of :-

Microvascular Peripheral Myocardial Stroke Heart Cataract Death

disease vascular infarction failure extraction related to
disease diabetes
0
Relative Risk

– 37% – 43% – 16% – 12% – 16% – 19% – 21%

–15
p = 0.035 p = 0.021 p < 0.0001 p < 0.0001
(%)

–30

–45

p < 0.0001

Stratton IM, et al. BMJ. 2000;321:405-412

17
UKPDS: Progressive decline in glycemic control
irrespective of treatment regime

Conventional
8

HbA1c (%)
7 Intensive

6
0
0 3 6 9 12 15
6.2% upper limit of normal range
Years from Randomization
UKPDS, 1998

18
 The majority of patients with T2D remain above glycaemic goals
12.4% have HbA1c > 10%1
10.0

20.2% have HbA1c > 9%1

9.0

37.2% have HbA1c > 8%1

8.0

63.0% of patients
with T2D have HbA1c ≥ 7.0%1 7.0 ADA/EASD target (< 7%)2,3

AACE/ACE target (≤ 6.5%)4

6.0
HbA1c

AACE, American Association of Clinical Endocrinologists;

ACE, American College of Endocrinology; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; HbA1c, glycosylated
haemoglobin; T2D, Type 2 Diabetes. 1. Saydah SH, et al. JAMA. 2004;291:335–342; 2. ADA. Diabetes Care. 2013;36:S11–S66;
3. Inzucchi SE, et al. Diabetes Care. 2012;35:1364–1379;
4. AACE/ACE. Endocr Pract. 2009;15:540–559.
19
Some therapy options for T2D are associated with weight gain
UK Prospective Diabetes Study 34

Conventional* (n = 411) Metformin (n = 342)

Glibenclamide (n = 277) Insulin (n = 409)
8.0

Change in weight (kg)

6.0

4.0

2.0

0.0
0 3 6 9 12
Years from randomization

T2D, Type 2 Diabetes. *Diet initially then sulphonylureas, insulin and/or

metformin if fasting plasma glucose > 15 mmol/L. UK Prospective
Diabetes Study 34. Lancet. 1998;352:854–865.
20
Low HbA1c targets may be associated with a high risk of severe hypoglycaemia
Increase in severe hypoglycaemia in the intensive control arm
compared with standard control

12 11.3 11.1
p < 0.001* p < 0.001*

≥ 1 severe hypoglycaemic
Patients experiencing
8
event (%)

4 HR = 1.86
(95% CI: 1.40, 2.40)
1.2

0
1 2 3
VADT ACCORD ADVANCE

Definitions of severe hypoglycaemia

VADT Severe change in consciousness, including loss of consciousness
ACCORD Requiring assistance of another person and plasma glucose < 2.8 mmol/L or symptoms that promptly resolved
with oral carbohydrate, intravenous glucose, or glucagon
ADVANCE Requiring assistance of another person and plasma glucose < 2.8 mmol/L

CI, confidence interval; HbA1c, glycosylated haemoglobin; HR, hazard ratio.

*Comparison between intensive control vs standard control. 1. Skyler JS, et al. J Am Coll Cardiol. 2009;53:298–304; 2. ACCORD
study Group. N Engl J Med. 2008;358:2545–2559; 3. ADVANCE
Study Group. N Engl J Med. 2008;358:2560–2572.
21
For Optimal Diabetes Management, We Should Target:
FPG & PPG

The Glucose Triad

A1c
The long-term average glucose level

FPG PPG
The basal glucose level The glucose peak level

22
To normalize blood glucose, both FPG and PPG must be
reduced

Most insulin is initiated when

HbA1c >8.5%

100
PPG
30% FPG
80 40%
% contribution to HbA1c

50% 45%
70%
60

40
70%
55% 60%
50%
20
30%

0
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
HbA1c range (%)

Adapted from Monnier L et al. Diabetes Care 2003;26:881–5

23
 Patients With Type 2 DM may spend more than
12 Hours per day in the P.P. State

Postprandial Postabsorptive Fasting

Duration of postprandial state

Breakfast Lunch Dinner Midnight 4 AM Breakfast

8 AM 11 AM 2 PM 5 PM

Adapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11.

Risks of postprandial hyperglycemia
Retinopathy2
Cardiovascular
disease1

Decreased
myocardial
Increased blood flow3
mortality6 Postprandial
hyperglycaemia
is associated with…

Impaired cognitive
Increased function
cancer risk5 (elderly patients)4

1. Cavalot F et al. J Clin Endocrn Metab 2006; 91:813–819

2.
Shiraiwa T et al. Diabetes Care 2005;28:2806-2807
3. Scognamiglio R et al. Circulation 2005; 112(2):179-184
4. Abbatecola AM et al. Neurology 2006; 67(2):235-240
5. Stattin P et al. Diabetes Care 2007; 30:561-567
6. Hanefeld M et al. Diabetologia 1996;39:1577–83
 More patients achieve HbA1c goal by adhering to PPG targets than FPG
targets

Percentage of patients achieving HbA1c target (≤7% [53 mmol/mol])

In patients meeting FPG target(≤5.55 mmol/L) In patients meeting PPG target (≤7.78 mmol/L)

No, 36% No, 6%

Yes, 64% Yes, 94%

Adapted from Woerle et al. Diabetes Res Clin Pract 2007;77:280–5

Not only OAD Mono-therapy fails but also combination OADs

2220 patients with T2DM treated with MET + SU

Patients on SU + Metformin with HbA1c > 8%

100%
85%
Patients with A1c > 8%

79%
80%
68%
60%
44%
40%

20%

0%
First year Second year Third year Fourth year
Years after addition of SU to MET

Cook et al. Diabetes Care 2005; 28:995-1000

28
Progressive loss of beta-cell function in the UKPDS

100

80

Beta-cell function (%)

60

40

20

0
–12 –10 –8 –6 –4 –2 0 2 4 6

Years from diagnosis

29
Impact of Intensive Therapy for Diabetes: Summary of
Major Clinical Trials

Microvascular CVD Mortality

UKPDS    
DCCT/EDIC*   
ACCORD  
ADVANCE 
VADT 
*In type 1 diabetes Initial trial Long term follow-up
CVD, cardiovascular disease

Adapted from Kendall et al. © International Diabetes Center 2009

UKPDS Group. Lancet 1998;352:854–65; Holman et al. N Engl J Med. 2008;359:1577–89; DCCT Research Group. N Engl J Med 1993;329;977–86; Nathan et al. N Engl J Med 2005;353:2643–53; Gerstein et al. N Engl
J Med 2008;358:2545–59; Patel et al. N Engl J Med 2008;358:2560–72; Duckworth et al. N Engl J Med 2009;360:129–39 (erratum in N Engl J Med. 2009;361:1028); Moritz. N Engl J Med 2009;361:1024–5 30
IDF Guidelines

If not at target (generally HbA1c <7%) Alternative approach

SU
First line Metformin
ɑ-glucosidase inhibitor
Recent updates to
treatment guidelines

Metformin • Advise people with

a-glucosidase inhibitor
Second line SU
DPP-4i
diabetes that
TZD maintaining HbA1c
below 7.0%
Basal insulin
[53 mmol/mol]
Premix insulin minimises the risk
GLP-1 agonist
Third line ɑ-glucosidase inhibitor of developing
DPP-4i
TZD
complications
• If starting insulin,
add basal insulin or
Premix insulin use premix insulin
Fourth line Basal insulin
Basal–bolus insulin

Adapted from the IDF treatment algorithm for people with type 2 diabetes. www.idf.org/treatment-algorithm-people-type-2-diabetes 31
ADA/EASD: Patient Centered Approach

Metformin SUs
Needs
SGLT-2 inhibitors Glinides

Disease
Dopamine-2 agonists Age GLP-1 RAs
progression

Amylin mimetics DPP-4is

α-glucosidase
TZDs
inhibitors
Preferences Tolerances
Insulin Bile acid sequestrants

32
 ADA/EASD 2017 Guidelines for the
Management of Type 2 Diabetes
Start with Monotherapy unless:
A1C is greater than or equal 9%, consider Dual Therapy.

A1C is greater than or equal to 10%, blood glucose is greater than or equal to 300 mg/dL, or patient is markedly symptomatic, consider Combination Injectable Therapy (see
guidelines).

Monotherapy Metformin Lifestyle Management

EFFICACY high
HYPO RISK low risk
WEIGHT neutral/loss
SIDE EFFECTS GI/lactic acidosis
COSTS low
If A1C target not achieved after approximately 3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference—choice dependent on a
variety of patient- & disease-specific factors):

Dual Therapy Metformin + Lifestyle Management

Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor agonist Insulin(basal)
EFFICACY high high intermediate intermediate high highest
HYPO RISK moderate risk low risk low risk low risk low risk high risk
WEIGHT gain gain neutral loss loss gain
SIDE EFFECTS hypoglycemia edema, HF,fxs rare GU, dehydration,fxs GI hypoglycemia
COSTS low low high high high high

If A1C target not achieved after approximately 3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific
preference—choice dependent on a variety of patient- & disease-specific factors):
Triple Therapy Metformin + Lifestyle Management
Sulfonylurea + Thiazolidinedione + DPP-4 inhibitor + SGLT2 inhibitor + GLP-1 receptor agonist + Insulin (basal) +

TZD SU SU SU SU TZD
or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i
or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or SGLT2-i or SGLT2-i
or GLP-1-RA or GLP-1-RA or Insulin or GLP-1-RA or Insulin or GLP-1-RA
or Insulin or (usually basal) or Insulin (usually basal)
Insulin
(usually basal) (usually basal) (usually basal)
If A1C target not achieved after approximately 3 months of triple therapy and patient (1) on oral combination, move to basal insulin or GLP-1 RA, (2) on GLP-1 RA, add basal insulin, or (3) on
optimally titrated basal insulin, add GLP-1 RA or mealtime insulin. Metformin therapy should be maintained, while other oral agents may be discontinued on an individual basis to avoid
unnecessarily complex or costly regimens (ie, adding a fourth antihyperglycemic agent).

Combination Injectable Therapy

ADA. Diabetes Care. 2017;40(suppl 1):S1-S135.

 First-line glucose-lowering medication for T2D
What are the changes?

2015 2018

General approach General approach

2015: 2018:

Metformin remains the Metformin is the

optimal drug for preferred glucose-
monotherapy lowering drug for most
people with T2D

T2D, type 2 diabetes

 First-line glucose-lowering medication for T2D

2018 • Metformin, on top of

lifestyle intervention,
remains as the
recommended first line
glucose-lowering
medication for patients
with T2D

T2D, type 2 diabetes

 High Response rate with new patients

7 out of 10 patients achieved HbA1c below 7% with

Metformin monotherapy regardless of Baseline HbA1c

Reference: Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135.
Major guidelines target an HbA1c of <7.0%

• The overall aim is to achieve glucose levels as close to normal as possible

• This can minimize development and progression of microvascular and macrovascular
complications

FPG PPG
ADA1,2/ HbA1c
<130 mg/dL <180 mg/dL
EASD2 <7.0%
(7.2 mmol/L) (10.0 mmol/L)

FPG PPG
HbA1c
IDF3 <6.0 mmol/L
<7.0%
<160 mg/dL
(110 mg/dL) (9.0 mmol/L)

FPG, fasting plasma glucose

1ADA. Diabetes Care 2009;32(Suppl. 1):S1–S97; 2ADA/EASD Consensus guideline. Diabetes Care 2009;32:193–203; 3IDF. IDF Clinical Guidelines Task Force. 2005
39
Pharmacologic Targets of Current Drugs Used in
the Treatment of T2DM

Thiazolidinediones
Decrease lipolysis in adipose
tissue, increase glucose uptake
in skeletal muscle and decrease
glucose production in liver

Sulfonylureas
Increase insulin secretion from
pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
Glinides absorption
Increase insulin secretion
from pancreatic -cells

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.
Pharmacologic Targets of Current Drugs Used in
the Treatment of T2DM
SGLT2 Inhibitors DPP-4 inhibitors
Inhibit glucose reabsorption in the renal Prolong GLP-1 action leading to improved
proximal tubule Resultant glucosuria leads to a pancreatic islet glucose sensing, increase
decline in plasma glucose glucose uptake

Thiazolidinediones
Decrease lipolysis in adipose
tissue, increase glucose uptake
in skeletal muscle and decrease
glucose production in liver

Sulfonylureas
Increase insulin secretion from
pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
Glinides absorption
Increase insulin secretion
from pancreatic -cells

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.
Insulin use is often delayed, despite poor glycemic control
Mean HbA1c at last

10
9.4% 9.1%
8.8%
visit (%)

8
3 OADs
2 OADs

1 OAD
Diet

2.9 years 4.7 years 2.5 years 2.7 years

42
Common reasons for clinical intertia

Insulin naïve patients Primary care physicians

25 90 85
80
20
% of respondents

% of respondents
70
60
15 15 15 60 55
15
50
10 40
10 29
30

5 20

10
0 0
Insulin Pain from Pain from Insulin Pain from Pain from
Fear of
makes injection blood tests makes Fear of injection blood tests
hypos
one fat one fat hypos

* Percentage of patients/physicians interviewed who provided this as a

reason for not starting insulin

Nakar et al. J Diabetes Complications 2007;21:220–6 43

ADA/EASD 2018 Consensus
Report
 Glucose-lowering medication in type 2 diabetes: Overall approach To avoid
clinical inertia
reassess and
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY) modify
IF HbA1c ABOVE TARGET PROCEED AS BELOW treatment
regularly
(3–6 months)
NO
Established ASCVD or CKD

Without established ASCVD or CKD

ASCVD predominates
HF OR CKD predominates
PREFERABLY Compelling need to minimise hypoglycaemia Compelling need to minimise weight
Cost is a major issue††‡‡
EITHER/ SGLT-2i with evidence of reducing HF gain or promote weight loss
OR SGLT-2i and/or CKD progression in CVOT if eGFR DPP-4i GLP-1RA SGLT-2i† TZD
GLP-1RA with proven
adequate‡
with proven CVD benefit*, GLP-1RA
OR EITHER/
CVD benefit* if eGFR with good SU|| TZD‡‡
If HbA1c above If HbA1c above If HbA1c above If HbA1c above OR SGLT-2i†
adequate† If SGLT-2i not tolerated or contraindicated efficacy for
or if eGFR less than adequate† add GLP-1RA target target target target weight loss**
with proven CV benefit*

If HbA1c above target If HbA1c above target

GLP-1RA SGLT-2i†
If HbA1c above target If HbA1c above target SGLT-2i† SGLT-2i†
OR OR
GLP-1RA
OR OR DPP-4i DPP-4i SGLT-2i† with good efficacy TZD‡‡ SU||
If further intensification is required or • Avoid TZD in the setting of HF for weight loss**
OR OR
patient is now unable to tolerate GLP-1RA TZD TZD
and/or SGLT-2i, choose agents Choose agents demonstrating CV safety: TZD GLP-1RA
demonstrating CV safety: • Consider adding the other class with
If HbA1c above target If HbA1c above target
proven CVD benefit*
• Consider adding the other class • DPP-4i (not saxagliptin) in the setting
(GLP-1RA and/or SGLT-2i) with of HF (if not on GLP-1RA)
If HbA1c above target If triple therapy required or SGLT-2i
proven CVD benefit • Basal insulin§ • Insulin therapy basal insulin
and/or GLP-1RA not tolerated or
• DPP-4i if not on GLP-1RA • SU|| with lowest acquisition cost
contraindicated use regimen with
• Basal insulin§ Continue with addition of other agents as outlined above lowest risk of weight gain OR
• TZD¶ • Consider DPP-4i OR SGLT-2i with
PREFERABLY
• SU|| lowest acquisition cost‡‡
DPP-4i (if not on GLP-1RA)
If HbA1c above target based on weight neutrality

Consider the addition of SU|| OR basal insulin:

• Choose later generation SU with lower risk of hypoglycaemia If DPP-4i not tolerated or
• Consider basal insulin with lower risk of hypoglycaemia# contraindicated or patient already on
GLP-1RA cautious addition of:
● SU|| ● TZD¶ ● Basal insulin

*Proven CVD benefit means it has label indication of reducing CVD events. For GLP-1RA strongest evidence for liraglutide>semaglutide>exenatide extended release. For SGLT-2i evidence modestly stronger for empagliflozin>canagliflozin; †Be aware that SGLT-2i vary by region and individual agent
with regard to indicated level of eGFR for initiation and continued use; ‡Both empagliflozin and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety; ¶Low dose may be better tolerated though less well
studied for CVD effects; ||Choose later generation SU with lower risk of hypoglycaemia; #Degludec / glargine U300<glargine U100 / detemir<NPH insulin; **Semaglutide>liraglutide>dulaglutide>exenatide>lixisenatide; ††If no specific comorbidities (i.e. no established CVD, low risk of
hypoglycaemia and lower priority to avoid weight gain or no weight-related comorbidities); ‡‡Consider country- and region-specific cost of drugs. In some countries, TZDs relatively more expensive and DPP-4i relatively cheaper
 Glucose-lowering medication in type 2 diabetes: Overall approach To avoid
clinical inertia
reassess and
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY) modify
IF HbA1c ABOVE TARGET PROCEED AS BELOW treatment
regularly
(3–6 months)
Without established
NO ASCVD or CKD Without established ASCVD or CKD
Established ASCVD or CKD
Established ASCVD or CKD
Compelling need to minimise hypoglycaemiaWithout established ASCVD need
or CKDto minimise weight
Without established ASCVD
Compelling
ASCVD predominates or CKD
HF OR CKD predominates gain or promote weight loss
ASCVD predominates PREFERABLY DPP-4i GLP-1RAneed to minimise
Compelling SGLT-2i †
hypoglycaemia TZD Compelling need to minimise weight
Cost is a major issue ††‡‡
EITHER/ HF OR
SGLT-2i with evidence of reducing HF CKD predominates
GLP-1RA
gain or promote weight loss Cost is a major issue ††‡‡
SGLT-2i
OR and/or CKD progression in CVOT if eGFR is DPP-4i GLP-1RA SGLT-2i† TZD EITHER/
PREFERABLY If with
HbAgood
GLP-1RA with proven
adequate‡
with proven CVD benefit*, If HbA 1c If HbA 1c If HbA1c 1c GLP-1RA OR SGLT-2i2
CVD benefit* EITHER/ if eGFR OR
SGLT-2iabovewith evidence
target of reducing
above HF
target above target above efficacy
targetfor with good EITHER/
SU|| TZD‡‡
adequate† SGLT-2i If HbA1c above If HbA1c above If HbA1c above If HbA1cweight
above loss8 OR SGLT-2i†
OR If SGLT-2i not tolerated or contraindicated
and/or CKD progression in CVOT if eGFR
target target target target
efficacy for
SU|| TZD‡‡
GLP-1RA with proven
or if eGFR less than adequate† add GLP-1RA weight loss**
adequate ‡
with proven CVD benefit*,with proven CV benefit*
OR
CVD benefit* if eGFR GLP-1RA SGLT-2i† If HbA1cIf above target
HbA1c above target If HbA1c above target
If HbA1c above target adequate† If HbA1c above If SGLT-2i
target
not tolerated
SGLT-2i † or contraindicated
SGLT-2i † GLP-1RA SGLT-2i†
SGLT-2i† SGLT-2i†
or if eGFR less than adequate† add GLP-1RA OR
OR OR OR
with proven CV benefit* GLP-1RA If HbA1c above target
OR OR OR OR DPP-4i
DPP-4i DPP-4i GLP-1RA TZD‡‡ SU||
Avoid TZD in the setting of HF
DPP-4i SGLT-2i† with good efficacy
If further intensification is required or •
OR OR SGLT-2i
2 with good efficacy
for weight loss** for
patient is now unable to tolerate GLP-1RA TZD TZD OR OR weight loss 8
and/or SGLT-2i, choose agents Choose agents demonstrating CV safety: TZD TZD
demonstratingIf CVHbAsafety: above target • Consider adding the other If
class HbA
with above target
TZD GLP-1RA TZD‡‡ SU||
1c
proven CVD benefit*
1c TZD GLP-1RA If HbA1c above target If HbA1c above target
• Consider adding the other class • DPP-4i (not saxagliptin) in the setting
(GLP-1RA and/or SGLT-2i) with of HF (if not on GLP-1RA) If HbA1c above target
If HbA1c above target If triple therapy required or SGLT-2i
proven CVD benefit • Basal insulin§ • Insulin therapy basal insulin
Avoid TZD in the setting of HF and/or GLP-1RA not tolerated or
• If further
DPP-4i if intensification
not on GLP-1RA is required • or SU|| •
contraindicated use regimen with If HbA1cwith
above
lowesttarget
acquisition cost
• patient is now
Basal insulin unable to tolerate GLP-1RA If HbA1c above target
gain and/or OR
§

• TZD¶
Continue with addition of other agents as outlined above If triple therapy required
lowest risk or SGLT-2i
of weight
• Consider DPP-4i OR SGLT-2i with
• and/or
SU|| SGLT-2i, choose agents
Choose agents demonstrating CV safety: GLP-1RA not tolerated PREFERABLY
or contraindicated lowest acquisition cost‡‡
demonstrating CV safety: • Consider adding Continuethe other with class with IfofHbA
addition other agents
target as outlined
above
DPP-4i (if not on GLP-1RA)
use based
regimen with • Insulin therapy basal insulin
1c above on weight neutrality
• Consider adding the other class proven CVD benefit* lowest risk of weight gain with lowest acquisition cost
(GLP-1RA and/or SGLT-2i) with proven • DPP-4i (not saxagliptin) in the setting of PREFERABLY OR
Consider the addition of SU|| OR basal insulin:
CVD benefit HF (if not on GLP-1RA) If HbA above target Consider DPP-4i OR SGLT-2i with
• Choose later generation SU1cwith lower risk of hypoglycaemia DPP-4i (if not on GLP-1RA)•
If DPP-4i not tolerated or
• DPP-4i if not on GLP-1RA • Basal insulin § • Consider basal insulin with lower risk of hypoglycaemia# contraindicated or patient already on
lowest acquisition cost‡‡
based on
GLP-1RA weight neutrality
cautious addition of:
• Basal insulin§ • SU|| ● SU|| ● TZD¶ ● Basal insulin
• TZD¶ Consider the addition of SU|| OR basal insulin:
SU CVD benefit means it has label indication of reducing CVD events. For GLP-1RA strongest •evidence
• *Proven
|| Choose later generation SU with lower risk of hypoglycaemiaempagliflozin>canagliflozin;
for liraglutide>semaglutide>exenatide extended release. For SGLT-2i evidence modestly stronger forIf DPP-4i not tolerated †Be awareorthatcontraindicated
SGLT-2i vary by region and or
individual agent
• Consider
with regard to indicated level of eGFR for initiation and continued use; ‡Both empagliflozin and canagliflozin have shownbasal
reductioninsulin with lower
in HF and reduction risk of
in CKD progression hypoglycaemia
in CVOTs; §Degludec or U100#
glarginepatient already on GLP-1RA
have demonstrated CVD safety; cautious
¶Low dose may be better tolerated though less well
|| # ††
studied for CVD effects; Choose later generation SU with lower risk of hypoglycaemia; Degludec / glargine U300<glargine U100 / detemir<NPH insulin; **Semaglutide>liraglutide>dulaglutide>exenatide>lixisenatide; If no specific comorbidities (i.e. no established CVD, low risk of
hypoglycaemia and lower priority to avoid weight gain or no weight-related comorbidities); ‡‡Consider country- and region-specific cost of drugs. In some countries, TZDs relatively more expensive and DPP-4iaddition of:
relatively cheaper
● SU6 ● TZD5 ● Basal insulin
 American Diabetes Association Recommendations for
Antihyperglycaemic Therapy in T2D
HbA1c ≥9%: consider dual therapy
TARGET HbA1c <7.0%* HbA1c ≥10%: consider combination injectable therapy

MONOTHERAPY Lifestyle therapy + metformin

If HbA1c target is not achieved after

3 months
DUAL THERAPY† Lifestyle therapy + metformin + 1 additional therapy
If HbA1c target is not achieved after SU TZD DPP-4i SGLT2i GLP-1 RA Insulin (basal)
3 months
TRIPLE THERAPY† Lifestyle therapy + metformin + 2 additional agents
If HbA1c target is not achieved after SU + TZD + DPP-4i + SGLT2i + GLP-1 RA + Insulin (basal) +
3 months or TZD or SU or SU or SU or SU or TZD
or DPP-4i or DPP-4i or TZD or TZD or TZD or DPP-4i
or SGLT2i or SGLT2i or SGLT2i or DPP-4i or SGLT2i or SGLT2i
or GLP-1 RA or GLP-1 RA or Insulin or GLP-1 RA or Insulin or GLP-1 RA
or Insulin or Insulin or Insulin
COMBINATION
INJECTABLE THERAPY

*Targets must be individualised; more or less stringent glycaemic goals may be appropriate for individual patients; †Order not meant to denote any specific preference.
DPP-4i = dipeptidyl peptidase-4 inhibitor; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SGLT2i = sodium-glucose cotransporter 2 inhibitor; SU = sulphonylurea; TZD = thiazolidinedione.
American Diabetes Association. Standards of medical care in diabetes-2017; Diabetes Care. 2017;40(suppl 1):S1-S135.
 Question

Which factor would you consider most when selecting a

new antihyperglycaemic treatment

2 3
Efficacy 1
2
Cost
Weight 6

Hypoglycaemia risk
Other side effects 5

Live Polling Results

 Intensification Options Based on American Diabetes Association Guidelines
Add a Third OAM or Consider an Injectable

TRIPLE THERAPY Lifestyle therapy + metformin + SU +

TZD DPP-4i SGLT2i GLP-1 RA Insulin (basal)

Efficacy high intermediate intermediate high highest

Hypo risk low risk low risk low risk low risk high risk

Weight gain neutral loss loss gain

GU, dehydration,
Side effects oedema, HF, fxs rare GI hypoglycaemia
fxs

Cost low high high high high

According to the American Diabetes Association’s treatment guidelines, if our patient is not to target
after 3 months of dual therapy with metformin and an SU, it may be time to consider adding an
additional therapy to this patient's treatment
fxs = bone fractures; GI = gastrointestinal; GU = genito-urinary; HF = heart failure.
American Diabetes Association. Standards of medical care in diabetes-2017; Diabetes Care. 2017;40(suppl 1):S1-S135.
From Optimizing glycemia to
CVD Protection.
 Cardiovascular disease and diabetes
~65% of deaths are due to CV disease

Coronary heart
disease deaths Cardiovascular Stroke risk
2- to 4-fold complications of 2- to 4-fold
T2DM

Impaired glucose tolerance (IGT)

and postprandial hyperglycemia
Heart failure are CV risk factors
2- to 5-fold Funagata Diabetes Study;
Honolulu Heart Program;
DECODE Study;
Bell DSH. Diabetes Care. 2003;26:2433-41.
Rancho Bernardo Study
Centers for Disease Control (CDC). www.cdc.gov.
 Cardiovascular outcome trials in T2D
SAVOR TECOS
(Saxagliptin) (Sitagliptin)
CAROLINA
(Linagliptin)
HR: 1,00 HR: 0,98 SUSTAIN-6 REWIND
(95%-CI: 0,89; 1,12) (95%-CI: 0,88; 1,09) (Dulaglutide)
(Semaglutide) CARMELINA
(Linagliptin)
EXAMINE ELIXA HARMONY
LEADER
(Alogliptin) (Lixisenatide)
(Liraglutide)
EXSCEL Outcomes
HR: 0,96 HR: 1,02 (Exenatide) (Albiglutide)
(95%-CI: UL ≤1,16) (95%-CI: 0,89; 1,17)

2013 2014 2015 2016 2017 2018 2019

EMPA-REG
CANVAS DECLARE
OUTCOME® (Canagliflozin) (Dapagliflozin)
DPP-4 inhibitors (Empagliflozin)
GLP-1 RAs

SGLT-2 inhibitors

HR, Hazard Ratio; CI, confidence UL, upper limit.

Modified from: 1. Johansen OE. World J Diabetes 2015; 6:1092-6; 2. Zinman 2015 N Engl J Med DOI: 10.1056/NEJMoa1504720 [Epub ahead of print].
EMPA – REG OUTCOME : Primary Outcome
EMPA – REG OUTCOME :CV Death , NF MI , NF Stroke
LEADER Primary outcome
CV death, non-fatal myocardial infarction or non-fatal stroke

Liraglutide

Primary composite outcome in time-to-event analysis was first occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke.
Cumulative incidences estimated using the Kaplan–Meier method, and hazard ratios using the Cox proportional-hazard regression model. Data analyses are truncated
at 54 months, as <10% of patients had an observation time >54 months
CI, confidence interval; CV, cardiovascular; HR, hazard ratio
Marso et al. N Engl J Med 2016;375:311–22
 LEADER summary

• Liraglutide reduced the risk for 3-point MACE by 13%

• All 3 components of MACE contributed to the risk reduction
• Liraglutide reduced the risk of CV death by 22%
• Consistency across all primary and secondary cardiovascular
outcomes

• No increase in hospitalization for heart failure

• No difference between those with or without heart failure at
baseline

• Liraglutide reduced the risk of all-cause death by 15%

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

Clinical decision-making as a result of CVOTs
Treatment guidelines updates
July September November January February
2016 2016 2016 2017 2017

Italy
Switzerland Canada USA

Norway

Germany Brazil

CVOT, cardiovascular outcomes trial

ADA 2018
ADA 2018
 Pharmacologic Therapy For T2DM: Recommendations (4)
• In patients with T2DM and established ASCVD, antihyperglycemic
therapy should begin with lifestyle management and metformin and
subsequently incorporate an agent proven to reduce major adverse
CV events and CV mortality (currently empagliflozin and
liraglutide), after considering drug-specific and patient factors
(Table 8.1). A

• In patients with T2DM and established ASCVD, after lifestyle

management and metformin, the antihyperglycemic agent
canagliflozin may be considered to reduce major adverse CV
events, based on drug-specific and patient factors (Table 8.1). C

Pharmacologic Approaches to Glycemic Treatment:

Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Clinical decision-making as a result of CVOTs
Label updates as a result of CVOTs – empagliflozin1

• Empagliflozin label update in Canada:

Add-on combination in patients with established cardiovascular disease: JARDIANCE is indicated

as an adjunct to diet, exercise and standard care therapy to reduce the incidence of cardiovascular death
in patients with type 2 diabetes mellitus and established cardiovascular disease who have inadequate
glycemic control (see CLINICAL TRIALS).

CVOT, cardiovascular outcomes trial

1. Boehringer Ingelheim (Canada). JardianceTM (empagliflozin) Product Monograph, 25 July 2016
78
 79

Pharmacologic Therapy for T2D Patients

Summary of Recommendations

Recommendation LOE
Metformin, if not contraindicated and if tolerated, is the preferred initial A
pharmacologic agent for the treatment of type 2 diabetes.
In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy A
does not achieve or maintain the A1C goal over 3 months, add an additional
antihyperglycemic agent based on drug-specific and patient factors
A patient-centered approach should be used to guide the choice of pharmacologic agents. E
Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular
disease, impact on weight, potential side effects, renal effects, delivery method (oral versus
subcutaneous), cost, and patient preferences.
In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, A
antihyperglycemic therapy should begin with lifestyle management and metformin and
subsequently incorporate an agent proven to reduce major adverse cardiovascular
events and cardiovascular mortality (currently empagliflozin and liraglutide), after
considering drug-specific and patient factors
In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after C
lifestyle management and metformin, the antihyperglycemic agent canagliflozin may
be considered to reduce major adverse cardiovascular events, based on drug-specific
and patient factors.
Metformin should be continued when used in combination with other agents, including A
insulin, if not contraindicated and if tolerated

©2018 by American Diabetes Association

Case Study
Mr. Samer

A 70--year-old patient with type 2 diabetes and is being treated for prostate
cancer with an androgen inhibitor. His fasting blood glucose remains between
140 mg/dL (7.8mmol/dl) and 180 mg/dL (10 mmol/L )despite treatment with a
sulfonylurea and basal insulin. His HbA1c is usually between 8.1% and 8.9%. He
also takes digoxin for mild heart failure and once-daily furosemide. His Serum
Creatinine is 1.0 mg/dl

He tends to stay outside all day working on his car or talking to neighbours, and
he forgets to drink liquids,.

He has episodes during which he becomes confused, and when testing his blood
glucose, it will be all the way down to 40 mg/dL (2.2 mmol/L). His wife does a
finger stick and then treats it.

81
Patient profile Clinical implications
• Age: 70 years • Elderly
• GFR: 74ml/min/1.73m2 • Moderate renal
impairment
• Stays out all day
• Doesn’t urinate
• Doesn’t drink liquids frequently
• FBG: 140mg/dl-180mg/dl • Dehydrated easily
• Hb1AC: 8.1-8.9% • Not well controlled
Medication history: Disease history
• Metformin • Diabetic
• SU’s • History of hypoglycemia
• Insulin
• Androgen inhibitor • Prostate cancer
• Heart failure
• Digoxin .Furosemide

82
What is your A1C target for Samer?

• A) A1C < 6.5%?

• B) A1C < 7.0%?
• C) A1C < 7.5%?
• D) A1C < 8.0%

83
What is the CV risk level of the patient?
a) Low risk
b) Medium risk
c) High risk

84
Risk Factors
• Diabetic
• Heart failure
• Elderly

85
What are the lifestyle modifications that need to be
done?

a) Diet ?
b) Exercise?
c) Patient Education?
d) All of the above ?

86
Best treatment option for the patient
a) Add on DPP4i to SU and insulin
b) Add on Empagliflozin to SU and insulin
c) Change the regimen to Empagliflozin+ Metformin +
adjust insulin dose
d) Change to Dapagliflozin + Metformin + adjusted
insulin dose
e) Other combination

87
Thank You!