This document discusses type 2 diabetes and cardiovascular disease. It provides the following key points: 1. Type 2 diabetes significantly increases the risk of cardiovascular disease, which is the leading cause of death in people with type 2 diabetes. Even modest reductions in blood sugar levels through treatment can substantially reduce cardiovascular risks. 2. Multiple modifiable risk factors like hypertension, dyslipidemia, and smoking are common in people with type 2 diabetes and contribute to increased cardiovascular risk. A multifactorial treatment approach targeting these risk factors alongside blood sugar control is recommended to reduce complications. 3. Incretin-based therapies that target the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide pathways

1. Email: usamaragab@medicine.zu.edu.eg, Usama.ragab.zu@gmail.com
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2. Agenda
• Type 2 Diabetes 101
• Incretin based therapy
• Algorithms of management
Dr. Usama Ragab Youssif 2

3. 3 | IDF Diabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed
Highlights
In 2021, IDF estimates show that:
1 in 2
Adults is undiagnosed
240 million people
11.5%
Of global health expenditure spent
on diabetes (USD 966 billion)
1 in 10
Adults (20-79 years)
has diabetes
537 million people
1 in 6
Live births (21 million) affected
by hyperglycaemia in pregnancy,
80% have mothers with GDM
6.7 million
Deaths attributed to diabetes
1 in 18
Adults (20-79 years) has
impaired fasting glucose
319 million people
1 in 9
Adults (20-79 years) has
impaired glucose tolerance
541 million people
1.2 million
Children and adolescents below
20 years have type 1 diabetes
3 in 4
People with diabetes live in
low and middle-income countries

4. 5 | IDF Diabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed
Number of people with diabetes
Aged 20–79 years globally and by IDF region

5. Diabetes in Middle-East and North Africa
Dr. Usama Ragab Youssif 6

6. 7 | IDF Diabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed
Top 10 countries with diabetes
In adults aged 20–79 years and diabetes-related health expenditure, 2021
10

7. Top 10 countries or territories for number of adults (20–79 years)
with diabetes in 2021 and 2045
Dr. Usama Ragab Youssif 8

8. Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1
• T2D approximately doubles the risk
of death2
• Diabetes caused 6.7 million deaths
in 20211
• CVD is the principal cause of death
in T2D2,3
1.76
1.85
1 1.5 2.0
T2D is increasingly prevalent and CVD is the leading
cause of death in this population
9
1. IDF Diabetes Atlas, 2021. 10th Edition. http://www.idf.org/diabetesatlas.
2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 3. Morrish et al. Diabetologia 2001;44(suppl 2):S14–21.
• Globally, 537 million people are living
with diabetes1
• Rising to 783 million by 20451
Relative risk for
all-cause mortality
Relative risk for
CV mortality
Dr. Usama Ragab Youssif

9. Key manifestations of CV disease
10
1. World Health Organization 2015: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1
2. http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp#
Peripheral arterial
disease
Disease of blood vessels
supplying arms and legs1
Coronary
heart disease
Disease of blood vessels
supplying heart muscle1
Stroke
Caused by disruption of blood
supply to the brain1
Heart failure
Failure of the heart to pump
blood with normal efficiency
(sometimes called congestive
heart failure)2
Dr. Usama Ragab Youssif

10. Diabetes is
ASCVD risk
equivalent
N Engl J Med 1998;339:229-34.
Dr. Usama Ragab Youssif 11

11. Modifiable CV risk factors are common in patients
with T2D1,2
12
Almost a third of diabetes patients were current smokers2
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.
Dr. Usama Ragab Youssif

12. Progression of Type 2 Diabetes and Related
Complications1
(1) Conceptual representation
Insulin level
Insulin resistance
Hepatic glucose
production
Postprandial
glucose
Fasting plasma glucose
Beta-cell function
Progression of Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Diabetes Diagnosis
Diabetes
4–7 years
Development of Macrovascular Complications
Development of Microvascular Complications
Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes.
Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.
Dr. Usama Ragab Youssif 13

13. Reduction in The Risk of Diabetes Related Complications
Stratton IM1, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner
RC, Holman RR. Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ.
2000 Aug 12;321(7258):405-12.
Any End point
Related to
Diabetes
Death Related
to Diabetes
Stroke Microvascular End
points
Amputation or Death
form Peripheral Vascular
Disease
Heart
Failure
Myocardial
Infarction
-21 %
-14 %
-16%
-12% -37%
-43%
-21%
1% Reduction in HbA1C
1%
Dr. Usama Ragab Youssif 14

14. Progression from NGT to T2DM
Blood Test levels for Diagnosis of Diabetes &
Prediabetes
(1)
FBG
(mg/dL)
2-H PG
(mg/dL)
HbA1c
(%)
Diabetes ≥126 ≥200 ≥6.5
Prediabetes 100-125 140-199 5.7-6.4
Normal <100 <140 <5.7
2
15
NGT: Normal Glucose Tolerance
T2DM: Type 2 Diabetes Mellitus
IGT: Impaired Glucose Tolerance
Ref. DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003
The Diabetes Risk Score A practical tool to predict type 2 diabetes risk
Dr. Usama Ragab Youssif

15. How to approach
16
Dr. Usama Ragab Youssif

16. What would
your ideal
diabetes drug
do?
• Effective in lowering HbA1c
• No hypoglycemia
• No effect on weight/ weight loss?
• Not CV harmful or to be
beneficial
• Safe with few/no side effects
• Comorbidities
• Patient preference
• Cost
• Others
17
There is no one size fits all
Dr. Usama Ragab Youssif

17. Pharmacotherapy Options
Traditional
Commonly used
Biguanides
SU
TZDs
Insulin
Not Commonly
used
AGIs
Glinides
Newer
Commonly used
DPP4i
GLP1 RA
SGLT2i
Not Commonly
used
Dopamine
agonist
Amylin mimetics
BAS
Dr. Usama Ragab Youssif 18

18. From diabetes triumvirate
Dr. Usama Ragab Youssif 19

19. The Ominous Octet
ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288.
Adapted from DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Slide credit: clinicaloptions.com
Liver α-cells
β-cells
Brain
Intestine
Kidney
Fat
HYPERGLYCEMIA
Muscle

20. Current Antihyperglycemic Medications
Slide credit: clinicaloptions.com
ADA. Diabetes Care. 2018;41:S73.
Amylin
Mimetics
Suppress
glucagon
-Glucosidase
Inhibitors
Slow intestinal
carbohydrate
absorption
Colesevelam
Sequesters
intestinal
bile acids
DPP-4 Inhibitors
Increase insulin
secretion, suppress
glucagon
SGLT2
Inhibitors
Block renal
glucose
reabsorption
Insulin
Replacement
Therapy
Bromocriptine
Modulates
hypothalamic
regulation of
metabolism
Biguanides
Reduce hepatic
glucose production
GLP-1 Analogues
Increase insulin
secretion
TZDs
Increase insulin
sensitivity
Sulfonylureas
Increase insulin
secretion
Multiple
mechanisms
of action
Glinides
Increase insulin
secretion

21. 120
60
0
100
120
140
140
80
360
300
240
The Pathogenesis of Type 2 Diabetes:
Contributions of Insulin and Glucagon
Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com
Carbohydrate Meal
-60 120 180 240
Time (min)
Insulin
(µU/mL)
Glucagon
(pg/mL)
Glucose
(mg/dL)
Healthy Subjects (n = 14)
60
0
Type 2 Diabetes (n = 12)

22. 120
60
0
100
120
140
140
80
360
300
240
The Pathogenesis of Type 2 Diabetes:
Contributions of Insulin and Glucagon
Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com
Carbohydrate Meal
-60 120 180 240
Time (min)
Insulin
(µU/mL)
Glucagon
(pg/mL)
Glucose
(mg/dL)
Healthy Subjects (n = 14)
Type 2 Diabetes (n = 12)
60
0

23. Incretin Concept: 1906
“[T]he internal secretion of the pancreas might be stimulated
and initiated … by a substance of the nature of a hormone or
secretin yielded by the duodenal mucous membrane.”
Intestinal Secretion of Insulin
Moore. Biochem J. 1906;1:28. Slide credit: clinicaloptions.com

24. The Incretin Effect Is Diminished in Persons With Type 2
Diabetes
Oral glucose load
Time, min
Control Subjects (n = 8)
Insulin,
mU/L Normal Incretin Effect
Subjects With Type 2 Diabetes (n = 14)
Diminished Incretin Effect
Time, min
Insulin,
mU/L
Nauck. Diabetologia. 1986;29:46. Slide credit: clinicaloptions.com
Intravenous glucose infusion
80
60
40
20
0
180
60 120
0
80
60
40
20
0
180
60 120
0

25. Role of Incretins in Glucose Homeostasis
Release
Active
GLP-1 and GIP
↑ Glucose
uptake by
muscles
Decreased
blood
glucose
↓ Glucose
production
 ↑ Glucose-dependent
insulin release, ↑ -cell
regeneration? (GLP-1
and GIP)
 ↓ Glucose-dependent
glucagon release from
-cells (GLP-1)
Inactive
↓ gut
motility
DPP-4
↑ Satiety
↓ appetite
Adapted from Drucker. Cell Metab. 2006;3:153. Nauck. Am J Med. 2011;124:S3. Slide credit: clinicaloptions.com
Pancreas

26. Dr. Usama Ragab Youssif 28
Glucose Regulation
Jabbour SA. Postgrad Med 2014;126:111-17.
Gerich JE. Diabet Med 2010;27:136-42.
Meyer C, et.al. Am J Physiol Endocrinol Metab 2002;282:E419-E27.

27. Na+
SGLT2
inhibitor1
*Loss of ~80 g/day of glucose =320 cal/day
GLUT2; glucose transporter 2
1. Bakris GL et al. Kidney Int 2009;75:1272; 2. Jardiance® (empagliflozin) summary of product characteristics
SGLT2 inhibitors enhance the excretion of glucose,
sodium and water into the urine
29
SGLT2 inhibitors reduce
glucose and sodium
reabsorption in the proximal
tubule, leading to urinary
glucose excretion,* natriuresis
and osmotic diuresis1,2
Filtered glucose
(~180 g/day)
and sodium1
Na+
Glucose
K+
Na+
SGLT2
Proximal
tubular cells
SGLT2
inhibitor
Glucose
GLUT2
Blood Lumen
~80 g/day
of glucose2
Na+
Na+
SmPC updated

28. To Address Complexity of T2D, Consider Targeting
Therapies to Complementary Pathophysiologic Defects
ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288. Slide credit: clinicaloptions.com
INSULIN
TZD
MET
SGLT2i
SFU
GLP-1 RA
DPP-4i
Liver α-cells
β-cells
Brain
Intestine
Kidney
Fat
HYPERGLYCEMIA
Muscle

29. Factors Affecting Pt Adherence to Glucose-
Lowering Medications
 Hypoglycemia
 Weight gain
 GI adverse events
 Inconvenience
 Aversion to injections
 Costs
 Stigma
Slide credit: clinicaloptions.com
Hauber AB, et al. Diabet Med. 2009;26:416-424.
Peyrot M, et al. Curr Med Res Opin. 2009;25:1985-93.
Fabunmi R, et al. Curr Med Res Opin. 2009;25:777-786.

30. Hypoglycemia risk and drugs
Dr. Usama Ragab Youssif 33

31. 1. NHS. Shared decision-making. https://www.england.nhs.uk/wp-content/uploads/2019/01/shared-decision-making-summary-guide-v1.pdf (accessed Feb 2023);
2. American Diabetes Association. Diabetes Care 2023;46:S1; 3. Nelson LA et al. Diabetes Res Clin Pract 2018;142:374
Shared decision making can improve disease outcomes and
treatment adherence1,2
34
Adherence is key but remains suboptimal among people with T2D3
Shared decision making2
Clinician: Practical steps to
manage risk factors and reduce the
risk of complications
Person: Needs and preferences
Review and assess laboratory results
Joint evidence-based decision on treatment plan
Shared decision making is a collaborative process that supports a person and their healthcare
professional to work together to reach a joint decision1

32. Guidelines and society recommendations endorse a multifactorial approach in people with
early T2D to manage risk factors and reduce their risk of complications1–3
35
• Overweight/obese
• Hypertension
• Dyslipidaemia
• Smoking4–6
• β-cell dysfunction
• Insulin resistance
• Hyperglycaemia7,8
A1C: blood glucose control3
A
BP: blood pressure control3
B
Cholesterol control3
C
Drugs to protect
the heart/kidneys3
D
Exercise/diet/achieve a
healthy body weight3
E
Screening for complications,
smoking cessation and
stress management3
S
Leading hypotheses shown; additional factors may contribute to progression of complications
1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Cosentino F et al. Eur Heart J 2020;7:255; 3. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42:S1;
4. Leon BM & Maddox TM. World J Diabetes 2015;6:1246; 5. Sposito AC et al. Cardiovasc Diabetol 2018;17:157; 6. Cade WT. Phys Ther 2008;88:1322; 7. Marwick TH et al. J Am Coll Cardiol 2018;71:339;
8. DeFronzo RA et al. Diabetes 2009;58:773; 9. Fowler MJ. Clinical Diabetes 2011;29:116; 10. Song MK et al. J Diabetes Res 2014;2014:e313718; 11. Bugger H & Abel ED. Diabetologia 2014;57:660;
12. Galicia-Garcia U et al. Int J Mol Sci 2020;21:6275; 13. Hayden MR et al. Cardiorenal Med 2013;3:265; 14. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 15. McCullough PA et al. Contrib Nephrol
2013;182:82; 16. Chen Y et al. Kidney Dis 2020;6:225
Neuropathy9
Retinopathy9
Metabolic10,11
and haemodynamic
changes
Atherosclerosis12
CV and kidney
complications14,15
Stroke12
Dementia13
Nephropathy6,10,16
CV disease12
MI10
Heart failure10,11

33. Glucose-Centric Algorithm for Glycemic Control
Endocrine Practice 29 (2023) 305e340
Dr. Usama Ragab Youssif 36

34. Complication-Centric Algorithm for Glycemic Control
Endocrine Practice 29 (2023) 305e340
Dr. Usama Ragab Youssif 37

35. ADA 2023 Standards of Medical Care recommends a multifactorial
approach to reduction in the risk of diabetes complications
38
Reduction in diabetes complications
Glycaemic
management
Blood pressure
management*
Lipid
management
Agents with CV
and kidney
benefit†
Lifestyle modifications and diabetes education
*Blood pressure should be measured at every routine clinical visit. When possible, individuals found to have elevated blood pressure (120–129/<80 mmHg) should have blood pressure confirmed using multiple
readings, including measurements on a separate day, to diagnose hypertension. Hypertension is defined as ≥130/≥80 mmHg based on ≥2 measurements obtained on ≥2 occasions. Individuals with blood
pressure ≥180/110 mmHg and CV disease could be diagnosed with hypertension at a single visit. All hypertensive people with diabetes should monitor their blood pressure at home, targets should be
individualised through a shared decision-making process that addresses CV risk, potential adverse effects of antihypertensive medications and person preferences; †Risk reduction interventions to be applied
as individually appropriate
American Diabetes Association. Diabetes Care 2023;46:S1

36. Identify barriers to goals if HbA1c is above target
Figure adapted from the ADA-EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for full
recommendations, please refer to the reference.
TZD, thiazolidinedione. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753
ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2:
Goal – achievement and maintenance of glycaemic and weight management goals
There are several treatment options ranked by level of efficacy
for glycaemic and weight management for people with T2D
39
Efficacy for weight loss
To avoid therapeutic inertia
reassess and modify
treatment regularly
(3–6 months)
Efficacy for glucose lowering
Very high:
Dulaglutide (high dose), semaglutide, tirzepatide
Insulin, combination oral, combination injectable (GLP-1 RA/insulin)
High:
GLP-1 RA (not listed above), metformin, SGLT2 inhibitor,
sulphonylurea, TZD
Intermediate:
DPP-4i
Very high:
Semaglutide, tirzepatide
High:
Dulaglutide, liraglutide
Intermediate:
GLP-1 RA (not listed above), SGLT2 inhibitor
Neutral:
DPP-4i, metformin
Achievement and management of weight-management goals
Set individualised weight-management goals and consider:
Consider a glucose-lowering regimen with
high-to-very-high dual glucose and weight efficacy
Glycaemia management: choose approaches that
provide the efficacy to achieve goals
Metformin OR agent(s) including combination therapy that
provide adequate efficacy to achieve and maintain goals
Consider avoidance of hypoglycaemia
a priority in high-risk individuals
Lifestyle
advice
Weight-management
programme
Medication for
weight loss
Metabolic
surgery

37. Figure adapted from ADA–EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for
full recommendations, please refer to the reference.
1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753
Please see speaker notes for footnotes and abbreviations
ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2:
Goal – cardio-renal risk reduction in high-risk people with T2D*†
SGLT2 inhibitors are recommended as a first-line treatment option in the
management of people with T2D at high risk of cardio-renal events
40
+ASCVD/indicators of
high risk‡
To avoid therapeutic inertia,
reassess and modify treatment
regularly (3–6 months)
+HF
SGLT2 inhibitor¶
with proven benefit in
this population
People with HF
Preferably SGLT2 inhibitor¶
with primary evidence of reducing
CKD progression
Use SGLT2 inhibitor in people with an
eGFR ≥20 ml/min per 1.73 m2;
once initiated, should be continued
until dialysis or transplantation
GLP-1 RA
with proven CV benefit
if SGLT2 inhibitor not
tolerated or
contraindicated
Or
People with CKD (on maximally tolerated dose of ACEi/ARB)
If HbA1c above target, for individuals on SGLT2 inhibitor,
consider incorporating a GLP-1 RA or vice versa
+CKD
People with ASCVD/indicators
of high risk
GLP-1 RA§
with proven
CVD benefit
• For individuals on a GLP-1 RA consider adding SGLT2
inhibitor with proven CVD benefit or vice versa
• TZD**
If HbA1c above target
SGLT2 inhibitor¶
with proven
CVD benefit
Either/
or
Identify barriers to goals if additional cardio-renal risk reduction or glycaemic-lowering needed

38. (A) refers to the level of evidence in the ADA evidence grading system. To consult the ADA evidence grading system 2023, please refer to page 9 of the reference
*For SGLT2 inhibitors, CV/renal outcomes trials demonstrate their efficacy in reducing the risk of composite MACE, CV death and ACM, MI, HHF and renal outcomes in individuals with T2D with
established/high risk of CVD
ACEi, angiotensin-converting enzyme inhibitors; ACM, all-cause mortality; ARB, angiotensin receptor blockers; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DKD, diabetic
kidney disease; MRA, mineralocorticoid receptor antagonist
American Diabetes Association. Diabetes Care 2023;46:S1
ADA 2023 Standards of Medical Care in Diabetes:
adults with T2D and CKD
ADA 2023 Standards of Medical Care includes several
treatment options for people with T2D and CKD
41
11.5a For people with T2D and DKD, use of an
SGLT2 inhibitor is recommended to reduce CKD
progression and CV events in people with an
eGFR rate ≥20 ml/min/1.73 m2 and urinary
albumin ≥200 mg/g creatinine. A
11.5c In people with T2D and DKD, consider use
of SGLT2 inhibitors (if eGFR rate is ≥20
ml/min/1.73 m2), or a GLP-1 RA or non-steroidal
MRA (if eGFR ≥25 ml/min/1.73 m2) additionally
for CV risk reduction. A
11.5d In people with CKD and albuminuria who
are at increased risk for CV events or CKD
progression, a non-steroidal MRA shown to be
effective in clinical trials is recommended to
reduce CKD progression and CV events. A
Preferably SGLT2 inhibitor*
with primary evidence of reducing
CKD progression
Use SGLT2 inhibitor in people with an eGFR
≥20 ml/min per 1.73 m2;
once initiated, should be continued until
dialysis or transplantation
GLP-1 RA
with proven CV benefit if
SGLT2 inhibitor not tolerated
or contraindicated
Or
People with CKD (on maximally tolerated dose of ACEi/ARB)
If HbA1c above target, for individuals on SGLT2 inhibitor,
consider incorporating a GLP-1 RA or vice versa
+CKD

39. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease
ASCVD, atherosclerotic cardiovascular disease
American Diabetes Association. Diabetes Care 2023;46:S1
What factors should be considered when selecting
metformin for people with T2D?
42
Neutral
Kidney effects
Route of administration Oral
• No increased risk of hypoglycaemia
• Gastrointestinal side effects (diarrhoea, nausea)
common
Safety considerations
HbA1c efficacy High
Weight Neutral (potential for modest loss)
Metabolism
effects*
HF Neutral
Effect on MACE Potential benefit
CV effects

40. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease
*Evidence is lacking on the effect of sulphonylureas on blood pressure; †Beyond glucose lowering effects
ASCVD, atherosclerotic cardiovascular disease
American Diabetes Association. Diabetes Care 2023;46:S1
What factors should be considered when selecting a second-generation
sulphonylurea as an add-on treatment for people with T2D?
43
Neutral†
Kidney effects
Route of administration Oral
Increased risk of hypoglycaemia
Safety considerations
HbA1c efficacy High
Weight Increase
Metabolism
effects*
HF Neutral†
Effect on MACE Neutral†
CV effects

41. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease
*A meta-analysis concluded that thiazolidinediones appear to decrease blood pressure, although this effect is small and may not be clinically significant2;
†Beyond glucose lowering effects. ASCVD, atherosclerotic cardiovascular disease; NASH, nonalcoholic steatohepatitis
1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Qayyum R & Adomaityte J. J Clin Hypertens (Greenwich) 2006;8:19
What factors should be considered when selecting a
thiazolidinedione as an add-on treatment for people with T2D?
44
Neutral†
Kidney effects1
HbA1c efficacy1 High
Weight1 Increase
Metabolism
effects*
HF1 Increased risk
Effect on MACE1 Potential benefit: pioglitazone
CV effects
Route of administration1 Oral
• No increased risk of hypoglycaemia
• Possible congestive HF (pioglitazone, rosiglitazone)
• Fluid retention (oedema, HF), benefit in NASH, risk of bone
fractures
Safety considerations1

42. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease
*The effect of DPP-4 inhibitors on blood pressure, beyond glucose-lowering effects, is neutral2–4; †Beyond glucose-lowering effects. ASCVD, atherosclerotic
cardiovascular disease. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al.
Front Endocrinol 2017;8:6; 4. Rosenstock J et al. JAMA 2019;322:1155
What factors should be considered when selecting a
DPP-4 inhibitor as an add-on treatment for people with T2D?
45
Neutral†
Kidney effects1
• No increased risk of hypoglycaemia
• Pancreatitis has been reported in clinical trials but causality
has not been established. Discontinue if suspected
• Joint pain
• Bullous pemphigoid (postmarking). Discontinue if suspected
Safety considerations1
HbA1c efficacy1 Intermediate
Weight1 Neutral†
Metabolism
effects*
HF1 Potential risk with saxagliptin
Effect on MACE1 Neutral†
CV effects
Route of administration1 Oral

43. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease
*Aside from lowering blood glucose, GLP-1 RAs have blood pressure-lowering effects2–5; †Beyond glucose-lowering effects. ‡Reduction in meal size, mindful eating
practices (e.g. stop eating once full), decreasing intake of high-fat or spicy food. ASCVD, atherosclerotic cardiovascular disease; GI, gastrointestinal.
1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al. Front Endocrinol 2017;8:6; 4. Vilsbøll
T et al. Diabetes Care 2007;30:1608; 5. Reid T. Clinical Diabetes 2012;30:3
What factors should be considered when selecting a
GLP-1 RA for people with T2D?
46
Albuminuria benefit in CVOTs, kidney outcome study ongoing
Kidney effects1
• No increased risk of hypoglycaemia
• Counsel persons on potential for GI side effects and their typically temporary
nature; provide guidance on dietary modifications to mitigate GI side effects‡;
consider slower dose titration for people experiencing GI challenges
• Pancreatitis has been reported in clinical trials but causality has not been
established. Discontinue if suspected
• Risk of thyroid C-cell tumours in rodents; human relevance not determined
• Evaluate for gallbladder disease if cholelithiasis or cholecystitis is suspected
Safety considerations1
HbA1c efficacy1 High
Weight1 Reduction
Metabolism
effects*
HF1 Neutral†
Effect on MACE1 Benefit: dulaglutide, liraglutide, semaglutide; neutral: exenatide,
lixisenatide
CV effects
Route of administration1 Injectable; oral (semaglutide)

44. See labels of individual agents for CV outcomes data, kidney dose considerations and information regarding use in people with kidney disease/assessment of kidney
function prior to initiation *Ertugliflozin is not approved for HF; †Benefit demonstrated for ertugliflozin for a pre-specified exploratory kidney outcome (40% reduction in eGFR, KRT, or
death from kidney causes) but not for its key kidney outcome (death from kidney causes, KRT, doubling of serum creatinine);6,7 ‡Discontinue, evaluate, and treat promptly if suspected. Be
aware of predisposing risk factors and clinical presentation (including euglycemic DKA), discontinue before scheduled surgery (e.g., 3–4 days), during critical illness, or during prolonged
fasting to mitigate potential risk. ASCVD, atherosclerotic cardiovascular disease; DKA, diabetic ketoacidosis; KRT, kidney replacement therapy. See slide notes for references
What factors should be considered when selecting an SGLT2
inhibitor for people with T2D?
47
Benefit:† canagliflozin, empagliflozin, dapagliflozin
Kidney effects1
• Hypoglycaemia when in combination with insulin or secretagogues (an adjustment of
these agents may be necessary to reduce the risk of hypoglycaemia)2─5
• DKA risk, rare in T2D‡
• Increased risk of genital mycotic infections
• Necrotising fasciitis of the perineum (Fournier gangrene), rare reports: institute
prompt treatment if suspected
• Attention to volume status, blood pressure; adjust other volume-contracting agents
as applicable
Safety considerations1
HbA1c efficacy1 Intermediate
Weight1 Reduction
Metabolism
effects
HF1 Benefit: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin*
Effect on MACE1 Benefit: empagliflozin, canagliflozin
CV effects
Route of administration1 Oral

45. Copyright ADA/EASD 2022
Glucose-dependent insulinotropic polypeptide (GIP)
receptor and GLP-1 receptor agonist (tirzepatide)
• Glucose-lowering mechanism of action: GIP receptor and GLP-1 receptor agonist; enhances
first and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-
dependent manner
• Clinical Efficacy profile: Very high glycaemic efficacy; low inherent risk of hypoglycaemia;
weight loss (high); cardiorenal effects unknown (trials in progress)
DaviesMJ,ArodaVR,CollinsBS,GabbayRA,GreenJ,MaruthurNM,RosasSE,DelPratoS,MathieuC,MingroneG,RossingP,TankovaT,TsapasA,BuseJB
DiabetesCare2022;https://doi.org/10.2337/dci22-0034.Diabetologia2022;https://doi.org/10.1007/s00125-022-05787-2.

46. Copyright ADA/EASD 2022
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 organisation
aimed at achieving therapeutic goals
DaviesMJ,ArodaVR,CollinsBS,GabbayRA,GreenJ,MaruthurNM,RosasSE,DelPratoS,MathieuC,MingroneG,RossingP,TankovaT,TsapasA,BuseJB
DiabetesCare2022;https://doi.org/10.2337/dci22-0034.Diabetologia2022;https://doi.org/10.1007/s00125-022-05787-2.
.

47. Treat to Failure
Traditional stepwise approach versus early intervention approach to diabetes management, adapted from Del Prato S, et al.
A stepwise approach often leads to unacceptable delays in achieving and maintaining glycemic goals. An early intervention approach can be considered a ‘proactive’ approach versus the ‘reactive’
stepwise approach and is suggested to provide better and more rapid glycemic control. OAD, oral antidiabetic drug.
1. Khunti K, et al. Prim Care Diabetes 2017;11:3–12; 2. Khunti K, et al. Diabetes Care 2013;36:3411‒7; 3. Del Prato S, et al. Int J Clin Pract. 2005;59:1345–55.
Early intervention approach
(conceptual data)
10
HbA
1c
%
9
8
7
6
2.9 years 7.2 years
6.7 years
Time
8.5%
OAD
monotherapy
9.7%
Insulin
8.7%
OAD dual
combination
9.1%
OAD triple
combination
Traditional stepwise
treatment approach
(actual data)
Dr. Usama Ragab Youssif 50

48. Dr. Usama Ragab Youssif
The 2022 ADA–EASD consensus report recommends that
combination therapy should be tailored to the individual
51
Combination therapy has several potential
advantages including:
1) Increased durability of the glycaemic
effect, addressing therapeutic inertia
2) Simultaneous targeting of the multiple
pathophysiological processes
characterised by T2D
3) Impact on medication burden,
medication-taking behaviour,
adherence and treatment persistence
4) Complementary clinical benefits
(e.g. on glycaemic control, weight and CV
risk profiles and additional cardio-renal risk
reduction*)
Glycaemic management:
choose approaches that provide the
efficacy to achieve goals:
Metformin OR agent(s) including COMBINATION
therapy that provide adequate EFFICACY to achieve
and maintain treatment goals
Consider avoidance of hypoglycaemia a
priority in high-risk individuals

49. Elderly
Dr. Usama Ragab Youssif 52

50. Treatment recommendations for elderly =
Simplify Simplify Simplify Simplify
Avoid strict
glycemic target
to avoid hypo
Metformin is
first line if
tolerated not CI
DPP4i is safe
tolerable
Assess
adherence avoid
polypharmacy
Dr. Usama Ragab Youssif 53

51.  High risk of hypoglycemia: sulfonylureas; meal-time insulin
1. ADA. Diabetes Care. 2021;44:S168. 2. pro.aace.com/disease-state-resources/diabetes/guidelines.
Medications With Low Risk of Hypoglycemia
Oral
Metformin
Pioglitazone
DPP-4 inhibitors
SGLT2 inhibitors
Injection
GLP-1 RA
Basal insulin
Slide credit: clinicaloptions.com

52. Patients with CKD
Dr. Usama Ragab Youssif 55

53. Choice of treatment
https://doi.org/10.1016/j.kint.2020.06.019
Dr. Usama Ragab Youssif 56

54. eGFR values are ml/min per 1.73 m2. *For agent-specific recommendations, please refer to the manufacturers’ prescribing information. KDIGO, Kidney Disease: Improving
Global Outcomes; TZD, thiazolidinedione. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int 2022;102:S1
KDIGO 2022 treatment algorithm for selecting glucose-lowering drugs for people with
T2D and CKD
Lifestyle therapy in addition to first-line therapy is the cornerstone of
glycaemic management for people with T2D and CKD (2/4)
57
GLP-1 RA (preferred)
DPP-4 inhibitor Insulin
Sulphonylurea TZD
Alpha-glucosidase inhibitor
• Guided by individual
preferences, comorbidities,
eGFR and cost
• Includes people with eGFR
<30 ml/min/1.73 m2 or those
treated with dialysis
Metformin
eGFR <45 eGFR <30 Dialysis
Discontinue
Reduce
dose
Discontinue
SGLT2 inhibitor
eGFR <20* Dialysis
Do not initiate Discontinue
Lifestyle therapy
First-line
therapy
Additional drug therapy
as needed for
glycaemic control
Physical activity, nutrition and weight loss

55. Patient factors
influencing the
selection of
glucose-lowering
drugs other than
SGLT2i and
metformin in
T2D and CKD
Dr. Usama Ragab Youssif 58
Kidney International. 2022 Nov 1;102(5):S1-27.

57. Final bottom-line
Dr. Usama Ragab Youssif 60

58. Profiles of Antihyperglycemic Medications
MET GLP-1 RA SGLT2i DPP4i AGi TZD
(moderate
dose)
COLSVL BCR-QR INSULIN PRAML
HYPO Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral
Moderate to
severe
Neutral
WEIGHT Slight loss Loss Loss Neutral Neutral Gain Gain Neutral Neutral Gain Loss
RENAL/GU
Contra-
indicated
if eGFR <30
mL/min/1.73 m2
Exenatide
not indicated
CrCl <30
Not indicated for
eGFR <45
mL/min/1.73 m2
Dose adjustment
necessary (except
linagliptin)
effective in reducing
albuminuria
Neutral Neutral
More
hypo risk
Neutral Neutral
More
hypo risk
Neutral
See #1
Genital mycotic
infections
Potential
benefit of LA
GLP-1 RA
Potential CKD
Benefit; See #1
GI Sx Moderate Moderate Neutral Neutral Moderate Neutral Neutral Mild Moderate Neutral Moderate
CHF
CARDIAC
ASCVD
Neutral
Neutral
Prevent Hf
hospitalization
manage HFrEF;
see #2
See #4
HHF with saxagliptin
Neutral
Moderate Neutral Neutral Neutral CHF risk
Neutral
Possible
ASCVD risk
Lowers
LDL-C
Safe Neutral
Potential
benefit of LA
GLP-1 RA
May reduce
stroke risk
See #3
BONE Neutral Neutral Neutral Neutral Neutral
Moderate
fracture risk Neutral Neutral Neutral Neutral Neutral
KETOACIDOSIS Neutral Neutral
DKA can occur in
various stress
settings
Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral
SU
GLN
Severe
Mild
Few AEs or possible benefits
Use with caution
Likelihood of AEs
1. Canagliflozin indicated for eGFR ≥30 mL/min/1.73 m2 in patients with CKD 3 + albuminuria.
2. Dapagliflozin–potential primary prevention of HF hospitalization and demonstrated efficacy in HFrEF.
3. Empagliflozin–FDA approved to reduce CV mortality. Canagliflozin– FDA approved to reduce MACE events.
4. Possible increased hospitalizations for heart failure with alogliptin and saxagliptin.
Slide credit: clinicaloptions.com
American Association of Clinical Endocrinology. Endo Pract. 2020;26:139.

59. Thank You
Dr. Usama Ragab Youssif 62