This document discusses key aspects of type 2 diabetes treatment including goals, approach, and pharmacologic agents. The main goals are to reduce cardiovascular risk factors and achieve individualized glycemic targets to minimize complications. The recommended treatment approach is lifestyle changes and metformin as initial therapy, followed by adding other agents if needed. Agents that are preferentially recommended have a low risk of hypoglycemia and weight gain. Incretin-based therapies such as GLP-1 receptor agonists and DPP-4 inhibitors are important non-insulin options. Insulin therapy may be needed to intensify treatment for patients not achieving goals.

1. Type 2 Diabetes
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
Disease Characteristics and Goals
Reduce risk of
complications
•BP, lipid, and glycemic
management to reduce risk
of macrovascular
complications
•BP control and glycemic
management to reduce risk
of microvascular
complications
Cardiovascular
risk factor
reduction a key
goal
•Treat cardiovascular risk
factors to achieve
individualized targets
•Smoking cessations,
antihypertensive agents, and
lipid medications are among
the recommended agents
Individualize
treatment
•Lifestyle changes +
metformin as initial
antihyperglycemic therapy
for most patients
•Glycemic goals and treatment
choices are individualized
• Insulin resistance and relative insulin insufficiency
https://online.epocrates.com/diseases/2411/Type-2-diabetes-mellitus-in-adults/Key-Highlights
BP, blood pressure
Key
complications:
Nerve, kidney, eye,
and cardiovascular
diseases

2. Type 2 Diabetes
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
Prediabetes
• Prediabetes is a metabolic condition characterized by
hyperglycemia
– Diagnostic criteria below those used to define Type 2
diabetes eg, fasting plasma glucose concentrations are 5·6
mmol/L or higher but less than 7·0 mmol/L (termed
impaired fasting glucose [IFG])
Est., estimated
Garber AJ, Abrahamson MJ, Barzilay JI, Endocrine Practice. 2016;22(1):84-113.
Stefan N, Fritsche A, Schick F, et al. TLancet Diabetes & Endocrinology. 2016;4(9):789-98.
USA
>38% est.
to have prediabetes
China
>50% est.
to have prediabetes
In terms of pathophysiology, prediabetes reflects failing pancreatic islet
β-cell compensation for an underlying state of insulin resistance, most
commonly caused by excess body weight or obesity.

3. Type 2 Diabetes
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
Phenotyping of patients with prediabetes
• Stefan et al. (2016) proposed stratifying patients into
low- and high-risk groups
– High-risk: low insulin secretion or low insulin sensitivity plus
non-alcoholic fatty liver disease (NAFLD)
– Low-risk: Other combinations related to insulin secretion,
insulin sensitivity, and NAFLD eg, high body mass index or
visceral obesity
.
CVD, cardiovascular diseases; NAFLD, non-alcohol fatty liver disease; NGR, normal glucose regulation
Stefan N, Fritsche A, Schick F, et al. TLancet Diabetes & Endocrinology. 2016;4(9):789-98.
Prediabetes
and no
stratification
at baseline
Maybe intensive lifestyle intervention
will restore NGR
Prediabetes
and
stratification
at baseline
Better predictive power
as to the effectiveness
of lifestyle intervention
in restoring NGR;
Improves classification of hyperglycemia
and risk of CVD in prediabetics

4. Diabetes Epidemiology
Definition
Etiology
Diagnosis
Treatment
Prevention
Epidemiology
415 million people worldwide have diabetes; by
2040 this will rise to 642 million
(2015 International Diabetes Federation estimates)
The estimated annual global health expenditure attributable to diabetes ranged from USD 612 billion (to
USD 1099 billion. Together, the North America and Caribbean Region and the Europe Region were
responsible for over 69% of the costs, and less than 10% of the costs were from the Africa Region,
South East Asia Region, and Middle East and North Africa Region combined.
MENA, Middle East and North Africa
da Rocha Fernandes J, Ogurtsova K, Linnenkamp U, et al. Diab. Res. Clinical Prac. 2016;117:48-54.
http://www.diabetesatlas.org/
Every 6 seconds
someone dies
from diabetes
3.2%
In Africa, more than
two-thirds are undiagnosed;
Prevalence in MENA: 9.1%
Regional
Prevalence
(%)
North America
& Caribbean
12.9%
South & Central
America
9.4%
South-
East
Asia
8.5%
9.1%
37% of the diabetics across the globe live in the
Western Pacific (a region comprising 39 countries,
including China)

5. Type 2 Diabetes: Etiology/Pathophysiology
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• ≥40 years old
• Hereditary predisposition
• Pre-diabetic
• Woman who had gestational diabetes
• Woman who gave birth to a ≥9 lb baby
• Overweight/excess abdominal weight
• High BP or cholesterol issues
• Psychosocial disorders/HIV infection/polycystic ovarian
syndrome/acanthosis nigricans
• Specific medications eg, antipsychotics/anti-
inflammatory steroids
What are the risk factors?
BP, blood pressure; HIV, human immunodeficiency virus
Cheng AY. and members of the Clinical Practice Guideline Committees. CJD. 2013;37 Suppl 1:227 pp.

6. Type 2 Diabetes: Etiology/Pathophysiology
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Blood glucose appearance is a function of meal-derived
sources and hepatic glucose production
– Regulation occurs by pancreatic and gut hormones
– Liver and skeletal muscle responsiveness to insulin decline
with progressive β-cell dysfunction
– Insulin is a key anabolic hormone secreted in response to
increased blood glucose and amino acids following a meal
What role does insulin play?
Brunton SA, Kruger DF, Funnell MM. Clinical Diabetes. 2016;34(1):34-43; www.slideteam.net
Aronoff SL, Berkowitz K, Shreiner B et al.Diabetes Spectrum. 2004;17(3):183-90.

7. Type 2 Diabetes: Etiology/Pathophysiology
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Insulin resistance is aggravated by aging, physical
inactivity, and overweight (BMI 25-29.9 kg/m2) or
obesity (BMI >30 kg/m2)
• Complexity of intracellular derangements suggest the
disease may be stratified into many subtypes
Etiology
Pathophysiology
The precise
mechanism by
which the diabetic
metabolic state
leads to
microvascular and
macrovascular
complications is
only partly
understood.
Uncontrolled BP and uncontrolled
glucose, increasing the risk of
microvascular complications such
as retinopathy and nephropathy
With respect to macrovascular
complications, high BP and
glucose raise risk, but so do lipid
abnormalities and tobacco use.
One unifying theory postulates a metabolic
syndrome that includes diabetes mellitus,
hypertension, dyslipidemias, and obesity, and
predisposes to coronary heart disease, stroke,
and peripheral artery disease. However, this
theory is not universally accepted.
https://online.epocrates.com/diseases/2424/Type-2-diabetes-mellitus-in-adults/Etiology

8. Type 2 Diabetes – Diagnostic Approach
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• impaired glucose tolerance, impaired fasting glucose, or
metabolic syndrome are risk factors
– Any one of these factors is associated with a 5-fold increase
in future T2D risk
• Three tests indicate prediabetes
– Fasting plasma glucose test (blood sugar is 100-125)
– Oral glucose tolerance test (blood sugar is 140-199 after
the second test)
– A1C test: (blood sugar is 5.7 to 6.4%)
Prediabetes
http://www.webmd.com/diabetes/type-2-diabetes-guide/what-is-prediabetes-or-borderline-diabetes
Garber AJ, Abrahamson MJ, Barzilay JI, et al,. Endocrine Practice 2016;22(1):84-113.

9. Type 2 Diabetes – Diagnostic Approach
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Symptomatic patients may present with: fatigue;
polyuria, polydipsia, polyphagia, or weight loss (usually
when hyperglycemia is more severe, e.g., >300 mg/dL);
blurred vision; paresthesias; unintentional weight loss;
nocturia; skin infections (bacterial or candidal); urinary
infections; or acanthosis nigricans
Diagnosis should be verified by repeat testing.
1
3
24
One of 4 tests can confirm
a diagnosis of diabetes
1. Fasting plasma glucose (FPG) >125 mg/dL
(most commonly used)
2. Random plasma glucose
≥200 mg/dL
with diabetes symptoms such as
polyuria, polydipsia, fatigue,
or weight loss
3. 2-hour
post-load glucose ≥200 mg/dL
on a 75 g oral glucose tolerance tests
4. HbA1c ≥6.5%
https://online.epocrates.com/diseases/2431/Type-2-diabetes-mellitus-in-adults/Diagnostic-Approach

10. Type 2 Diabetes – Goals for Glycemic Control
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Strong risk factors, which also indicate the need for
screening, include: older age; overweight/obesity; black,
Hispanic, or Native American ancestry; family history of
Type 2 Diabetes; history of gestational diabetes;
presence of prediabetes; physical inactivity; polycystic
ovary syndrome; hypertension; dyslipidemia; or known
cardiovascular disease
For patients
with concurrent serious
illness and at high risk
for hypoglycemia
Diagnosis should be verified by repeat testing.
A1C
≤6.5%
A1C
>6.5%
For patients without
concurrent serious illness
and at low hypoglycemic risk
A1C, glycated hemoglobin
http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/a1c
http://answers.webmd.com/answers/1180327/what-blood-sugar-levels-are-considered-normal-and-what-levels-are-diabetic
http://www.webmd.com/diabetes/tc/criteria-for-diagnosing-diabetes-topic-overview/
Garber AJ, Abrahamson MJ, Barzilay JI, et al.Endocrine Practice 2016;22(1):84-113.
2. Glucose enters red blood cells and
glycates with molecules of hemoglobin (A1C)..
By measuring the percentage of A1C in
the blood, one gets
an overview of your average
blood glucose control for the past
few months.
1. Hemoglobin, a protein that
links up with sugars such as
glucose, is found inside red blood cells.
Its job is to carry oxygen from the
lungs to all the cells of the body.

11. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Since patients are 2x likely to die from CVDs vs. the
general population, a 1◦ goal is treatment of CVD risk
factors to individualize targets
Approach
Cornerstonetreatmentforall
patients
Initialglucose-lowering
pharmacotherapies
CVDriskfactors
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
This is a progressive disease
and prompt initiation and
intensification of
pharmacotherapy to achieve
and maintain clinical goals is
central to diabetes care.
https://online.epocrates.com/diseases/2441/Type-2-diabetes-mellitus-in-adults/Treatment-Approach
CVD, cardiovascular disease

12. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• The priority in management is to minimize the risks of
hypoglycemia and weight gain. The AACE preferentially
recommends agents that do not increase these risks
Pharmacologic Agentsa
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
Abbreviations: AACE = American Association for Clinical Endocrinology; AGI = α-glucosidase inhibitors; BCR-QR = bromocriptine quick release; DPP4I = dipeptidyl peptidase 4
inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas;
TZD = thiazolidinediones; a Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight gain, few adverse events, and/or the possibility of benefits beyond
glucose lowering. b Use with caution. Handelsman Y, Bloomgarden ZT, Grunberger G,et al. Endocrine Practice. 2015;21 Suppl 1:1-87.
Metformin;
GLP1RA;
SGLT2I; DPP4I;
AGI; TZDb;
SU/glinideb
GLP1RA;
SGLT2I;
TZDb; Basal
insulinb; DPP4I;
Colesevelam;
BCR-QR; AGI;
SU/glinideb
GLP1RA;
SGLT2I; DPP4I;
TZDb; Basal
insulinb;
Colesevelam;
BCR-QR; AGI;
SU/glinideb
1First-line
treatment
2Metformin
(or other
first-line agent) plus
3First- and
second-line
agent plus

13. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Research on two incretins ie, glucagon-like peptide-1
(GLP-1) and gastric inhibitory peptide (GIP), led to the
development of GLP-1 receptor (GLP-1R) agonists and
DPP-IV inhibitors
Incretins: Key non-insulin therapies
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
DPP IV, Dipeptidyl Peptidase IV; GLP-1,R Glucagon-like peptide- receptors; MOA, mechanism of action;
Chatterjee S, Davies MJ. Postgrad Med J. 2015;91(1081):612-21.
Can be used in conjunction with insulin to
optimize control, reduce its weight gain
effects and lower daily insulin dose
requirements
GLP-1R agonist use
Improved HbA1c (up to 1.6%);
minimal risk of hypoglycemia and often
significant weight loss/neutrality depending
on the incretin and patient factors
Result
Can be used safely in worsening renal
impairment, with some agents such as
linagliptin,
which is mainly excreted enterohepatically
requiring no dose adjustment even in end-
stage renal failure
DPP IV inhibitor use
MOA
Increase insulin secretion (via β cells)
and reduce glucagon secretion,
hepatic glucose production and glucose uptake
from the stomach and promote satiety

14. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Synthetic insulin (6,000 Da) consists of an A chain of 21
amino acids and a B chain of 30 amino acids
• In the body, insulin is generated by cleavage of the C-
peptide from proinsulin
Insulin Synthesis
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
Brunton SA, Kruger DF, Funnell MM. Role of Emerging Insulin Clinical Diabetes. 2016;34(1):34-43
Fu Z, Gilbert ER, Liu D. Current Diabetes Reviews. 2013;9(1):25-53; http://www.slideteam.net/.

15. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Typically-used insulin classes are shown here
– Administration modes are via
pen/pump/syringe/subcutaneous infusion
– Many novel insulin products and delivery
systems may provide T2D patients to initiate
insulin more comfortably and earlier in the
disease process
Types of Insulin
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
http://guidelines.diabetes.ca/cdacpg_resources/Ch12_Table1_Types_of_Insulin_updated_Aug_5.pdf
Bolus
(prandial)
insulins
Basal
insulins
Premixed
insulins

16. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Insulin should be intensified within 3-6 months of failure
to meet glycemic targets (Brunton et al, 2016)
– Benefits of early use/intensification eg, improvements in
glycemic control/QoL/treatment satisfaction
– Insulin is often initiated late in the natural history of the
disease
The Insulin Conundrum
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
QoL, quality of life
Brunton SA, Kruger DF, Funnell MM. Clinical Diabetes. 2016;34(1):34-43.
Patient Barriers
Concerns over safety and efficacy of insulin
Hypoglycemia or weight gain concerns
Psychological eg, a perceived failure to take
the hormone
Concern that insulin is associated with
complications or even death
Fear of a loss of independence
Clinician Barriers
Need for education about the benefits of
appropriately-initiated insulin therapy
Patients reluctance to use injected insulin
may preclude initiation of a chat about the
hormone
Time-consuming for staff to provide patient
training regarding insulin use/Remote
practices may not have access to needed
training materials
Overall goal of insulin and non-insulin therapies is
to lower basal hepatic glucose production and
increase muscle glucose uptake

17. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Guidelines promote personalized management with a
special focus on safety beyond efficacy based on
prespecified approaches
AACE/ACE Management Algorithm (Part 1)
Metformin
Dual-drug
combinations education
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Endocrine Practice 2016;22(1):84-113.
Lifestyle therapy,
including
medically
Supervised
weight loss.
The A1C target
must be individualized.;
Glycemic control
Targets include fasting
& postprandial
glucoses
Patient characteristics,
net costs to patients,
formulary restrictions,
& personal preferences
are among the factors
to be taken into
account in the choice
of therapies.
Minimizing risk
of hypoglycemia
is a priority.
Minimizing risk
of weight gain
is a priority.
Total cost of care
adds up eg,
monitoring requirements,
initial acquisition
cost of medications,
weight gain, safety etc..

18. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Guidelines promote personalized management with a
special focus on safety beyond efficacy based on
prespecified approaches
AACE/ACE Management Algorithm (Part 2)
Metformin
Dual-drug
combinations education
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Endocrine Practice 2016;22(1):84-113.
Algorithm stratifies
choice of therapies
based on initial A1C.
Combination therapy
Is usually required &
should involve agents
with complementary
actions.
Lipid/blood pressure
profiles and related
comorbidity assessments
should form part of
comprehensive
management.
Initially therapy
should be evaluated
frequently until
stable & then less
often..
Keep therapy
as simple as
possible to
optimize adherence
The algorithm includes
every FDA-approved
class of diabetes
medications

19. Type 2 Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• 180 medicines are currently being developed to treat
diabetes. Other therapies are listed here.
Emerging therapies
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
http://www.phrma.org/sites/default/files/pdf/diabetes2014.pdf
https://online.epocrates.com/diseases/2443/Type-2-diabetes-mellitus-in-adults/Emerging-Therapies
Bariatric surgery Cinnamon
Other agents
eg, salsalate,
human insulin
inhalation
powder
Therapeutic benefits vary;
younger patients (40-50)
with more recent-onset
disease had higher benefits
than older patients with
longer-duration illness.
More study is needed to
confirm findings that cinnamon
reduces blood sugars with
minimal effect on HbA1c..
Further study is needed to
confirm HbA1c-lowering
capacity of salsalate; Although
rapid-acting inhaled insulin
Is FDA-approved, this drug is
not preferred over injectable
Insulins. The latter drugs have
a longer safety track record.

20. Diabetes Treatment
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Novel therapies, including immunomodulation, are being
investigated to treat/prevent all forms of diabetes
Future Directions
Smoking
cessation
Blood
pressure
control
Statin use
Aspirin use
for patients
with known
coronary
heart disease
ACE inhibitors
for patients
with chronic
kidney
disease/protei
nuria
Metformin
Dual-drug
combinations Self-
management
program
Nutrition
education
Chatterjee S, Davies MJ.. Postgrad Med J. 2015;91(1081):612-21.
Preserving/increasing β-cell
function • ‘Bionic’
pancreas
• Islet transplants
Immunomodulation
• Antigen-specific
and non-
antigen-specific
agents
• Stem cell
transplantation
Intensify prevention
strategies
• Optimizing lifestyle changes/
using metformin in prediabetes
may prevent T2DM, but difficult
to translate clinical data into
real-world practice
Pharmacological
therapies
• Oral insulin
• Fecal
transplants

21. Type 2 Diabetes
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• Goals
Patient Education
Cheng AY. and members of the Clinical Practice Guideline Committees. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention
and management of diabetes in Canada.
CJD. 2013;37 Suppl 1:227 pp.
Smoking
cessation
S
M
A
R
T
Specific,
Measurable,
Attainable,
Relevant,
Time-bound
Diabetes Education and
Nutrition
Enable timely, culturally
and literacy appropriate diabetes education and resources
Physical activity/
weight loss/medication
Hypoglycemia/
Self-monitoring of
blood glucose (SMBG)
Foot care/Mental Health
and Mood Disorders

22. Type 2 Diabetes: Prevention
Definition
Epidemiology
Etiology
Diagnosis
Treatment
Prevention
• 86 million are living with prediabetes, a serious health
condition that increases a person’s risk of type 2
diabetes and other chronic diseases.
Control of the main disease drivers
http://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htm
https://online.epocrates.com/diseases/2444/Type-2-diabetes-mellitus-in-adults/Prevention
Modest weight loss;
diet; exercise;
certain
phamracotherapies
subject to
consideration of side
effects
Annual influenza
and
pneumococcal
polysaccharide
vaccines as
appropriate;
Regular dental
care; Diabetes
education as
needed
Prediabetes Type 2 diabetes