Module 3:

Pharmacotherapy for
Diabetes Management

10
8
Overview of Management
of Diabetes

10
9
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
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Welcome to the Sanofi

After this chapter you should be able to

Diabetes A a
c
de
my Programme.
This educational programme
was developed in
collaboration with the
American Diabetes
Association.

This chapter provides an

overview of the therapeutic
landscape for people living
Define glycemic targets for patients living with diabetes with diabetes.

Before proceeding, read the

listed learning objectives.

Describe the various non-insulin agents approved for management

of type 2 diabetes

Describe the various types of insulins

Outline various ways insulin therapy can be delivered for people

living with type 1 diabetes
Section
1lycemic targets for patients living with
G
diabetes
 Presenter Notes
2022-11-18 [Link]
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What measures do we use to assess glucose Diabetes control is assessed

by g yc
lem
ci measures, such A1C
measurement, or continuous

control? glucose monitoring (CGM)

using either time in range
(TIR) and/or glucose
management indicator
(GMI), and blood glucose
monitoring (BGM). [1] A1C is
the metric used to assess
glycemic control in clinical
• Hemoglobin A1C trials which demonstrated
the benefits of improved
glycemic control. [1]
•
Blood glucose via self monitoring (using a traditional Other measures of average
glycemia such as fructosamine

glucometer)
and 1,5-anhydroglucitol,
glycated albumin are
available, but their
translation into average
• Continuous glucose monitor (CGM) glucose levels and their
prognostic significance are
not as clear as for A1C and
• Fructosamine CGM. [1] Reference:
American
Diabetes Association Proe fss
oinal
• 1,5-anhydroglucitol Practice Committee. 6.
Glycemic Targets: Standards
of Medical Care in
• Glycated albumin Diabetes—2022 Diabetes
Care 2022;45(Suppl. 1):S83
S96.

American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated hemoglobin; CGM, continuous glucose
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. monitoring.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---
Reference:

Hemoglobin A1C
American
Diabetes Association Proe fss
oinal
Practice Committee. 6.
Glycemic Targets: Standards
of Medical Care in
Diabetes—2022 Diabetes
Care 2022;45(Suppl. 1):S83
S96.
• A1C reflects what the average glucose was over
approximately the previous 3 months

• A1C is the primary tool for evaluating glycemic control and

has a strong predictive value for diabetes complications

• The A1C should be performed in a laboratory that uses NGSP-

certified assays (see [Link]) to ensure accuracy and
standardization.

American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated hemoglobin; NGSP, National
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. Glycohemoglobin Standardization Program.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---
Reference:

How often should the A1C be performed?

American
Diabetes Association Proe fss
oinal
Practice Committee. 6.
Glycemic Targets: Standards
of Medical Care in
Diabetes—2022 Diabetes
Care 2022;45(Suppl. 1):S83
S96.
• At least two times a year in patients who are meeting
treatment goals (and who have stable glycaemic control)

• At least every 3 months and as needed in patients who

have had a change in therapy and/or who are not meeting
their glycaemic goals.

American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. hemoglobin.
 Presenter Notes
2022-11-18 [Link]

How does A1C correlate with the average -----------------------------------------

---
References:

blood glucose?
American Diabetes
Association Po re
fs
oinal Practice
Committee. 6. Glycemic
Targets: Standards of
Table 1: Estimated average glucose (eAG)1 Medical Care in Diabetes—
2022 Diabetes Care
A1C (%) mg/dL* mmol/L 2022;45(Suppl. 1):S83 S96.
eAG/A1C Conversion
Calculator. Accessed on 11th
5 97 (76–120) 5.4 (4.2–6.7) August 2022. Available at:

6 126 (100–152) 7.0 (5.5–8.5)

ľ h e íelationship between A1C and eAG is [Link]
org/diapro/glucose_calc
descíibed by the foímula 28.7 X A1C – 46.7
7 154 (123–185) 8.6 (6.8–10.3)
= eAG.2
8 183 (147–217) 10.2 (8.1–12.1)
Data in parentheses are 95% CI. A calculator for converting A1C results into eAG,
9 212 (170–249) 11.8 (9.4–13.9) in either mg/dL or mmol/L, is available at [Link]/eAG.

10 240 (193–282) 13.4 (10.7–15.7) *These estimates are based on ADAG data of 2,700 glucose measurements over 3
months per A1C measurement in 507 adults with type 1, type 2, or no diabetes.
11 269 (217–314) 14.9 (12.0–17.5) The correlation between A1C and average glucose was 0.92.

12 298 (240–347) 16.5 (13.3–19.3)

1. American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated hemoglobin; ADAG, A1C-derived
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. average glucose; eAG, estimated average
2. eAG/A1C Conversion Calculator. Accessed on 11th August 2022. glucose.
Available at: [Link]
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
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Clinicians should use

Limitations of A1C accuracy judgment when using A1C as

the only method for
assessing glycemic control,
especially if the result is
close to the threshold that
might prompt a change in
Conditions that affect red blood cell turnover: medication therapy. [1]
Any condition that affect red
blood cell turnover
• Glucose-6-phosphate dehydrogenase (hemolytic and other
anemias, glucose-6-
• Hemolytic anemia phosphate dehydrogenase
deficiency, recent blood
• Blood transfusion transfusion, use of drugs
that stimulate
• Erythropoietin therapy erythropoesis, end-stage
kidney disease, and
• End stage kidney disease pregnancy) may result in
discrepancies between the
A1C result and the patient’s
• Pregnancy true mean glycemia.
Hemoglobin variants must
be considered, particularly
when the A1C result does
not correlate with the
Some hemoglobin variants patient’s CGM or BGM
levels. [1] Reference:
American Diabetes
People who are heterozygous for the common hemoglobin variant Association Proe fsso
Committee. 6. Glycemic
inal Practice

HbS have lower A1C by about 0.3 % points when compared with Targets: Standards of
Medical Care in Diabetes—
those without the trait. 2022 Diabetes Care
2022;45(Suppl. 1):S83-S96.

American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated hemoglobin; HbS, hemoglobin
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. variant.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
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A1C does not provide a

Other limitations of A1C

measure of glycemic
variability or hypoglycemia.
For patients prone to
glycemic variability,
especially patients with type
1 diabetes or type 2
diabetes with severe insulin
deficiency, glycemic control
• A1C does not assess glycaemic is best evaluated by the
combination of results from
BGM/CGM and A1C. [1]
variability Discordant results between
BGM/CGM and A1C can be
the result of the conditions
• A1C does not assess hypoglycaemia outlined above or glycemic
variability, with BGM missing
the extremes. [1]
Reference:
American Diabetes
Association Proe fsso
inal Practice
If there are discrepancies between results from blood Committee. 6. Glycemic
Targets: Standards of
glucose monitoring and the expected A1C suspect Medical Care in Diabetes—
2022 Diabetes Care

one of the reasons for limitations mentioned above. 2022;45(Suppl. 1):S83-S96.

American Diabetes Association Professional Practice Committee. 6. Glycemic Targets: A1C, glycated
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S83 S96. a hemoglobin.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
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Glucose Assessment by Continuous Glucose CGM is now a standard

method for glucose
monitoring for most adults

Monitoring (CGM) with type 1 diabetes. [3]

CGM is rapidly improving
diabetes management. As
stated in the
recommendations, time in
range (TIR) is a useful metric
• CGM measures interstitial glucose of glycemic control and
glucose patterns, and it
• Interstitial glucose correlates well with plasma glucose when glucose correlates well with A1C in
most studies. [3] Use of CGM
levels are steady. devices should be
considered from the outset of
the diagnosis of diabetes
• CGM readings may lag behind plasma glucose if glucose levels are rising that requires insulin

or falling rapidly. management

BGM and CGM can be useful
to gudie medical nutrition
• There are two basic types of CGM devices: therapy and physical
activity, prevent
hypoglycemia, and aid
• Professional: (owned, and applied by the clinic).Readings are not medication management. [3]

available to the patient but can be downloaded by the clinician for Reference:Diabetes
American
Association
Committee.
Technology:
Medical Care
P
o
e
ro
fsn
7. ial Practice
Diabetesof
Standards
inCare
Diabetes—
evaluation of glycaemic control. 2022 Diabetes
2022;45(Suppl.
S112. 1):S97–

• Personal: (owned and applied by the user). Glucose levels are

available to the patient and can be accessed in real-time (rtCGM) or
by intermittently scanning their CGM.

American Diabetes Association Professional Practice Committee. 7. Diabetes Technology: CGM, continuous glucose monitoring; rtCGM, real time
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S97–S112. CGM.
 Presenter Notes

Markers of glycemic control from the continuous

2022-11-18 [Link]
-----------------------------------------
---
References:

glucose monitor American Diabetes

Association Po
re
fss
oinal Practice
Committee; 6. Glycemic

Information obtained from the CGM is summarized in a standard report Targets: Standards of
Medical Care in Diabetes—

called the Ambulatory Glucose Profile or AGP. 2022. Diabetes Care

2022;45 (Suppl. 1):S83–S96.

Table 2: Standardized CGM metrics for clinical care

1. Number of days CGM device is worn (recommend 14 days)
2. Percentage of time CGM device is active (recommend 70% of data from 14 days)
3. Mean glucose
4. Glucose management indicator
The AGP report 5. Glycemic variability (%CV) target ≤36%*
includes: 6. TAR: % of readings and time >250 mg/dL (>13.9 mmol/L) Level 2 hyperglycemia
7. TAR: % of readings and time 181–250 mg/dL (10.1–13.9 mmol/L) Level 1 hyperglycemia
8. TIR: % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range
9. TBR: % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1 hypoglycemia
10. TBR: % of readings and time <54 mg/dL (<3.0 mmol/L) Level 2 hypoglycemia
*Some studies suggest that lower %CV targets (<33%) provide additional protection against
hypoglycemia for those receiving insulin or sulfonylureas.

American Diabetes Association Professional Practice Committee. 6. Glycemic AGP, ambulatory glucose profile; CGM, continuous glucose monitoring; CV,
Targets: Standards of Medical Care in Diabetes—2022 Diabetes Care coefficient of variation; TAR, time above range; TBR, time below range; TIR,
2022;45(Suppl. 1):S83 S96. time in range.
 Presenter Notes
Figure 1: Decision Cycle For Patient-centered Glycemic Management 2022-11-18 [Link]
In T2D -----------------------------------------
---
GMI tells you what your
approximate A1C level is likely
to be, based on the average
glucose level from your CGM
readings for 14 or more
days. [4]
GMI gives you the A1C level
that w d
o
ul usually be expected
from a large number of
individuals with diabetes

Example
who have the same average
CGM glucose level as you.
[4] References:
Battelino T, Danne T,

of an Bergenstal R M, et al. Clinical

Targets for Continuous
Glucose Monitoring Data

AGP
Interpretation:
Recommendations From the
International Consensus on
Time in Range. Diabetes

report
Care. 2019;42(8):1593-
1603.

Battelino T et al. Diabetes Care. 2019;42(8):1593- AGP, ambulatory glucose profile; CGM, continuous
1603. glucose monitoring; GMI, glucose management
 Presenter Notes
2022-11-18 [Link]

Significance of glucometrics obtained from the CGM

-----------------------------------------
---
References
Advani A. Positioning time in
range in diabetes
management. Diabetologia.
2020;63(2):242-252.

Time in range (TIR)1,2

Vigersky RA, McMahonC. The
rea
lto
inshp
i of hemoglobin A1C to
time-in-range in patients
• Correlates with A1C (Glucose management indicator or with diabetes. Diabetes
Technol Ther 2019;21: 81–
85
GMI) Wright EE Jr, Morgan K, Fu
• May correlate with risk of diabetes-related complications DK, et al. Time in Range: How
to Measure It, How to Report
• Acceptable end-point to assess glycemic control in clinical It, and Its Practical
Application in Clinical
studies Decision-Making. Clin
Diabetes. 2020;38(5):439-
448.

Time below range (TBR)1,3 Tumminia A, Crimi S, Sciacca

L, et al. Efficacy of real-time
continuous glucose
• Assess risk of severe hypoglycemia monitoring on glycaemic
control and glucose
• Can be used to modify insulin plan variability in type 1 diabetic
patients treated with either
insulin pumps or multiple
Time above range (TAR)3 insulin injection therapy: a
randomized controlled
crossover trial. Diabetes
• Can be used to modify insulin timing and dose Metab Res Rev.
2015;31(1):61-68.

Glucose variability4
A1C, glycated hemoglobin; CGM, continuous glucose
• Correlates with diabetes complications monitoring; GMI, glucose management indicator;
TAR, time above range; TBR, time below range; TIR,
time in range.
1. Advani A. Diabetologia. 2020;63(2):242-252.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---
Reference:

Benefits of CGM in clinical practice

American Diabetes
Association P o
e
ro
fsn
ial Practice
Committee. 7. Diabetes
Technology: Standards of
Medical Care in Diabetes—
2022 Diabetes Care
2022;45(Suppl. 1):S97–
S112.

• Can be useful to minimize hypoglycaemia risk

• Information obtain may help guide medical nutrition therapy
and physical activity recommendations
• Data can be uploaded to a cloud based platform to
facilitate remote clinical care
• May help prevent future complications of diabetes

American Diabetes Association Professional Practice Committee. 7. Diabetes Technology: CGM, continuous glucose
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S97–S112. monitoring.
 Presenter Notes

CGM targets in different populations, 2022-11-18 [Link]

-----------------------------------------
---

consensus panel report 2019 Patient should have >70% of

CGM data in last 2 weeks to
interpret results and apply
these targets. [4] Reference:
Figure 2: CGM-based targets for different diabetes Battelino T, Danne T,
populations Bergenstal R M, et al. Clinical
Older/High- Targets for Continuous
Pregnancy:
risk: Pregnancy: Glucose Monitoring Data
T1D & T2D >140 Gestational &
T1D# & T2D T1D## mg/dL T2D*** Interpretation:
(7.8 Recommendations From the
>250 >250 mg/dL mmol/L) International Consensus on
mg/dL
(13.9 (13.9 >140 Time in Range. Diabetes
mmol/L) mmol/L) mg/dL
>180 mg/dL * 63-140 mg/dL Care. 2019;42(8):1593-
(7.8 (3.5-7.8
(10.0
mmol/L)
>180 * mmol/L) mmol/L)  #For age<25 year,1603.
if the A1C goal is 7.5%,
mg/dL
(10.0
mmol/L)
then set TIR target to approximately
60%.
 ##Percentage of TIR are based on
limited evidence.
70-180 63-140 mg/dL  ***Percentages of TIR have not been
(3.9-10.0
mg/dL (3.5-7.8
mmol/L) included because there is very limited
mmol/L)
evidence in this area. More research is
needed.
70-180 mg/dL  *Includes percentage of value >250
(3.9-10.0
mmol/L) mg/dL
 **Includes percentage of values <54
mg/dL
<63 mg/dL
(3.5 <63 mg/dL
<70 mg/dL mmol/L) (3.5
(3.9 * mmol/L)
mmol/L)
* *
* <70 mg/dL
<54 mg/dL
<54 mg/dL
<54 mg/dL (3.0
(3.9 (3.0
(3.0 mmol/L)
mmol/L) mmol/L)
mmol/L)

A1C, glycated hemoglobin; CGM,

Battelino T et al. Diabetes Care. 2019;42(8):1593- continuous glucose monitoring; T1D, 12
1603. type 1 diabetes; T2D, type 2 diabetes; 3
TIR, time in range.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Glycaemic targets in different populations ---

Reference:
American Diabetes
Association; 14. Children and
Adolescents: Standards of
Medical Care in Diabetes—
2022. Diabetes Care
2022;45(Suppl. 1):S208–
A1C for most non pregnant adults is an A1C of <7% (53 mmol/mol), or lower if this can be
S231.

safely achieved without hypoglycaemia or adverse side effects

A1C <8% (64 mmol/mmol) in people with several co-morbidities and limited life-
expectancy, in whom the side effects and burden of treatment outweigh the
benefit of lower glucose values.

In children and adolescents: blood glucose targets:

• A1C of <7.5% (58 mmol/mol) may be appropriate for most, but should be individualized
• A1C <8% may be appropriate in the setting of risk of hypoglycaemia or hypoglycaemia
unawareness
• A1C <6.5% is associated with lower risk of microvascular disease and may be appropriate if
there is a low burden of treatment and low risk of hypoglycaemia.
• Before exercise: blood glucose targets 90-250 mg/dL (5.0-13.9)

American Diabetes Association; 14. Children and Adolescents: A1C, glycated

Standards of Medical Care in Diabetes—2022. Diabetes Care hemoglobin.
2022;45(Suppl. 1):S208–S231.
 Presenter Notes
2022-11-18 [Link]

Decision guide to determine stringency of

-----------------------------------------
---
Patient and disease factors
used o t determine optimal

glycaemic target Figure 3: Approach to Individualization of Glycemic

Targets
glycemic targets.
Characteristics and
predicaments toward the left
justify more stringent efforts
to lower A1C; those toward
the right suggest less
stringent efforts. A1C 7% 53
mmol/mol. [1] References:
American Diabetes
Association Po re
fss
oinal Practice
Committee; 6. Glycemic
Targets: Standards of
Medical Care in Diabetes—
2022 Diabetes Care
2022;45 (Suppl. 1):S83–S96.

American Diabetes Association Professional Practice Committee; 6. Glycemic Targets: A1C, glycated
Standards of Medical Care in Diabetes—2022 Diabetes Care 2022;45 (Suppl. 1):S83–S96. hemoglobin. 12
5
Section
2
Describe the various non-insulin agents approved for
management of type 2 diabetes
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: ADA Guidelines: Patient-Centric Approach -----------------------------------------
---
The ADA 2022 guidelines for
the e ra
tm
t ent of T2DM emphasise
Figure 4: Decision Cycle For Patient-centered Glycemic Management In on a patient-centric
T2D
Review and Agree on Management As per the ADA 2022 approach.
guidelines, In this approach,
a
factors such as patient
Plan Assess Key Patient preferences, assessment of
• Review management plan
Characteristics patient- centric approach is
• Mutual agreement on changes literacy and numeracy skills
• Current lifestyle
•Ensure agreed modification of • Comorbidities, i.e., ASCVD, CKD, HF recommended for theand addressing of
treatment cultural
therapy is implemented barriers to care need to be
• Clinical characteristics, i.e., age,
in a timely fashion to avoid clinical HbA1C, weight T2D, which takes intoconsidered
account tothe decide on an
inertia • Issues such as motivation and optimum therapeutic
• Decision cycle undertaken protocol. [10]
depression following factors:
regularly (at least once/twice • Cultural and socioeconomic
a year) context
Consider Specific FactorsThat The attributes of an ideal
Impact Choice Of Treatment therapy ear discussed in the
Ongoing Monitoring and Support • Individualized HbA1C target subsequent frame. [10]
• Impact on weight and hypoglycemia
Including Goals of •
References:
• Emotional well-being Side effect profile of medication
• American Diabetes
Complexity of regimen, i.e., frequency,
• Check tolerability of medication care mode of administration Association Pore
fso
sinal Practice
• Monitor glycemic status  Prevent •Choose regimen to optimize adherence Committee; 4.
• Biofeedback including BGM, weight, complicatio and persistence Comprehensive Medical
step count HbA1C, blood pressure, ns • Access, cost, and availability of Evaluation and Assessment
lipids  Optimize quality medication of Comorbidities: Standards
of life
Shared Decision-making to Create A of Medical Care in Diabetes -
2022. Diabetes Care
Management Plan
Implement Management Plan 2022;45(Suppl. 1):S46-S59.
•Involves an educated and informed
•Patients not meeting goals generally
patient (and their
should be seen at least every 3
family/caregiver)
months as long as progress is being • Seeks patient preferences
made; more frequent contact •Effective consultation includes
initially is often desirable for DSMES
motivational interviewing,
Agree on Management Plan goal setting, and shared decision-
• Specify SMART goals: making
- Specific • Empowers the patient
- Measurable • Ensures access to DSMES
- Achievable
- Realistic
- Time limited
ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease;
BGM,
American Diabetes Association Professional Practice Committee; 4. Comprehensive Medical Evaluation and blood glucose monitoring; CKD, chronic kidney disease; DSMES, diabetes self-management
Assessment of Comorbidities: Standards of Medical Care in Diabetes - 2022. Diabetes Care 2022;45(Suppl.
127
1):S46-S59.
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Pharmacological Approach -----------------------------------------
---
Pharmacological treatment of
T2DM involves prescribing anti-
diabetic drugs and/or
insulin. Sulphonylureas,
Currently Available non- insulin Anti-Diabetic Drugs for the Treatment of T2DM as per ADA 2022 non-sulphonylurea
secretagogues, dipeptidyl
Guidelines: peptidase-4 (DPP-4)
inhibitors and glucagon-like
peptide-1 (GLP-1) agonists
increase pancreatic insulin
∙ Biguanides secretion; biguanides
∙ Glucagon-like peptide-1 (GLP-1) receptor
decrease hepatic glucose
∙ Sulphonylureas agonists production; α-glucosidase
inhibitors decrease gut
∙ Dual GLP-1 carbohydrate absorption;
∙ Thiazolidinediones thiazolidinediones increase
∙ Bile acid sequestrants peripheral glucose disposal;
and sodium-glucose co-
∙ Alpha-glucosidase inhibitors transporter 2 (SGLT2)
∙ Dopamine-2 agonists inhibitors block reabsorption
∙ Meglitinides of glucose in the kidneys
and increase glucose
∙ Amylin mimetics excretion.[11] References:
∙ Dipeptidyl peptidase-4 (DPP-4) inhibitors American Diabetes
Association Po re
fss
oinal Practice
∙ Sodium-glucose co-transporter 2 (SGLT2) Committee; 9.
Pharmacologic Approaches
inhibitors to Glycemic Treatment:
Standards of Medical Care
in Diabetes—2022 Diabetes
Care 2022;45(Suppl.
1):S125–S143.

American Diabetes Association Professional Practice Committee; 9. ADA, American Diabetes Association; DPP-4, dipeptidyl peptidase-4
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical GI, gastrointestinal; GLP-1, glucagon-like peptide-1; SGLT2, sodium-
Care in Diabetes—2022 Diabetes Care 2022;45(Suppl. 1):S125–S143. glucose co- transporter 2 ; T2DM, type 2 diabetes mellitus. 12
8
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Pharmacological Approach -----------------------------------------
---
Pharmacological treatment of
T2DM involves prescribing anti-
Drug targets of currently available non-insulin anti-Diabetic Drugs diabetic drugs and/or
insulin. Sulphonylureas,
non-sulphonylurea
secretagogues, dipeptidyl
peptidase-4 (DPP-4)
inhibitors and glucagon-like
peptide-1 (GLP-1) agonists
increase pancreatic insulin
secretion; biguanides
decrease hepatic glucose
production; α-glucosidase
inhibitors decrease gut
carbohydrate absorption;
thiazolidinediones increase
peripheral glucose disposal;
and sodium-glucose co-
transporter 2 (SGLT2)
inhibitors block reabsorption
of glucose in the kidneys
and increase glucose
excretion.[12] References:
Feingold KR. Oral and Injecta
ble
N
(onn
Is-u
i)l
Pharmacological Agents for t
he Treatment of Type 2 Diabe
tes. [Updated 2021 Aug n: Fe
ingold KR, Anawalt B, Boyce
A, et al., editors. Endotext [In
ternet]. South Dartmouth (M
A): [Link], Inc.; 2000. A
vailable at: [Link]
[Link]/books/NBK27914
1

Feingold KR et al. Endotext [Internet]. Available at: GI, gastrointestinal; SGLT2, sodium-glucose co-
transporter 2. 12
[Link]
9
 Presenter Notes
2022-11-18 [Link]

Physiologic effects of either GIP/GLP-1 or Both -----------------------------------------

---
Reference:
Baggio LL, Drucker DJ.
Glucagon-like peptide-1 receptor
co-agonists for treating
metabolic disease. Mol
Metab. 2021;46:101090.

GIP, gastric inhibitory peptide; GLP-1,

Baggio LL, et al. Mol Metab.
glucagon like peptide; TG, triglycerides.
2021;46:101090.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Biguanides
---
Reference:
DeFronzo RA, Goodman AM.
Effi
cacy of metformin in patients
with non-insulin-dependent
diabetes mellitus. The
Multicenter Metformin Study
Group. N Engl J Med.
1995;333(9):541-549
Efficacy: Lowers A1C from 0.9-1.4%

Advantage: Weight neutral, widely available, good safety profile

Available as:
• Metformin Immediate Release
• Extended Release (Glucophage)

Preparation: Oral tablets or suspension

Primary Target: Decrease hepatic glucose release by the liver, insulin sensitivity at the muscle

Side effects: Gastrointestinal upset (bloating, diarrhea), lactic acidosis. Should not be used in
patients with end stage liver or kidney disease.

DeFronzo RA et al. N Engl J Med. 1995;333(9):541- A1C, glycated

549 hemoglobin.
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Disadvantages -----------------------------------------
---
The main side effect of
metformin is gastrointestinal
(GI) intolerance, which
includes nausea, abdominal
pain and diarrhoea. As
ADA 2022 Recommendations for Use of Metformin Based on eGFRs shown on the screen, the
percentage of GI intolerance
is more in patients taking
metformin as compared with
those taking placebo. It
eGFR (mL/min/1.73 m ) Recommendations regarding metformin
2
occurs in approximately 30%
of patients and is frequent if
the drug is rapidly up-
≥ 60 No dosage adjustment necessary. Monitor renal function at least annually. titrated. This can be
minimised by gradually up-
titrating the drug and
administering it after food.
>45 to <60 No dosage adjustment necessary. Metformin plasma concentrations mayAnother be disadvantage of
higher metformin is that it cannot
compared to patients with an eGFR ≥60. Monitor renal function every 3be toused
6 in patients with
liver disease or in people
months with alcohol abuse or binge
drinking, who are at a higher
eGFR 30 to 45 Do not initiate therapy. If the patient is already taking metformin then may risk of developing liver
continue at a reduced dose up to a maximum of 500 mg twice daily with disease. The reason is that
these patients are at a higher
close monitoring of kidney function. risk of developing lactic
acidosis.[15] The ADA 2022
recommendations for use of
eGFR <30 Discontinue metformin in patients with
chronic renal dysfunction
are presented on the screen.
Metformin can be used with
caution in patients with an
estimated glomerular
filtration rate (eGFR) of <60
ADA American Diabetes Association.11. Chronic Kidney Disease and Risk ADA, American DiabetesmL/min
Association;
and is
Management: Standards of Medical Care in Diabetes—2022 Diabetes Care eGFR, estimated glomerular
contraindicated in patients
2022;45(Suppl. 1):S175–S184. filtration rate. with an eGFR of <30 13
mL/min.[16] 2
References:
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Sulfonylureas
---
Reference:
Heller SR; ADVANCE
Collaborative Group. A
summary of the ADVANCE
Trial. Diabetes Care. 2009;32
Efficacy: Lowers A1C by 1.5 to 2% Suppl 2(Suppl 2):S357-S361.

Advantage: Widely available. Can be dosed once or twice daily. Effective at lowering glucose

Primary target: Secretagogue, they Bind to the sulphonylurea receptors and cause the closure of the ATP-
sensitive K+ channel, resulting in insulin secretion

Available as:
• Glimepiride
• Glipizide IR and XL
• Glyburide and Glyburide micronized)
• Glicazide
• Glibenclamide
• Glimepiride

Preparation: Oral

Side effects: hypoglycemia, weight gain, increased risk of cardiovascular disease

A1C, glycated hemoglobin; ATP, adenosine

Heller SR. Diabetes Care. 2009;32 Suppl 2(Suppl 2):S357-
triphosphate; IR, immediate release; XL, extended
S361.
release.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Comparison of cardiovascular mortality It has been established that

sup
lhonyu
lreas cause
hypoglycaemia. This

associated with sulphonylureas and metformin hypoglycaemia may directly

be related to weight gain.
[15] With long-term use, a
progressive decline in the
efficacy of sulphonylureas
has been observed.[18]
The 5-year survival rates and unadjusted risk ratios (with 95% CIs) for mortality, cardiovascular mortality and Several studies have
reported that sulphonylureas
hospital admission for the patients in the study cohorts increase the risk of
cardiovascular diseases
(CVDs). According to the
Cohort Mortality Cardiovascular mortality Cardiovascular admission results of the study by Evan
et al., sulphonylureas are
associated with higher
5-year n RR (95% CI) n RR (95% CI) n RR (95%cardiovascular
CI) mortality
rates when compared with
survival rate metformin.[19,20]
References:
Sheehan MT. Current
Metformin 0.81 (0.79- 107 1.00 38 1.00 229 1.00 therapeutic options in type 2
diabetes mellitus: a practical
monothera 0.83) approach. Clin Med Res.
py 2003;1(3):189-200.
Phung OJ, Schwartzman
Sulphonylure 0.68 (0.67- 597 3.12 (2.54- 253 3.71 (2.64- 567 1.11 (0.61-2.03)
E, Allen R e
tW
,al. Sulphonylureas
and risk of cardiovascular
as 0.69) 3.84) 5.22) disease: systematic review
monotherapy and meta-analysis. Diabet
Med. 2013;30(10):1160-
1171.
Forst T, Hanefeld M, Jacob S,
et a.l Association of
sulphonylurea treatment
with all-cause and
cardiovascular mortality: a
Evans JMM, et al. Diabetologia. 2006;49:930- CI, confidence interval; RR, relative
systematic review and meta-
936. ratio. analysis of observational
studies. Diab Vasc Dis Res.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Non-suphonylurea secretagogue References:

1. Nathan DM, Buse JB,
Davidson MB, et al. Medical
management of
hyperglycemia in type 2
diabetes: a consensus
Efficacy:Lowers A1C by 1.5 to 2%1 algorithm for the initiation
and adjustment of therapy:
a consensus statement of
the American Diabetes
Association and the
Primary target: Secretagogue, they bind to the sulphonylurea receptors different than the European Association for the
binding site of sulphonylureas and cause the closure of the ATP-sensitive K+ channel, Study of Diabetes. Diabetes
Care. 2009;32(1):193-203. 2.
resulting in insulin secretion2 de Wet H, Proks P. Molecular
action of sulphonylureas on
KATP channels: a real
partnership between drugs
Available as:2 and nucleotides [published
correction appears in
Biochem Soc Trans. 2015
• Nateglinide Dec;43(6):1297]. Biochem
Soc Trans. 2015;43(5):901-
• Repaglinide 907.
3. Lv W, Wang X, Xu Q, et al.
Mechan
sm
i s and Characteristics of
Sulfonylureas and
Preparation: oral tablets, short half-life (can be used in patients with renal insufficiency) Glinides. Curr Top Med
Chem. 2020;20(1):37-56.

Side effect: weight gain, hypoglycemia3

1. Nathan DM et al. Diabetes Care. 2009;32(1):193-

203.
A1C, glycated hemoglobin; ATP, adenosine
2. De Wet H et al. Biochem Soc Trans. 2015;43(5):901-
triphosphate.
907.
3. Lv W et al. Curr Top Med Chem. 2020;20(1):37-56.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Thiazolidinediones (TZD)
---
References:
1. McFarland MS, Huddleston
L, am
Tme
d
ari K, et al. Comparison of
hemoglobin A1c goal
achievement with the
addition of pioglitazone to
maximal/highest tolerated
Efficacy: Lowers A1C by 0.67% (SD ± 0.92) and 0.78%1 doses of sulfonylurea and
metformin combination
therapy. J Drug Assess.
2012;1(1):34-39. 2. Tyagi S,
Advantage: some benefit for treatment of fatty liver Gupta P, Saini AS, et al. The
peroxisome proliferator-
activated receptor: A family
of nuclear receptors role in
Primary target: The mechanism of action includes activation of the gamma isoform of the peroxisomevarious diseases. J Adv
proliferator-activated receptor (PPAR gamma), a nuclear receptor. It is an insulin sensitizer that targets
Pharm Technol Res.
2011;2(4):236-240.
insulin resistance at the muscle.2 3. Rizos CV, Elisaf MS,
Mikhailidis DP, et al. How safe
is the use of
Available as: 2 thiazolidinediones in clinical
practice?. Expert Opin Drug
Saf. 2009;8(1):15-32.
• Pioglitazone
• Rosiglitazone
Preparation: Oral

Side effects: Weight gain, edema, macular edema and heart failure 3

1. McFarland MS et al. J Drug Assess. 2012;1(1):34-39. A1C, glycated hemoglobin; PPAR, peroxisome
2. Tyagi S et al. J Adv Pharm Technol Res. 2011;2(4):236- proliferator-activated receptor; SD, standard
240. deviation.
3. Rizos CV et al. Expert Opin Drug Saf. 2009;8(1):15-32.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

α-Glucosidase inhibitors References:

1. Alssema, M., Ruijgrok, C.,
Blaak, E.E. et al. Effects of
alpha-glucosidase-inhibiting
drugs on acute postprandial
glucose and insulin
responses: a systematic
review and meta-
Efficacy: Lowers A1C by 0.5-0.8%1 analysis. Nutr.
Diabetes 11, 11 (2021).
2. Dirir AM, Daou M, Yousef
AF, o Yusef LF. A review of alpha-
Advantages: good safety profile, lowers postprandial hyperglycemia glucosidase inhibitors from
plants as potential
candidates for the treatment
of type-2 diabetes
[published online ahead of
Available as: Acarbose1,2 print, 2021 Aug
16]. Phytochem Rev.
2021;21(4):1-31.

Primary target: α-Glucosidase inhibition modifies digestion and absorption of dietary

carbohydrates. Dietary glucose absorption is reduced lowering postprandial hyperglycemia. 2

Preparation: oral tablet

Side effects: Abdominal bloating, diarrhea, flatulence. May raise liver enzymes.2

1. Alssema et al. Nutr. Diabetes 11, 11 (2021).

A1C, glycated
2. Dirir AM et al. Phytochem Rev. 2021;21(4):1-
hemoglobin.
31.
 Sodium-glucose co-transporter co-transporter type 2
Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

(SGLT2) inhibitors References:

1. Mikhail N. Place of sodium-
glucose co-transporter type 2
Efficacy: Lowers A1C by 0.5%-0.8%1 inhibitors for treatment of
type 2 diabetes. World J
Diabetes. 2014;5(6):854-
Advantages: Has cardiovascular benefits (reduces all cause CV mortality, reduces risk of hospitalization in patients
859. with
2. Granata
heart failure with reduced and preserved ejection fraction), has renal benefits (reduces all cause mortality and kidney- A, Pesce F,
Iacoviello M , et al. (2022).
related mortality, reduces progression of CKD and rates of progression to haemodialysis in people with CKDSGLT2 and Inhibitors: A Broad
albuminuria), promotes weight loss. 2 Impact Therapeutic Option
for the Nephrologist. Front.
Nephrol. 2:867075.
Available as: 3. FDA Drug Safety
Communication
• Canagliflozin (2022). FDA revises labels of
SGLT2 inhibitors for diabetes
• Dapagliflozin to include warnings about to
o much acid in the blood and
• Empagliflozin serious urinary tract infectio
ns. Accessed on August 11th
• Ertugliflozin 2022. Available at: [Link]
[Link]/drugs/drug-safety
-and-availability/fda-revises-l
abels-sglt2-inhibitors-diabete
Preparation: Oral tablets s-include-warnings-about-too
-much-acid-blood-and-seriou
s

Primary target: SGLT2 co-transporters in the kidney tubules. These transporters are responsible for reabsorption of most
(90 %) of the glucose filtered by the kidneys. The inhibition of SGLT2 co-transporters lowers glucose by reducing renal re-
absorption of glucose which will lead to urinary glucose excretion. 2

Side effects: Genitourinary infections, dehydration, euglycemic DKA.3

1. Mikhail N. World J Diabetes. 2014;5(6):854-859.
2. Granata A et al. Front. Nephrol. 2:867075. A1C, glycated hemoglobin; CV, cardiovascular; CKD,
3. FDA Drug Safety communication (2022). Accessed on August 11th, 2022. Available at: chronic kidney disease; DKA, diabetic ketoacidosis;
[Link] SGLT2, sodium glucose co-transporter 2.
tes-include-
 Presenter Notes
2022-11-18 [Link]

Dipeptidyl peptidase-4 (DPP4) inhibitors

-----------------------------------------
---
References:
1. Gomez-Peralta F, Abreu C,
GomeR
z-o
g
d
u
irez S, et al. Safety and
Efficacy of DPP4 Inhibitor
Efficacy: Lowers A1C by 0.6–0.8%.1 and Basal Insulin in Type 2
Diabetes: An Updated
Review and Challenging
Clinical Scenarios. Diabetes
Advantages: Good safety profile especially in elderly patients, safe in people with reduced eGFR.
Ther. Weight2018;9(5):1775-1789.
2. Gallwitz B. Clinical Use of
neutral DPP-4 Inhibitors. Front
Endocrinol (Lausanne).
2019;10:389.
Primary target: Promotes the secretion of insulin in glucose-dependent manner, and suppresses [Link]
p
Kasina SVSK, Baradhi KM.
ieptd
iyl
hepatic glucose production 2 Peptidase IV (DPP IV) Inhibito
rs. [Updated 2022 May 29]. I
n: StatPearls [Internet]. Treas
ure Island (FL): StatPearls Pu
Available as: 2 blishing; 2022 Jan. Available
at: [Link]
gov/books/NBK542331/
• Alogliptin 4. FDA Drug Safety
Communication:
• Linagliptin FDA warns that DPP-4 inhibit
ors for type 2 diabetes may c
• Saxagliptin ause severe joint pain. Acces
sed on August 11th 2022. Av
• Sitagliptin ailable at: [Link]
v/drugs/drug-safety-and-avail
ability/fda-drug-safety-comm
unication-fda-warns-dpp-4-in
Preparation: Oral hibitors-type-2-diabetes-may
-cause-severe-joint-pain

Side effects: Nausea, vomiting, diarrhea, bloating, skin rash, musculoskeletal and joint pain 3,4
1. Gomez-Peralta F et al. Diabetes Ther. 2018;9(5):1775-1789.
2. Gallwitz B. Front Endocrinol (Lausanne). 2019;10:389.
3. Kasina SVSK et al. In: StatPearls [Internet]. Available at: https:// A1C, glycated hemoglobin; eGFR,
[Link]/books/NBK542331/ estimated glomerular filtration rate.

[Link] Drug Safety Communication. Accessed on August 11th 2022.

 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Glucagon-like peptide 1 (GLP-1) receptor agonists ---

Reference:
Trujillo JM, Nuffer W, Smith
BA. G L
1
P
- receptor agonists: an
updated review of head-to-
head clinical studies. Ther
Adv Endocrinol Metab.
Efficacy: Lowers A1C by 0.78% to 1.9% 2021;12:2042018821997320
.

Advantages: Promotes weight loss, reduces risk of atherosclerotic cardiovascular disease, improves fatty liver, no
renal clearance

Primary target: Stimulates insulin release in glucose-dependent manner, decrease glucagon at pancreas, decrease
hepatic glucose production, increases incretin effect, helps with satiety at the brain, improves insulin sensitivity at
muscle (due to weight loss)

Available as:
• Dulaglutide - once weekly injection
• Exenatide - Twice daily injection
• Exentatide extended release - once weekly injection
• Liraglutide - once daily injection
• Lixisenatide Once daily injection
• Semaglutide Once weekly injection

Preparation: Subcutaneous; Oral (Rybelsus only)

Side effects:
Trujillo et Nausea
al. Ther Adv , vomiting, diarrhea, pancreatitis (rare)
Endocrinol Metab. A1C, glycated
2021;12:2042018821997320. hemoglobin.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Glucose-dependent insulinotropic polypeptide (GIP) Reference:

Min T, Bain SC. The Role of
Tirzepatide, Dual GIP and GLP-1

and glucagon-like peptide-1 (GLP-1) receptor agonist Receptor Agonist, in the

Management of Type 2
Diabetes: The SURPASS
Clinical Trials. Diabetes Ther.
2021;12(1):143-157.

• Efficacy: Lowers A1C by 1.6% - 2.4%

• Advantages: promotes significant weight loss, average weight loss 20%
after 74 weeks

•
Primary target: Stimulates insulin release in glucose-dependent manner,
decrease glucagon at pancreas (for GLP-1RA), decrease hepatic glucose
production, reduces satiety in the brain, improves insulin sensitivity at
muscle (due to weight loss)

•
Available as:
• Tirzepatide,Subcutaneous
• Preparatio once weekly injection
n: Nausea, vomiting, diarrhoea,
• Side constipation
effects:
Min T, et al. Diabetes Ther. 2021;12(1):143- A1C, glycated hemoglobin; GLP-1
157. RA, glucagon like peptide 1 receptor
agonists.
Section 3: Describe the various types of
insulins
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Insulin
Reference:
American Diabetes
Association Professional
Practice Committee; 9.
Pharmacologic Approaches
to Glycemic Treatment:
Standards of Medical Care
in Diabetes—2022.
• Primary target: Stimulates glucose transport across the cell Diabetes Care. 2022; 45
(Suppl_1):S125–S143.
membrane

• Efficacy: Highest

• Available as:
• Human
• Analog

• Preparation:
• Human - Subcutaneous/Inhaled
• Analog - Subcutaneous

American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches

to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45
 Presenter Notes

Comparison between Types of insulins

2022-11-18 [Link]
-----------------------------------------
---
Reference:
American Diabetes Associatio
n.
n
Isu
n
il
Category Onset of action Peak Duration & Other Injectables (Insulin
Names Basics). Accessed on August
11th 2022. Available at https:
//[Link]/healthy-li
Ultrafast acting 10 minutes ~45 minutes 2-3 hours Aspart-modified,
ving/medication-treatments/i
lispro- modified
nsulin-other-injectables/insuli
n-basics

Rapid 15 minutes ~1 hour 2-4 hours Glulisine, lispro,

aspart, inhaled
insulin
Short-acting 30 minutes 2-3 hours 3-6 hours Regular (human insulin)

Intermediate-acting 2-4 hours 4-12 hours 12-18 hours Neutral protamine

insulin Hagedorn (NPH)
(Human insulin)

Long acting insulin 2-4 hours No peak 18-24 hours Detemir, insulin
glargine U-100

Ultra-long acting insulin 6 hours No peak Up to 36 hours Glargine U-300,

Degludec

Once weekly basal 6 hours No peak 1 week Icodec insulin

insulin
(acetlylated (Investigation
insulin)
ADA. Insulin & Other Injectables (Insulin Basics). Accessed on August 11th 2022. al)
NPH, neutral protamine
Available at
hagedorn..
[Link]
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---
Reference:
American Diabetes

Human Insulins Association Professional

Practice Committee; 9.
Pharmacologic Approaches
to Glycemic Treatment:
Standards of Medical Care
in Diabetes—2022.
• Rapid-acting- Inhaled insulin Diabetes Care. 2022; 45
(Suppl_1):S125–S143.

• Short-acting- Regular

• Intermediate-acting- NPH

• Premixed Insulin products- NPH/regular 70/30

• Concentrated human regular insulin- U-500 human

regular
American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches NPH, neutral protamine
to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45 hagedorn.
(Suppl_1):S125–S143.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---
Reference:
American Diabetes

Analog Insulins Association Professional

Practice Committee; 9.
Pharmacologic Approaches
to Glycemic Treatment:
Standards of Medical Care
in Diabetes—2022.
Diabetes Care. 2022; 45
Rapid-acting (Suppl_1):S125–S143.

• Lispro biosimilar , Lispro , Lispro-aabc , Glulisine , Aspart , Aspart modified

(faster acting)

Long-acting
• Glargine biosimilars , Glargine U100 , Glargine U300 , Detemir , Degludec

Premixed insulin
• Lispro/ NPH 50/50 , Lispro/NPH 75/25 , Aspart/ NPH 70/30

Premixed insulin/GLP-1RA
• Glargine/Lixisenatide , Degludec/Liraglutide

American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches GLP-1RA, glucagon like peptide-1 receptor
to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45 agonists; NPH, neutral protamine hagedorn..
(Suppl_1):S125–S143.
 Presenter Notes

When should insulin therapy be considered in people with 2022-11-18 [Link]

-----------------------------------------
---

type 2 diabetes? Insulin is prescribed in

patients with T2DM when
there is poor glycaemic
• A1C >10% control with glycated
• Blood glucose: >300mg/dL haemoglobin (HbA1c) values
• Weight Loss >10%, blood glucose levels
• Hyperglycemic symptoms despite using >300 mg/dL weight loss or
symptoms of
combination of non-insulin anti-diabetic
hyperglycaemia despite
drugs1 combination therapy with
oral anti-diabetic drugs. In
patients in whom the HbA1c
level is very high, for
example, >9%, insulin is
likely to be more effective
If A1C is above goal
If A1C is above goal than most other agents as a
third-line therapy.[38]
OR
With Insulin has to be added
Hyperglycemic sequentially in the treatment
Normal fasting of T2DM. Insulin is initiated
symptoms exist1,2
glucose 2 with low doses of 0.1 to 0.2
U/kg body weight of basal
insulin. Generally, 1 to 2
non-insulin agents are also
prescribed simultaneously. In
Initiate basal patients in whom HbA1c
insulin Use basal insulin targets are not achieved,
+ 1 to 3 RAA twice-daily premixed insulin
- Low doses of 0.1- injections 2 or a more advanced basal
0.2 U/kg body plus mealtime insulin
regimen is started. In case
weight1 the HbA1c values are still
high, although the fasting
glucose values are normal,
insulin needs to be up-
Choice of basal titrated to basal insulin plus
1. Inzucchi et al. Diabetes Care. 2012;35(6):1364-1379. insulin depends 1 to 3 injections of rapid-
[Link] Diabetes Association Professional Practice on availability acting analogues. Downward
A1C,adjustment
glycated needs to be
Committee; 9. Pharmacologic Approaches to Glycemic
haemoglobin;
advised in case RAA, ofrapid
Treatment: Standards of Medical Care in Diabetes—2022.
acting analog.
hypoglycaemia.[38] Insulin
 Presenter Notes

Algorithm for initiation of insulin in patients with T2D 2022-11-18 [Link]

-----------------------------------------
---
Intensifying to injectable therapies in type 2 diabetes Reference:
American Diabetes
If Injectable therapy is needed to reduce A1Ca Association Po re
fss
oinal Practice
Committee; 9.
Pharmacologic Approaches
Consider GLP-1 RA in most patients prior to insulinb to Glycemic Treatment:
INITIATION: Initiate appropriate starting dose for agent selected (varies
If already on Standards
GLP-1 RA or
of Medical Care
in Diabetes—2022.
within class) if GLP-1 RA not
Diabetes Care. 2022; 45
TITRATION: Titrate to maintenance dose (varies within class) appropriate OR insulin
(Suppl_1):S125–S143.
preferred
If above A1C target

Add basal insulinc

Choice of basal insulin should be based on patient-specific considerations,
aConsider insulin as the first injectable if
including cost. evidence of ongoing catabolism, symptoms
of hyperglycemia are present, when A1 C
levels (>10% [86 mmol/mol]) or blood
Add basal analog or bedtime NPH insulin glucose levels (≥300 mg/dl [16.7 mmol/L])
INITIATION: Start 10 units per day OR 0.1-0.2 units/kg per day are very high, or a diagnosis of type 1
TITRATION: diabetes is a possibility. bWhen selecting
■ Set FPG target GLP-1 RA, consider: patient preference,
■ Choose evidence-based titration algorithm, e.g., increase 2 units every 3 days A1C lowering, weight-lowering effect, or
to reach FPG target without hypoglycemia frequency of injection. If CVD, consider
■ For hypoglycemia determine cause, if no clear reason lower dose by 10-20% GLP-1 RA with proven CVD benefit. Oral or
injectable GLP-1 RA are appropriate.
cFor patients on GLP-1 RA and basal

insulin combination, consider use of a

Assess adequacy of basal insulin dose fixed-ratio combination product
Consider clinical signals to evaluate for overbasalization and need to consider adjunctive therapies (e.g., basal dose (IDeglira or iGlarlixi).
more than ~0.5 units/kg/day, elevated bedtime-morning and/or post-preprandial differential, hypoglycemia [aware
or unaware], high variability)

A1C, glycated hemoglobin; CVD, cardiovascular disease; GLP-

American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to
1RA, glucagon like peptide-1 receptor agonist; FPG, fasting
Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45
plasma glucose; T2D, type 2 diabetes.
 Presenter Notes
2022-11-18 [Link]

If A1C still elevated after starting basal insulin -----------------------------------------

---
Reference:
American Diabetes
Association Po re
fss
oinal Practice
Intensifying to injectable therapies in type 2 diabetes Committee; 9.
(Contd.) Pharmacologic Approaches
to Glycemic Treatment:
Standards of Medical Care
If above A1C target in Diabetes—2022.
Diabetes Care. 2022; 45
(Suppl_1):S125–S143.
If on bedtime NPH, consider
Add prandial insulind converting to twice-daily NPH
Consider GLP-1 RA Usually one dose with the largest meal or meal with greatest PPG excursion; regimen
if not already regimen prandial insulin can be dosed individually or mixed with NPH as appropriate Conversion based on individual
For addition of GLP-1 INITIATION: needs and current glycemic
RA, consider lowering -- 4 units per day or 10% of basal insulin dose control. The following is one
insulin dose -- If A1C <8% (64 mmol/mol) consider lowering the basal dose by 4 units per possible approach:
day or 10% of basal dose
dependent on current TITRATION: INITIATION:
glycemic assessment -- Increase dose by 1-2 units or 10-15% twice weekly -- Total dose = 80% of
and patient factors -- For hypoglycemia determine cause, if no clear reason lower corresponding current bedtime NPH
dose by 10-20% dose
-- 2/3 given in the
morning
-- 1/3 given at bedtime
If above A1C target TITRATION:
Titrate based on
dIf adding prandial insulin to NPH, consider initiation of a self-mixed or premixed insulin individualized needs
regimen to decrease the number of injections required. If above A1C target

American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches A1C, glycated hemoglobin; GLP-1RA, glucagon like peptide-1
to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45 receptor agonist; NPH, neutral protamine hagedorn; PPG,
(Suppl_1):S125–S143. postprandial glucose.
 Presenter Notes
2022-11-18 [Link]

If A1C still elevated -----------------------------------------

---
Reference:
American Diabetes
Association Po re
fss
oinal Practice
Intensifying to injectable therapies in type 2 diabetes Committee; 9.
(Contd.) Pharmacologic Approaches
to Glycemic Treatment:
Standards of Medical Care
in Diabetes—2022.
If above A1C target Diabetes Care. 2022; 45
(Suppl_1):S125–S143.

Stepwise additional
injections of prandial insulin Consider setf-mixed/split insulin regimen
(i.e., two, then three Consider twice daily
Can adjust NPH and short/rapid-acting premixed insulin regimen
additional injections insulins separately
INITIATION:
INITIATION:
Usually unit per unit at
-- Total NPH dose= 80% of current NPH dose the same total insulin
-- 2/3 given before breakfast dose, but may require
adjustment to
-- 1/3 given before dinner individual needs
Proceed to full basal-bolus -- Add 4 units of short/rapid-acting insulin TITRATION:
regimen (i.e., basal insulin to each injection or 10% of reduced NPH
and prandial insulin with dose Titrate based on
each meal individualized needs
TITRATION:
-- Titrate each component of the regimen
based on individualized needs

American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches A1C, glycated hemoglobin; NPH,
to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45 neutral protamine hagedorn.
(Suppl_1):S125–S143.
[Link] various ways insulin therapy can be
delivered for people living with type 1 diabetes
and type 2 diabetes
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Insulin: Delivery Modes -----------------------------------------
---
Currently, several modalities
are av a
a
lb
e
il to deliver insulin.
Injecting using a syringe is
the most common form of
Figure 8: Insulin Delivery Modalities insulin delivery; however,
there are other options,
including using insulin pens
and pumps. Continuous
Syringe subcutaneous insulin
infusion is used in intensive
diabetes management by
means of a pump. Other
approaches are intradermal,
and non-invasive methods
such as intranasal, inhaled
insulin, which are under
considerable research.

15
2
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Insulin: Delivery Modes -----------------------------------------
---
Currently, several modalities
are av a
a
lb
e
il to deliver insulin.
Injecting using a syringe is
the most common form of
Figure 8: Insulin Delivery Modalities (Contd.) insulin delivery; however,
there are other options,
including using insulin pens
and pumps. Continuous
Syringe subcutaneous insulin
infusion is used in intensive
diabetes management by
means of a pump. Other
Cannul approaches are intradermal,
Tubin a and non-invasive methods
such as intranasal and
g inhaled insulin, which are
Infusion under considerable
research. Insulin pumps
Set when integrated with
continuous glucose monitor
(CGM) can provide real-time
Display glucose information.

Batter
y

Operatin
Insulin g
Reservoir Buttons
15
3
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Insulin: Delivery Modes -----------------------------------------
---
Currently, several modalities
are av a
a
lb
e
il to deliver insulin.
Injecting using a syringe is
the most common form of
Figure 8: Insulin Delivery Modalities (Contd.) insulin delivery; however,
there are other options,
including using insulin pens
and pumps. Continuous
Pens subcutaneous insulin
infusion is used in intensive
diabetes management by
means of a pump. Other
approaches are intradermal,
and non-invasive methods
such as intranasal and
inhaled insulin, which are
under considerable
research. A smart insulin
pen is a reusable injector
pen with an intuitive
smartphone app that can
help people with diabetes
better manage insulin
delivery. This smart
system calculates and tracks
doses and provides helpful
reminders, alerts, and
reports. [40,41]
Reference:
1. American Diabetes
Association.
Devices & Technology (What
is a smart insulin pump?). Ac
cessed on August 11th 2022.
Available at: [Link]
[Link]/tools-support/devic
1. ADA. Devices & Technology (What is a smart insulin pump?). es-technology/smart-insulin-
Available at: pen
[Link] 2. Gildon BW. InPen Smart
sulin-pen Insulin Pen System: Product 15
2. Gildon BW. Diabetes Spectr. 2018;31(4):354-358. Review and User 4
Experience. Diabetes Spectr.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------

Special considerations for insulin storage: ---

Reference:
United States Food & Drug
Administration
(USFDA), Information Regard
• Unopened insulin (i.e. not previously used) should be stored in the refrigerator between ing Insulin Storage and Switc
hing Between Products in an
Emergency (Insulin Storage a
36°F- 46°F (2°C-8°C). nd Effectiveness). Accessed o
n Aug 11th 2022. Available at
• Insulin vials, cartridges, or pens that have been opened may be kept at room : [Link]
mergency-preparedness-drug
s/information-regarding-insuli
temperature, between 59°F-86°F (15°C-30°C), for 28 days, or about 1 month. (Insulin n-storage-and-switching-bet
ween-products-emergency#:
detemir can be stored at room temperature for up to 42 days.) ~:text=Unopened%20and%2
0stored%20in%20this,days%
• Insulin should never be frozen, kept in direct sunlight, or stored in an environmental 20and%20continue%20to%2
0work.
temperatures greater than 86°F (30°C). Exposure to extremes of temperature can lead to
Diabetes Disaster Response
Coalition (DDRC), Safe storag
loss of insulin effectiveness and a worsening of glycaemic control. e of insulin. Accessed on Aug
ust 11th 2022. Available at: h
• When traveling with insulin keep cool on ice packs. Advise patient to not place insulin
ttps://[Link]/sites/
default/files/2019-08/ddrc-sto
in stowaway luggage because temperatures in the airplane may reach [Link]
levels.
International Diabetes
• Insulin for pump use that has been removed from the original vial should be used within
Federation D
IF
)( Europe, Storage
of Insulin (Europe Awareness
two weeks or discarded because it is next to the body temperature. Paper). Accessed on August
11th 2022. Available at:
• Regular insulin, the basal insulin analogs (glargine, detemir, and degludec) and[Link]
the rapid-
ope/Storage_of_Insulin_-
acting insulin analogs (lispro, aspart and glulisine) are clear and colourless and_IDF_Europe_Awareness_Pap
should not
er_-_FINAL.pdf
be used if they become cloudy or viscous.
1. USFDA, Information Regarding Insulin Storage and Switching Between Products in an Emergency (Insulin Storage and
Effectiveness)
[Link]
n-products-
emergency#:~:text=Unopened%20and%20stored%20in%20this,days%20and%20continue%20to%20work.
2. DDRC, Safe storage of insulin. [Link]
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Factors that may affect insulin injection Reference:

Gradel AKJ, Porsgaard T,
Lykkesfeldt J, et al. Factors
Affecting the Absorption of
Subcutaneously
Administered Insulin: Effect
Factors related to the injection site/patient that influence insulin on Variability. J Diabetes Res.
pharmacokinetics 2018;2018:1205121.

Site of injection Insulin is absorbed faster from the abdomen.

Less clinically important with rapid-acting insulins, insulin glargine,
and insulin detemir.

Lipohypertrophy Injection into these areas delays insulin absorption.

Jet injectors Increase absorption

Insulin dose Larger doses are associated with more volume of injected insulin which
may delay absorption

Local temperature and Local massage may increase absorption

massage of injected site

Exercise Insulin absorption may occur faster if it is injected into a limb within
an hour of intense exercise

Gradel et al. J Diabetes Res.

2018;2018:1205121.
 Presenter Notes
2022-11-18 [Link]
-----------------------------------------
---

Key Features of Insulin Pumps, and smart insulin pens Reference:

Gildon BW. InPen Smart
Insulin Pen System: Product
Review and User
Experience. Diabetes Spectr.
2018;31(4):354-358.

These devices provide dosage calculations for patients based on

• Insulin to carbohydrate ratio
• Insulin sensitivity factor

These devices record the total daily insulin delivered

They may be programmed to provide alerts when glucose levels are

out of target range when used with continuous glucose monitors, or
dosing reminders.

This information may help avoid potential insulin stacking and

hypoglycemia.
Gildon BW. Diabetes Spectr. 2018;31(4):354-
358.
 Presenter Notes
2022-11-18 [Link]
PAGE TITLE: Insulin: Delivery Modes -----------------------------------------
---
Currently, several modalities
are av a
a
lb
e
il to deliver insulin.
Injecting using a syringe is
the most common form of
Figure 8: Insulin Delivery Modalities (Contd.) insulin delivery; however,
there are other options,
including using insulin pens
and pumps. Continuous
Intradermal method subcutaneous insulin
infusion is used in intensive
diabetes management by
means of a pump. Other
approaches are intradermal,
and non-invasive methods
such as intranasal and
inhaled insulin, which are
under considerable
research. Reference (for the
figure placed on slide):
Drug Shah RB, Patel M, Maahs DM,
Shah VN. Insulin delivery
Epidermi methods: Past, present and
future. Int J Pharm Investig.
s 2016;6(1):1-9.

Dermis

Subcutaneo

us Muscle

Shah RB et al. Int J Pharm Investig. 2016;6(1):1- 15

9. 8
PAGE TITLE: References

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References:
40. American Diabetes Association. Devices & Technology (What is a smart insulin pump?). Accessed on August 11th
2022. Available at: [Link]
41. Gildon BW. InPen Smart Insulin Pen System: Product Review and User Experience. Diabetes Spectr. 2018;31(4):354-
358.
42. United States Food & Drug Administration (USFDA), Information Regarding Insulin Storage and Switching Between Products in an
Emergency (Insulin Storage and Effectiveness). Accessed on Aug 11th 2022. Available at:
[Link]
insulin-storage-and-switching-between-products-emergency#:~:text=Unopened%20and%20stored%20in%20this,days%20and%20continu
e%20to%20work
.
43. Diabetes Disaster Response Coalition (DDRC), Safe storage of insulin. Accessed on August 11th 2022.
Available at: [Link]
44. International Diabetes Federation (IDF) Europe, Storage of Insulin (Europe Awareness Paper). Accessed on August 11th
2022. Available at: [Link]
45. Gradel AKJ, Porsgaard T, Lykkesfeldt J, et al. Factors Affecting the Absorption of Subcutaneously Administered Insulin: Effect on Variability. J
Diabetes Res. 2018;2018:1205121.
46. Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: Past, present and future. Int J Pharm Investig. 2016;6(1):1-9.

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