This document provides an overview of SGLT-2 inhibitors and GLP-1 agonists for the treatment of diabetes. It begins with defining key terms and discussing the pathophysiology of diabetes and cardiovascular complications. It then explains the mechanisms of action of SGLT-2 inhibitors and GLP-1 agonists, noting they work independently of insulin. The document reviews the benefits and risks of these drug classes and provides guidance on their appropriate uses and cautions. It concludes by discussing the guidelines for incorporating SGLT-2 inhibitors and GLP-1 agonists into the management of type 2 diabetes.

1. SGLT-2 Inhibitors and GLP-1 Agonists-
Do’s and Dont’s
Geetha Bhat, MD
Assistant Prof of Medicine
Division of Endocrinology
Cooper Medical School of Rowan University

2. Learner Objectives
• Understand the pathophysiology of diabetes as it relates to
sodium-glucose transport 2 inhibitors (SGLT-2i) and Glucagon
–like peptide -1 (GLP-1) agonists.
• Recognize the mechanism of action of new therapeutic
options for diabetes mellitus.
• Describe the benefits and side effects of SGLT-2i and GLP-1
agonists.

3. Outline
 Overview of Antihyperglycemic medications with focus on
SGLT 2 inhibitors and GLP-1 receptor agonists
 Mechanism of action of SGLT-2 inhibitors and GLP-1 agonists
 Benefits and Risks of SGLT-2 inhibitors and GLP-1 agonists
 Do’s and Don’t’s with SGLT-2 inhibitors and GLP-1 receptor
agonists
 Guidelines on using SGLt-2 inhibitors and GLP-1 receptor
agonists - – where do they fit in the algorithm of management
of Type 2 diabetes ?

4. Definition
• Medications to treat diabetes: anti-hyperglycemic
medications, hypoglycemic medications, anti-diabetes
drugs, diabetes therapies
• Atherosclerotic cardiovascular disease (ASCVD)
• Congestive heart failure (CHF)
• Chronic kidney disease (CKD)
• Euglycemic Diabetes Ketoacidosis (euDKA)
• Sodium-glucose Cotransporter-2 Inhibitors (SGLT-2 i)
• Glucagon like peptide -1 ( GLP-1) agonists = GLP-1
receptor agonists (GLP-1RA)
• Gastric inhibitory polypeptide (GIP)

5. Diabetes and Cardiovascular disease
• Cardiovascular disease (CVD) is the leading cause of death in patients
with diabetes mellitus
• Diabetes itself is considered CHD equivalent
• CV risk increases with diabetes duration
presence of co-morbidities
Hypertension, Dyslipidemia, Metabolic syndrome, and chronic kidney
disease (CKD)
• Diabetic patients with existing CVD have the highest risk of a
subsequent CV events
• 1/3 of patients presenting with myocardial infarction have
undiagnosed diabetes mellitus

6. Microvascular Complications of
Type 2 Diabetes
● In 2005-2008, of adults ≥40 years of age with diabetes, 4.2
million (28.5%) had diabetic retinopathy.
 655,000 (4.4%) had advanced diabetic retinopathy
● In 2010, about 73,000 non-traumatic lower-limb
amputations were performed in adults ≥20 years of age
with diabetes.
● About 60% of non-traumatic lower-limb amputations
among adults ≥20 years of age are in people with
diabetes.
● Diabetes was listed as the primary cause of kidney
failure in 44% of all new cases in 2011.
Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden
in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014.

7. Type 2 Diabetes
• Effective treatment will require multiple
drugs in combination
• Treatment should be based upon established
pathogenic abnormalities
• Therapy must be started early in the natural
history of T2DM to prevent progressive
b-cell failure.

9. Class Mechanism Advantages Disadvantages Cost
Biguanides • ActivatesAMP- • Extensive experience • Gastrointestinal Low
(Metformin) kinase • No hypoglycemia • Rare Lactic acidosis
• ↓ Hepatic • Weight neutral • B-12 deficiency
glucose production • ? ↓ CVD events • Contraindications
SUs /
Meglitinides
•Closes KATP
channels
•↑ Insulin
secretion
• Extensive experience
• ↓ Microvascular risk
• Hypoglycemia
• Weight gain
• Low durability
• ? ↓ Ischemic
preconditioning
Low
TZDs • Activates PPAR-γ • No hypoglycemia • Weight gain Low
• ↑ Insulin • Durability • Edema / heart
sensitivity • ↓ TGs, ↑ HDL-C failure
• ? ↓ CVD events (pio) • Bone fractures
• ? ↑ MI (rosi)
• ? Bladder ca (pio)
Properties of Established Anti-
Hyperglycemic Agents
Diabetes Care 2012;35:1364–1379. Diabetologia 2012;55:1577–
1596

10. What are Incretins ?
• Incretins are hormones produced by the gastrointestinal
tract in response to oral nutrients and have important
actions on glucose homeostasis.
• 1) Glucagon like peptide -1 ( GLP-1) : secreted by the L cells
in the small intestine
• 2) Gastric inhibitory polypeptide (GIP) : secreted by the K
cells in the proximal gut.
• Substantial impairment – only 40% of normal
response in type 2 diabetes

11. Incretins

12. Actions of GLP-1 in target tissues.
Deborah Hinnen Diabetes Spectr 2017;30:202-210
©2017 by American Diabetes Association

13. Incretin effect is impaired in T2DM
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
Injectables
• Sitagliptin
• Saxagliptin
• Linagliptin
• Alogliptin
Block DPP-4, the
enzyme that degrades
GLP-1:
Oral agents
Drucker. Curr Pharm Des. 2001;7(14):1399-1412. Drucker. Mol Endocrinol. 2003;17(2):161-171.
Incretin Therapies to Treat Type 2
Diabetes
Exendin-4 Based:
• Exenatide
• Exenatide QW
• Lixisenatide
Human GLP-1:
• Liraglutide
• Albiglutide
• Dulagutide
• Semaglutide

14. His Gly Glu Gly Thr Phe Thr Ser Asp Leu
Ser
Lys
Phe Leu Arg Val Ala Glu Glu Glu Met
Gln
Ile
Glu
Trp Leu Lys Asn Gly Gly Pro Ser Ser
Gly
Ala
Ser Pro Pro Pro
GLP-1 Receptor Agonists
GLP-1 RA
1. Christensen M, et al. Idrugs. 2009;12:503-513. 2. Ratner RE, etal. Diabet Med. 2010;27:1024-1032.
3. Stewart M, et al. ADA 2008, poster 522-p. 4. Glaesner, et al. Diabetes Metab Res Rev. 2010;26:287-296. 5. Meier JJ. Nat Rev Endocrinol. 2012;8:728-
742.
Human GLP-1
Analogues[4]
Exendin-4
analogues
Liraglutide
Albiglutid
e
Lixisenatid
e
Exenatide
BID
Exenatide
QW
*Not approved
His Ala Glu Gly Thr Phe Thr Ser Asp
Val
Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe
Ile Ala Trp Leu Val Lys Gly Arg Gly
Structural modifications confer albumin
(liraglutide, albiglutide) or IgG Fc fraction
(dulaglutide) binding
Dulaglutide Semaglutide*

15. GLP-1 Receptor Agonists
ER, extended release; FDA, Food and Drug Administration; GLP-1, glucagon-like peptide-1. Davies, MJ, et al. Diabetes Care
2018;doi:10.2337/dci18-0033.
Benefits
• Hba1c reduction 0.5
to 2.0 %
• Improved satiety
• Promote weight loss
• Improved
cardiovascular
outcomes
(liraglutide
dulaglutide and
semaglutide)
Risks
• Common side effects of
nausea, vomiting and
diarrhea
• Increase hypoglycemic
effect of insulin and
sulfonylureas
• Increased risk gallbladder events
• Increased retinopathy
complications in patients with
baseline retinopathy and rapid
improvement in glycemic
control (semaglutide)
*As of July 31, 2018, a business decision was made to discontinue manufacturing of albiglutide
FDA-Approved
Agents
• albiglutide*
• dulaglutide
• exenatide
• exenatide ER
• liraglutide
• semaglutide
• lixisenatide
8

16. Short-acting
FPG PPG
Long-acting
FPG PPG
GLP-1RA duration Influences FPG,
PPG and A1c
FPG, fasting plasma glucose; PPG, postprandial plasma glucose
Fineman MS et al. Diabetes Obes Metab 2012;14:675-688.
FPG, fasting plasma glucose; PPG, postprandial plasma glucose
Fineman MS et al. Diabetes Obes Metab 2012;14:675-688

17. GLP-1 agonists – Do’s
• Initiate therapy with the lowest dose and titrate
slowly to avoid gastrointestinal side effects.
• Counsel patients to stop medication with severe
nausea, vomiting and diarrhea – inc risk of Acute
Kidney Injury (AKI)
• Advise patients that sugars may not significantly
improve for 2–4 weeks after initiating treatment
with long-acting GLP-1 receptor agonists.
• Down titrate doses of insulin , sulfonylureas to
avoid hypoglycemia

18. GLP-1 agonists – Do’s
• Long-acting GLP-1 analogues should be taken on
or around the same day each week
• Dulaglutide, liraglutide and lixisenatide – no
dose reduction in patients with mild, moderate,
or severe renal impairment (estimated
glomerular filtration rate 15–89 mL/min/1.73
m2)
• Dulaglutide - preferred in patients with ESRD
• Use in Obese patients , in patients with CVD/
high risk for CVD, Steato hepatitis.

19. GLP-1 agonists- Dont’s
• Do not use in patients with history of pancreatitis or
known pancreatic dysfunction
• Do not use in patients with Type 1 diabetes
• Do not use with DPP-4 inhibitors
• Avoid in patients with gastroparesis and untreated
gall bladder disease

20. GLP-1 agonists- Dont’s
• Do not use in personal or family history significant
for multiple endocrine neoplasia 2A, multiple
endocrine neoplasia 2B, or medullary thyroid
cancer
• Exenatide BID and Q weekly dose should not be
used in patients with severe renal impairment (cr cl
<30 mL/min) or end-stage renal disease (ESRD) and
should be used with caution in patients with
moderate renal impairment
• Monitor patients with severe retinopathy closely
when on semaglutide and dulaglutide.

21. SGLT- 2 Inhibitors

22. SGLT2 (Sodium-glucose Cotransporter-2)
Inhibitors
SGLT2, sodium-glucose cotransporter-2.
1. Chao E, Henry R. Nature Rev DrugDiscov. 2010;9:551-
559.
2. Davies MJ, et al. Diabetes Care.2018
September; [Epub ahead of print]
dci180033.
• SGLT2 inhibitors are oral medications that
reduce plasma glucose by enhancing
urinary excretion of glucose, decreasing
return of glucose to circulation and
decreasing blood glucose levels1,2
• SGLT2 mediates most (≈90%) glucose
reabsorption from the proximal renal
tubular lumen back into circulation1
Return
to
circulation
Urinary excretion
Glucose
25
Lower Hba1c by 0.6 to 1%
Bowman’
s
capsule
Proximal
renal
tubule
FDA-approvedagents
• Canagliflozin
• Dapagliflozin
• Empagliflozin
• Ertugliflozin

23. Na+/
Glucose
SGLT-2 Inhibition
Insulin-Independent Reversal
of Glucotoxicity
Insulin
sensitivity in
muscle1,2
Insulin
sensitivity in
liver2
Gluconeogenesis2,
Improved β-cell
function4,5
GLUT-2, glucose transporter 2.
1. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14; 2. Merovci A, et al. J Clin Invest.
2014;124(2):509-514;
3. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883; 4. Ferrannini E, et al. J Clin Invest.
2014;124(2):499-508;
5. Polidori D, et al. Diabetologia. 2014;57(5):891-901.
Tubular
Lumen
3Na+
2K+
ATP
GLUT-2
Glucose
GLUT-1
Glucose
SGLT-2
Glucose
SGLT-1
Na+
Proximal
Tubule
3Na+
2K+
ATP

24. SGLT-2 inhibitors

25. SGLT2 Inhibitors: Risks and Benefits
ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol; SGLT2, sodium-glucose
cotransporter-2; T2D, type 2 diabetes; TG,triglycerides.
1. Kim Y, et al. DiabetesMetabSyndrObes.2012;5:313-327.
2. Inzucchi SE, et al. Diabetes Care2015;38:140-159.
3. Davies, MJ, et al. Diabetes Care 2018;doi:10.2337/dci18-0033. (Epub ahead ofprint)
Benefits
• Low hypoglycemia rates1
• Small reduction in TGs1
• Insulin-independent glucose
lowering effect (irrespective of
T2D duration)2
• Decreased uric acid2
• Decreased albuminuria2
• Reduction in BP3
• Weight loss3
• Cardiac and renal benefits :
(empagliflozin and canagliflozin)3
Risks
• Small increase in hemoglobin/hematocrit1
• Urinary tract infections2
• Polyuria / dehydration2
• Small increase in LDL-C2
• Diabetic ketoacidosis3- Euglycemic
• Genital mycotic infections3
• Acute kidney injury3
• Dehydration3
• Orthostatic hypotension3
• Lower limb amputation (canagliflozin)3
• Fractures (canagliflozin)3
26

26. SGLT2 Inhibitors: FDA-Approved
Agents
FDA-approved SGLT2 Inhibitors
Agent Administration
Canagliflozin • Oral- 100 mg, 300 mg once daily
• Taken before the first meal of the day
Dapagliflozin • Oral- 5mg,10mg once daily
• Oral- 10mg, 25 mg Taken in the
morning with or without food
• Oral- 5mg,15mg once daily
Empagliflozin
Ertugliflozin

27. SGLT2 Inhibitors:Canagliflozin
CVD, cardiovascular disease; FDA, U.S. Food and Drug Administration, SGLT2, sodium-glucose cotransporters 2; T2D,
type 2 diabetes.
1. Tucker M. (2017, May 16); FDA Adds Boxed Warning toCanagliflozinforAmputation Risk. [News alert] Retrieved
from https://www.medscape.com/viewarticle/880059.
2. Invokana (canagliflozin) [Prescribing information]. 2013, Titusville, NJ: Janssen Pharmaceuticals, Inc.
FDA issuesblackboxwarningoncanagliflozin
amputationrisk
In patients with T2D who have established CVD or are at risk
for CVD, canagliflozin has been associated with lower limb
amputations, most frequently of the toe and mid-foot, as
well as the leg. Before initiating treatment, consider factors
that may increase amputation risk. Monitor patients
receiving canagliflozin for infections or ulcers of the lower
limbs, and discontinue if these occur.1,2
May 16, 2017

28. August 2020
FDA removes Boxed Warning about risk of leg
and foot amputations for the diabetes
medicine canagliflozin (Invokana, Invokamet,
Invokamet XR)

29. SGLT2 Inhibitors: FDA
Warning
FDA, U.S. Food and Drug Administration; SGLT2, sodium-glucose cotransport-2, T2D, type 2 diabetes.
U.S. FDA. (2018, August 29). SGLT2(sodium-glucose cotransporter-2) Inhibitors forDiabetes: Drug SafetyCommunication—Regarding
Rare Occurrences of a Serious Infectionof the GenitalArea. Safety alert: Retrieved from
https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm.
FDAissueswarningonSGL
T2
inhibitorsfordiabetes
Cases of a rare but serious infection of the genitals and
area around the genitals have been reported with the
class of T2D medicines called SGLT2 inhibitors. This
serious rare infection, called necrotizing fasciitis of the
perineum, is also referred to as Fournier’s gangrene.
August 29, 2018
4

30. Risk factors for DKA/ EuDKA
• Infection
• Low carbohydrate diet or an overall reduction of
caloric intake
• Reduction in dose of exogenous insulin or
discontinuation of exogenous insulin,
discontinuation of an oral insulin secretagogue
• Alcohol use

31. Essential pathophysiology of DKA and euDKA consequent of the use
of SGLT2 inhibitors.
Julio Rosenstock, and Ele Ferrannini Dia Care
2015;38:1638-1642
©2015 by American Diabetes Association

32. SGLT-2 inhibitors – Do’s
• SGLT2 inhibitors are a preferred adjunct medication in
patients with ASCVD, CKD , CHF assuming there is an
acceptable eGFR
• Can also be used as monotherapy when metformin is
contraindicated
• Counsel patients to maintain hydration status to avoid
dehydration
• Monitor sugars and titrate medications like insulin and
sulfonylureas/ meglitinides to avoid hypoglycemia
• Patients may need reduction in diuretic and
antihypertensive medication dosage

33. SGLT-2 Inhibitors – Dont’s
• Do not initiate therapy with Empagliflozin, dapagliflozin and canagliflozin
in patients with an eGFR less than 45 mL/min/1.73m2
• Do not start Ertugliflozin with an eGFR consistently less than 60
mL/min/1.73m2.
• All SGLT2 inhibitors are contraindicated in patients with an eGFR less
than 30 mL/min/1.73m2.
• Avoid SGLT2 inhibitors in patients with recurrent Urinary tract infections
/ Genital mycotic infections , history of recurrent Diabetic ketoacidosis.
• Use SGLT2 inhibitors with caution in patients with Severe PVD, previous
lower limb amputations and bone fractures
• Not approved for use in patients with Type 1 diabetes

35. AACE/ACE 2018 Glycemic Control
Algorithm
AG, alpha-glucosidase; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2, sodium-glucose
cotransporter 2; SU/GLN, sulphonylureas/glinides; TZD, thiazolidinediones.
Garber, AJ, et al. Endocr Pract.2018;24(1):91-120.
Metformin is
typically first-
line therapy.
Metformin,
GLP1 RAs,
SGLT2
inhibitors,
DPP-4
inhibitors, and
AG inhibitors
are all
acceptable
first- line
therapy.

36. Type 2 diabetes treatment algorithm

37. ADA/EASD 2018 T2D Management Consensus
Recommendations
• The major change from prior consensus reports is based on new evidence that
specific SGLT2 inhibitors inhibitors or GLP-1 RAs improve CV outcomes, as well as
secondary outcomes such as HF and renal disease progression, in patients with
established CVD or CKD.
• SGLT-2 inhibitors or GLP-1 receptor agonists with proven CV benefit are
recommended as part of glycemic management for patients with Type 2
diabetes (T2D) and established ASCVD.
• SGLT-2 inhibitors are recommended in patients with ASCVD in whom Heart
failure (HF) coexists or is of special concern.
• For patients with T2D and CKD, with or without CVD, consider the use of an
SGLT2 inhibitor shown to reduce CKD progression or a GLP-1 receptor agonist
shown to reduce CKD progression (if SGLT2 inhibitor contraindicated or not
preferred).
ADA, American Diabetes Association; ASCVD, atheroscleroticcardiovascular disease; CKD, chronic kidney disease, CVD, cardiovascular disease; EASD, European Association for the Study of Diabetes; GLP-1 RA, glucagon-likepeptide-1 receptor agonist; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2
inhibitor;T2D, type 2 diabetes.
• Davies, MJ, et al. Diabetes Care 2018;doi:10.2337/dci18-0033

38. AACE/ACE: Therapeutic and Cardiovascular
Priorities For Selecting T2D Therapeutics
• Metformin: Low hypoglycemia risk, good antihyperglycemic
efficacy, may promote modest weight loss, robust CV safety relative
to sulfonylureas
• GLP-1 RAs: Robust A1C-lowering, usually associated with weight
loss and BP reductions, low hypoglycemia risk, available in several
formulations; reduced or neutral effect on CV events, dependent
on formulation
• SGLT-2 inhibitors: Decreased A1C, weight, and systolic BP, low
hypoglycemia risk; empagliflozin associated with significantly lower
rates of all-cause and CV death and lower risk of hospitalization for
HF
• DPP-4 inhibitors: Modest A1C-lowering properties, weight-neutral,
low hypoglycemia risk; available in combination tablets with
metformin, SGLT-2 inhibitor, or Thiazolidinediones (TZD).

39. Considerations for Selecting
Therapies
● A- Current HbA1c and magnitude of reduction needed to
reach goal
● B- Potential effects on body weight and BMI
Potential for hypoglycemia – age, lack of awareness of
hypoglycemia, disordered eating habits
● C- Complications - Effects on CVD risk factors – blood
pressure and blood lipids
Comorbidities – CAD, heart failure, CKD, liver dysfunction
● D- Duration of disease
● E- Life expectancy, expenses – Patient factors – adherence
to medications and lifestyle changes, preference for oral
vs injected therapy, economic considerations
Inzucchietal. Diabetes Care 2012;35:1364‐79.

40. Summary
• Treatment decisions should be individualized
• Not solely be based on A1C or blood glucose levels-
should consider patient’s individual cardiovascular (CV)
risk profile.
• Typical 1st line treatment options- Metformin
with GLP-1 agonists and/or SGLT-2 inhibitors
• Select treatments based on safety/ efficacy and
positive effect on CV risk parameters, especially
weight and blood pressure
• Monitor every 3 to 4 months to achieve individualized
goals.

41. References
• 1. Acharya T, Deedwania P. The Role of Newer Anti-Diabetic Drugs in Cardiovascular Disease. JAAC. May
23, 2018 .
• 2. ADA Standards of Care 2021 ; Diabetes Care 2021;44(Suppl. 1):S125–S150 |
https://doi.org/10.2337/dc21-S010
• 3. Chao E, Henry R. Nature Rev Drug Discov. 2010;9:551-559.
• 4. Davies MJ, et al. Diabetes Care. 2018 September dci180033.
• 5. Drucker DJ, Nauk MA. Lancet. 2006; 368: 1696-1705.
• 6. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes
and Its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services;
2014.
• 7. Diabetes Care 2012;35:1364–1379. Diabetologia 2012;55:1577–1596
• 8. Tucker M. (2017, May 16); FDA Adds Boxed Warning to Canagliflozin for Amputation Risk. [News alert]
Retrieved from https://www.medscape.com/viewarticle/880059
• 9. U.S. FDA. (2018, August 29). SGLT2(sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety
Communication—Regarding Rare Occurrences of a Serious Infection of the Genital Area. Safety alert:
Retrieved from
https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm61
8908.htm
• 10. N Engl J Med 2021;384:1248-60. Glucose-Lowering Drugs to Reduce
• Cardiovascular Risk in Type 2 Diabetes
• DOI: 10.1056/NEJMcp2000280
• 11. Diabetes Care 2013 Aug; 36(Supplement 2): S127-S138.
• https://doi.org/10.2337/dcS13-2011
• 12. Inzucchi et al. Diabetes Care 2012; 35:1364‐79.