SGLT-2 Inhibitors & GLP-

1 Agonists
Emily Clemens, PharmD, PGY2 Ambulatory Care/Education
Pharmacy Resident
Claire Mattison, PharmD, PGY2 Ambulatory Care Pharmacy
Resident
Poll
Do you feel comfortable prescribing
empagliflozin or another SGLT-2
inhibitor?
Do you feel comfortable prescribing
semaglutide or another GLP-1 agonist?

Are you aware of the VA Criteria for Use

and where to find these documents?
Objectives
Describe the mechanism of action of GLP1 agonists and SGLT2
inhibitors

Summarize primary literature regarding the impact of both

drug class on diabetes-related comorbidities

Review the criteria for use of semaglutide and empagliflozin

Discuss the use of these agents in clinical practice

Given a patient case, decipher if a GLP1 agonist or SGLT2

inhibitor would be appropriate
Glucagon-like Peptide 1
(GLP-1) Receptor Agonists
GLP-1
• Hormone made
in the small
intestine
• Multiple sites of
action
• Inhibits hepatic
glucose
production

Ahren. Diabetes 2015 Mar; 64(3): 715-717.

 How Does it Work?
Peripheral
Pancreas effects Central effects
effects

Increases insulin Slows gastric

Induces satiety
secretion (beta cells) emptying

Promotes islet cell

Slows small Decreases food
growth and
intestinal transit intake
neogenesis

Reduces glucagon Reduces hepatic

Promotes weight loss
release (alpha cells) glucose production

MacDonald PE. Diabetes 2002: S434-S442.

How Does it Work?

GLP-1 Agonist
• Acts similar to DPP-4 Inhibitor
GLP hormone • Inhibits enzyme,
dipeptidyl
peptidase, that
breaks down GLP

• Avoid combination of GLP-1 agonists and DPP-4 inhibitors

• Combination increases risk of side effects without glucose
benefit
Currently Available
Subcutaneous injectables
Daily
• Liraglutide (Victoza®)
• Lixisenatide (Adlyxin®)
• Exenatide (Byetta®)
Weekly
• Semaglutide (Ozempic®)
• Dulaglutide (Trulicity®)
• Exenatide (Bydureon®)
Oral semaglutide (Rybelsus®)
Dosing: daily (3-14 mg; titrated)

PIONEER studies

GI side effects prevalent

VA Cost: $17.10/tablet
Oral semaglutide (Rybelsus®)

HgbA1c Weight loss

Non-inferior to
liraglutide Non-inferior to
empagliflozin
Superior to
sitagliptin and
empagliflozin Superior to
Average of 1.2% liraglutide and
lowering sitagliptin
GLP-1 Benefits

HgbA1c decrease by up to 1%

Weight loss (~5% total body

weight)

CVD and CKD outcomes

 Cardiac Benefit
• Liraglutide lowered risk of CVD and all-cause death among
LEADER patients with T2DM
• Semaglutide lowered composite outcome CVD, non-fatal MI and
SUSTAIN stroke
• Only non-fatal stroke was statistically significant alone
• Dulaglutide lowered composite outcome CVD, non-fatal MI and
REWIND stroke
• Only non-fatal stroke was statistically significant
• Exenatide showed no significant difference on CV outcomes
EXSCEL among patients with T2DM

• Lixisenatide showed no significant difference on CV outcomes

ELIXA among patients with T2DM
 Renal Benefit
• Liraglutide reduced new-onset persistent macroalbuminuria by 26%
LEADER among patients with T2DM

• Semaglutide decreased the rate of persistent macroalbuminuria

SUSTAIN among patients with T2DM

• Dulaglutide reduced albuminuria and decreased the rate of renal

AWARD function decline

• Lixisenatide lowered the rate of increased urinary albumin-to-

ELIXA creatinine ratio
Sodium Glucose Co-
transporter 2 (SGLT-2)
Inhibitors
Sodium Glucose
Co-transporter 2
(SGLT-2)

• Protein located
proximal convoluted
tubule
• 90% of glucose
reabsorption of
kidney filtrate
SGLT-2 Inhibitors
Empagliflozin (Jardiance®)

Canagliflozin (Invokana®)

Dapagliflozin (Farxiga®)

Ertugliflozin (Steglatro®)

* Sotagliflozin – upcoming SGLT-1 and -2 inhibitor

 Cardiac Benefit
• Canagliflozin reduced MACE outcomes and HF hospitalizations
CANVAS among patients with T2DM

• Empagliflozin reduced MACE outcomes, CV death, all-cause

EMPA- mortality, and heart failure hospitalizations among patients with
REG T2DM

• Dapagliflozin lowered risk of CVD and heart failure hospitalization

DECLARE rates
• No difference in MACE or all-cause mortality
 Heart Failure Benefit
• Dapagliflozin reduced worsening heart failure or CV death by
26% for patients with HFrEF
DAPA-HF • 45% of subjects had T2DM
• Most NYHA II-III
• Median duration of follow-up was 18.2 months

EMPEROR- • Empagliflozin vs. placebo

• In progress - completed by November 9, 2020
Preserved

EMPEROR- • Empagliflozin vs. placebo

Reduced • In progress - completed by July 20, 2020
 Renal Benefit
• Canagliflozin lowered composite of end-stage kidney
disease, doubling of serum creatinine, or death from renal
CREDENCE or cardiovascular disease) by 30%, in addition to a
significant reduction in albuminuria

EMPA- • Empagliflozin vs. placebo

• In progress - completed by June 30, 2022
KIDNEY

• Dapagliflozin vs. placebo

DAPA-CKD • In progress - completed by November 27, 2022
VA Criteria for Use and
Prescribing Options
Formulary Diabetes Agents
Novolog Lantus Levemir
(aspart) (glargine) (detemir)

Regular,
70/30, & Metformin
Glipizide IR
NPH IR/SA
insulins

Pioglitazon
Glimepiride Alogliptin
e
Non-Formulary Diabetes
Medications
GLP-1 Agonists

• Preferred: semaglutide

SGLT-2 Inhibitors

• Preferred: empagliflozin
GLP-1 Agonists
Criteria for Use (CFU)
GLP-1 CFU – Exclusion Criteria
T1DM

Personal/family Hx of thyroid cancer or

MEN-2

Severe GI disease (ex: gastroparesis)

Hx of pancreatitis

Hx diabetic retinopathy*

* semaglutide
Semaglutide and Retinopathy
• Two-year trial found more events of diabetic
retinopathy complications with semaglutide (3%) vs.
placebo (1.8%)
 Risk higher for those with diabetic retinopathy at
baseline
• Not an absolute contraindication
• Should have a baseline eye exam and monitor for
progression of retinopathy
• Consider liraglutide or dulaglutide if retinopathy
present
GLP-1 CFU

Inclusion
Criteria

With CV Without CV
disease and/or disease and/or
CKD CKD
GLP-1 CFU – Inclusion Criteria
CV Disease and/or CKD
• T2DM
• On metformin or another agent if unable to tolerate
• Add-on therapy (HgbA1c not at goal) or substitution for
another agent (not metformin)
• Not a good candidate for empagliflozin
AND at least one of the following:
• Established CV disease
• eGFR < 60 ml/min or UACR ≥ 30 mg/g
 Established CV Disease
Prior MI, stroke, or TIA (>90 days)

Prior coronary, carotid, or peripheral

revascularization
≥ 50% stenosis on of coronary, carotid, or
lower extremity arteries
Hx symptomatic CAD or asymptomatic
ischemia

CHF NYHA Class II-III

GLP-1 CFU – Inclusion Criteria
No CV disease or CKD
• T2DM
• Inadequate control on two oral medications
• Including metformin, unless unable to tolerate
OR
• Inadequate control on titrated basal insulin +
metformin (or other agent if unable to tolerate)
• Not a good candidate for empagliflozin
SGLT-2 Inhibitors
Criteria for Use (CFU)
SGLT2 CFU – Exclusion Criteria

On dialysis Pregnant or nursing

Pancreatic
Urinary conditions
disorders

HgbA1c >10%
 SGLT2 CFU – Exclusion Criteria
Pancreatic
disorders
Urinary Conditions
suggesting
insulin deficiency
• Type 1 diabetes • History of frequent UTIs
• Recurrent pancreatitis • Use of indwelling
• Pancreatic surgery catheters
• Need for self-
catheterization
• Hx of increased post-void
residual
SGLT-2 CFU

Inclusion
Criteria

With CV Without CV
disease, CHF, disease, CHF,
or CKD or CKD
SGLT2 CFU – Inclusion Criteria
CV Disease, CKD, or CHF (NYHA Class II-III)
• T2DM
• Metformin or another agent if unable to use
metformin
AND at least one of the following:
• CV disease
• HF with reduced EF and NYHA Class II-III
• eGFR 30-59mL/min OR UACR ≥ 30mg/g
SGLT2 CFU – Inclusion Criteria
No CV disease or CKD
• T2DM
• eGFR ≥ 45 ml/min
• Inadequate control on two oral medications
• Including metformin, unless unable to
tolerate
OR
• Inadequate control on titrated basal insulin
and metformin (or other agent if unable to
tolerate)
SGLT2 Concerns

DKA UTI Pancreatitis

Fungal
Amputation Dementia
infections

Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Often euglycemic
Fungal
Amputation Dementia
infections
Consider alcohol use
and caloric restriction
Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Risk:
Fungal
Amputation Dementia
4% males; 18% females
infections
Consider Hx of UTI
Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Increased risk of DKA

Fungal
Amputation Dementia
infections Consider pancreatic
deficiency

Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Fungal Risk: 2% to 6%
Amputation Dementia
infections Circumcision and
hygiene

Diuretic Hypotensio
Age
use n
SGLT2 Concerns
Controversial results
DKA UTI Pancreatitis
seen in canagliflozin

Fungal
Amputation Dementia
infections

Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Worsening symptoms of
Fungal
UTI and Amputation
DKA Dementia
infections

Diuretic Hypotensio
Age
use n
 SGLT2 Concerns

DKA UTI Pancreatitis

Fungal
Increased risk of ADR’s
Amputation Dementia
infections

Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Increased risk of
Fungal dehydration and
Amputation Dementia
infections hypotension

Diuretic Hypotensio
Age
use n
SGLT2 Concerns

DKA UTI Pancreatitis

Decrease SBP by ~4
mmHg
Fungal
Amputation Dementia
Increase risk of falls;
infections
assess volume status

Diuretic Hypotensio
Age
use n
GLP-1 and SGLT-2 in Practice
Glucose Effect
GLP-1 Agonist
• Acts on both fasting and
post-prandial blood glucose
• Does not increase risk of
hypoglycemia
 Could potentiate lows if used
with insulin
• Decrease HgbA1c by ~1%
SGLT-2 Inhibitors
• Acts on both fasting and
post-prandial blood glucose
• Does not increase risk of
hypoglycemia
 Could potentiate lows if used
with insulin
• Decrease HgbA1c by 0.3-
0.9%
Dosing
GLP-1 Agonist SGLT-2 Inhibitors
• Semaglutide 0.25mg SQ • Empagliflozin 10mg PO daily
once weekly x 4 weeks, then
0.5mg once weekly
• Can titrate to 25mg daily

• Titration is required to
• Glucose and comorbidities
decrease risk of GI side did not overly improve with
effects 25mg vs. 10mg

• May increase to 1mg SQ

• Side effects of empagliflozin
once weekly to attain often dose dependent
additional benefit
Follow-Up
GLP-1 Agonist
• Assess patient’s other
medications
 If glucose is controlled, may
discontinue medications that
increase the risk for
hypoglycemia (e.g. glipizide)
SGLT-2 Inhibitors
• Assess patient’s other
medications
 If glucose is controlled, may
discontinue medications that
increase the risk for
hypoglycemia (e.g. glipizide)
• Potential to increase SCr
 Follow up with BMP 4-8 weeks
after initiation
 D/C if SCr is > 20% from
baseline
 Insulin Therapy
Benefit in avoiding May require reduction
GLP-1 and SGLT-2
further insulin of basal-bolus doses
may be additive
titrations in the depending on glycemic
therapy to basal
future control and
and basal-bolus
hypoglycemia risk
regimens
 • TP is a 61 YOM with a PMH significant
Patient for T2DM, BPH, COPD, and CAD s/p PCI
2/2019
Case #1 • He presents today for annual follow-up
• Screen for
• Vitals:
contraindications
 BP: 118/72 mmHg
• BP WNL
• No Hx of UTI or  HR: 68 BMP
fungal infections
• No Hx of pancreatitis
• Labs:
• No cuts/sores on feet  HgbA1c: 6.8%
 eGFR: 72 ml/min
• Hx of CAD
• DM Medications:
• Start empagliflozin
 Metformin SA 2g daily
10mg
 Glargine 36 units QHS
 • TP returns 3 months later, and states
Patient he cannot take empagliflozin any
longer
Case #2  Experienced “jock itch” and
• D/C empagliflozin bothersome increased urination

• Given Hx of CAD, • Labs:

could add on GLP-1  HgbA1c: 7.1%
 eGFR: 80 ml/min
• Screen for
contraindications • DM Medications:
• No Hx pancreatitis or  Metformin SA 2g daily
thyroid cancer
 Glargine 40 units QHS
• No GI conditions
 Empagliflozin 10mg daily
• Start semaglutide
0.25mg weekly • What would you consider next for
DM?
 • SL is a 68 YOM with PMH of T2DM and
Patient CKD
 Recently discharged after a TURP
Case #3 procedure, complicated by a urethral
• D/C empagliflozin stricture. Upon discharge, he was
instructed to self-catheterize weekly
due to risk of UTI
and catheter use • Vitals:
 BP: 126/70 mmHg
• Options to replace:
• Increase basal  HR: 74 BMP
insulin
• Lifestyle
• Labs:
modifications  HgbA1c: 8.2%
• Add GLP1 agonist  eGFR: 65 ml/min; UACR>30mg/g

• DM Medications:
Metformin 1g BID WM Alogliptin 25mg daily
Glargine 10 units daily Empagliflozin 25mg daily
 • SL is a 68 YOM with PMH of T2DM and
Patient CKD
 Recently discharged after a TURP
Case #4 procedure, complicated by a urethral
• Meets GLP-1 stricture. Upon discharge, he was
instructed to self-catheterize weekly
criteria:
• Hx of CKD • Vitals:
• A1c uncontrolled  BP: 126/70 mmHg
on multiple agents  HR: 74 BMP
• Not a candidate
for empagliflozin • Labs:
• Screen for  HgbA1c: 8.2%
contraindications  eGFR: 65 ml/min; UACR>30mg/g

• Start semaglutide • DM Medications:

0.25mg weekly Metformin 1g BID WM Alogliptin 25mg daily
Glargine 10 units daily
• D/C alogliptin
 Takeaways
GLP-1 agonists and SGLT-2 inhibitors are indicated for patients with
1 uncontrolled diabetes and comorbidities of CAD and/or CKD

If a patient is a candidate for empagliflozin, trial SGLT-2 therapy before

2 adding GLP-1 agonists

Review concerns with both agents when considering therapy for patients
3 (e.g. pancreatitis, UTI, GI conditions)
Assess the appropriateness of patients’ other medications with these new
4 agents (e.g. DPP4 and GLP-1 should not be combined; diuretic and SGLT-2
use should be monitored)
Once these medications are added, ensure patient has adequate follow
5 up (e.g. insulin dose decrease, BMP/A1c draw, discontinue
hypoglycemic agents)
 SGLT-2 Inhibitors & GLP-
1 Agonists
Claire Mattison, PharmD, PGY2 Ambulatory Care Pharmacy
Resident
Emily Clemens, PharmD, PGY2 Ambulatory Care/Education
Pharmacy Resident