M2 - Lect 13 - Type 2 Diabetes Cont.

Question 1

Examples of Sodium Glucose Cotransporter 2

(SGLT2) Inhibitors

Answer 1

Canagliflozin (Invokana®),
Dapagliflozin (Forxiga®),
Empagliflozin (Jardiance®),
Ertugliflozin (Steglatro®)

Question 2

SGLT2 inhibitors MOA

Answer 2

SGLT2 is the primary mediator of glucose reabsorption in the kidneys - by inhibiting SGLT2 –> increase glucose excretion

Question 3

SGLT2 is expressed in the following tissues

Answer 3

– Kidney

– Islet α-cells

Question 4

SGLT1 is expressed in the following tissues

Answer 4

– Kidney
– Heart
– Small intestine
➢May delay intestinal glucose absorption
➢May enhance incretin hormone secretion

Question 5

Advantages of SGLT2 inhibitors

Answer 5

▪ Does not cause hypoglycemia
▪ Can be prescribed with other therapies for diabetes
▪ Are effective at all stages of type 2 diabetes
▪ Have beneficial effects on the cardiovascular system

Question 6

Disadvantages of SGLT2 inhibitors

Answer 6

▪ Increases genital and urinary tract infections
▪ May increase hepatic glucose production (via
increasing glucagon secretion???)
▪ May increase ketoacidosis
▪ Increased risk of amputation (only seen with
canagliflozin)

Question 7

β-cell exposure to equivalent circulating glucose
concentrations will stimulate a greater amount of insulin
release if the glucose is administered

Answer 7

orally vs. intravenously

Question 8

GLP-1’s “Incretin Effect” is

Answer 8

Glucose-Dependent

GLP-1 ability to enhance glucose-stimulated insulin secretion is
glucose-dependent, being more potent at higher plasma glucose
levels
• Thus, the risk of hypoglycemia with GLP-1 is significantly less
compared to other diabetic therapies

Question 9

Pharmacological Actions by which

GLP-1 Receptor Agonists Improve Glycemia

Answer 9

• GLP-1 promotes glucose stimulated insulin secretion
➢Ability to enhance glucose-stimulated insulin secretion is glucosedependent,
being more potent at higher plasma glucose levels
(low risk for hypoglycemia)
• GLP-1 inhibits glucagon secretion, which reduces hepatic
glucose production in patients with diabetes
• GLP-1 inhibits gastric emptying
➢Delays appearance of nutrients (e.g. glucose) into the circulation
• GLP-1 inhibits appetite
➢Leads to reductions in body weight and adiposity

Question 10

GLP-1 analogs that are resistant to DPP-4

Answer 10

➢Exenatide (Byetta®) [T1/2 ~ 2 hours]
❖Synthetic version of the Gila monster salivary hormone,
exendin-4
➢Liraglutide (Victoza®) [T1/2 ~ 12 hours]
❖Acylated GLP-1 analog that noncovalently binds to
albumin
➢Albiglutide (Tanzeum®) [T1/2 ~ 4-7 days]
❖GLP-1 dimer fused to albumin
➢Lixisenatide (Lyxumia®) [T1/2 ~ 2.5 hours]
❖Structurally related to exendin-4
➢Semaglutide (Ozempic®) [T1/2 ~ 1 week]
❖Longer-acting alternative to liraglutide

Question 11

Advantages of GLP-1R Agonists

Answer 11

▪ Also cause body weight loss (liraglutide approved for
obesity)
▪ Less risk of hypoglycemia (do not promote insulin
secretion when circulating glucose levels are low/normal)
▪ Reduced cardiovascular risk with GLP-1R agonists (seen
with all GLP-1R agonists for most part except lixisenatide
and exenatide)

Question 12

Disadvantages GLP-1R Agonists

Answer 12

▪ Primarily gastrointestinal concerns (nausea, diarrhea,
vomiting)
▪ Increase in heart rate
▪ Pancreatitis???
▪ Increased risk of hypoglycemia if co-prescribed with
sulfonylureas

Question 13

DPP-4 Inhibitors- Mechanism of Action

Answer 13

Inhibit DPP-4 activity to prevent the breakdown of

endogenously released GLP-1

Question 14

Examples of DPP-4 Inhibitors

Answer 14

➢Sitagliptin (Januvia®, Janumet®)
➢Vildagliptin (Galvus®)
➢Saxagliptin (Onglyza®, Komboglyze®)
➢Alogliptin (Nesina®, Kazano®, Oseni®)
➢Linagliptin (Tradjenta®, JentaDueto®)

Question 15

Advantages of DPP-4 Inhibitors

Answer 15

▪ Less risk of hypoglycemia (do not promote insulin
secretion when circulating glucose levels are low/normal)
▪ Oral versus injectable (patient preference)

Question 16

Disadvantages of DPP-4 Inhibitors

Answer 16

▪ Primarily gastrointestinal concerns (nausea, diarrhea,
vomiting)
▪ Pancreatitis???
▪ Increased risk of hypoglycemia if co-prescribed with
sulfonylureas
▪ Increased risk of hospitalization for heart failure (only seen
with the DPP-4 inhibitor saxagliptin)
▪ Don’t cause weight loss like GLP-1 receptor agonists