2. OBJECTIVES
• Overview non-insulin treatment for diabetes (DM) and their clinical
considerations
• Discuss the ADA Standards of Care in Diabetes 2024
• Apply clinical knowledge to select appropriate regimen for patients with diabetes
4. TREATMENT OF DIABETES MELLITUS
Name different classes of medication that can
lower blood glucose levels
5. 1. INSULIN SECRETAGOGUES
SULFONYLUREAS
• Mechanism of action (MOA):
• Binding to a sulfonylurea receptor (SUR) =>
Promote insulin release by β cells of the pancreas
• ↓ hepatic glucose production
• ↑ peripheral insulin sensitivity
• Duration of action: 12-24 hours
• Side effects (SEs):
• Hypoglycemia and hyperinsulinemia (especially
short-acting formulations)
• Weight gain
• Use caution in renal impairment due to increased
duration of effects
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: glypizide (Glucotrol),
glimepiride (Amaryl), glyburide
(Micronase), gliclazide (Diamicron)
6. 1. INSULIN SECRETAGOGUES
MEGLITINIDES
• Mechanism of action:
• Binding to different site of SUR => Promote
insulin release by β cells of the pancreas
• More rapid & shorter than SU
• Classified as postprandial glucose regulators
• Take before each meal
• Side effects:
• Hypoglycemia and hyperinsulinemia
• Weight gain
• Caution in patients with hepatic impairment
• AVOID combination of glinide and sulfonylurea
agents due to additive risk for hypoglycemia
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: repaglinide (Prandin),
nsteglinide (Starlix)
7. 2. BIGUANIDE
Foretz, M., Guigas, B. & Viollet, B. Metformin: update on mechanisms of action and repurposing potential.Nat Rev Endocrinol 19, 460–476 (2023). https://doi.org/10.1038/s41574-023-00833-4
8. 2. BIGUANIDE
• Mechanism of action:
• reduce hepatic gluconeogenesis
• increase glucose uptake
• decrease insulin resistance
• SEs:
• Nausea, vomiting and diarrhea → start small dose and slow titration,
take with meals.
• Long-term use: decrease B12 level
• Rare SE: lactic acidosis
• Hypoglycemia (when combine with insulin or insulin secretagogues)
• AVOID in renal dysfunction (eGFR < 30 ml/min/1.73 m2)
• Interrupt therapy in patients with eGFR of 30–60 mL/minute/1.73 m2
if undergoing procedures using iodinated contrast dye. Reinitiate
after 48 hours if normal SCr
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: metformin
(Glucophage)
9. 3. ΑLPHA-GLUCOSIDASE INHIBITORS
• Mechanism of action: inhibit α-Glucosidase
enzymes in the intestinal brush borders → prevent
the breakdown of carbohydrates into glucose
• Reduce postprandial blood glucose
• No hypoglycemia
• Side effects:
• Diarrhea
• Flatulence
• Abdominal cramping
• AVOID in patients with colonic ulceration, inflammatory
bowel disease or intestinal obstruction
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: acarbose (Precose)
Pc:Sage Journals
10. 4. THIAZOLIDINEDIONES
• Mechanism of action: increase glucose uptake via
activation of PPARγ (a nuclear transcription regulator)
→ transcript insulin responsive genes → increase
insulin sensitive
• Delayed onset 2/2 modification of gene expression
• SEs:
• Weight gain, edema, osteopenia (women)
• Hepatotoxicity has been occasionally reported
• Bladder cancer (pioglitazone)
• Increased ovulation and teratogenic effects
• AVOID in patient with heart failure (fluid retention can
worsen HF), hepatic impairment (> 3x UNL), pregnancy
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Pc: Lianna F & Nicholas W
Eg: rosiglitazone (Avandia),
Piolitazone (Actos)
11. 5. AMYLIN ANALOG
• Mechanism of action: synthetic amylin analog. Amylin is a
hormone secreted by β cells to:
• delay gastric emptying
• improve satiety via centrally-mediated appetite suppression
• ↓ glucagon secretion
• Characteristics:
• No insulin secretory effect
• May be used in conjunction with insulin
• Insulin dose should be decreased by 50% to avoid severe
hypoglycemia
• SC injection immediately prior to meals
• Side effects: hypoglycemia, nausea, vomiting and anorexia
• AVOID in patients with diabetic associated gastroparesis,
hypoglycemic unawareness
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Pramlintide, Lexicomp Online, Lexi-DruOnline, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; June 22, 2020
Eg: pramlintide (Symlin)
12. 6. INCRETIN MODULATOR
GLUCAGON-LIKE PEPTIDE RECEPTOR AGONISTS (GLP-1 RAS)
• MOA: mimic the release of incretin hormones,
which is released postprandial
• slow gastric emptying
• potentiate glucose-mediated insulin secretion
• suppress postprandial glucagon release
• CNS-mediated loss of appetite
• reduce liver fat content
• Characteristics:
• Injectable
• May require a dose reduction of insulin/insulin secretagogues
to avoid hypoglycemia
• Can cause weight loss
• SEs
• Common: GI (N/V/D), abdominal distention
• Severe: Pancreatitis, thyroid C-cell tumors (in rodents)
• AVOID if gastroparesis, pancreatitis, thyroid C-cell tumors
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: exenatide (Byetta, Bydureon),
dulaglutide (Trulicity), liraglutide
(Victoza), semaglutide (Ozempic)
13. BASAL INSULIN/GLP-1 RA FIXED-RATIO COMBINATIONS
Endocrinology & Nephrology. PSAP 2019 book 3
14. GIP/GLP-1 RA
Mounjaro (tirzepatide)
• Mechanism of action: duo-acting by being both glucose-
dependent insulinotropic polypeptide (GIP) and GLP-1 RAs
=> Similar action as GLP-1 RA but stronger: more effective for blood
sugar control and weight loss
• The first and only drug of its kind approved at this time
• SEs: more SEs than GLP1-RA, dyspepsia, decreased appetite
• Caution: Switch to a non-oral contraceptive method or add a
barrier contraceptive for 4 weeks after starting treatment and after
each dose escalation
15. 6. INCRETIN MODULATOR
DIPEPTIDYL PEPTIDASE-4 INHIBITORS
• MOA
• Inactivate enzyme DPP-4 → allow incretin
hormones to increase the secretion of insulin in
response to meals
• Prevent the secretion of glucagon
• SEs:
• Common: well tolerated. Headaches and
nasopharyngitis are reported
• Severe: pancreatitis, increased risk of severe,
disabling joint pain, angioedema (when combine
ACEI/ARB)
• AVOID alogliptin and saxagliptin in patients with or
at risk of heart failure
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: linagliptin (Trajenta),
sitagliptin (Januvia), alogliptin
(Nesina), saxagliptin (Onglyza)
16. 7. SODIUM–GLUCOSE COTRANSPORTER (SGLT-2)
INHIBITORS
• Mechanism of action: decrease reabsorption of glucose from the
kidneys by increasing the urinary excretion of glucose to lower
glucose
• Side effects:
• Vulvovaginal candidiasis
• Urinary tract infections
• Increased urinary frequency
• Hypotension due to increased urinary frequency
• Euglycemic ketoacidosis → not use in critical ill hospitalized patients (cannot
eat)
• CAUTION in renal dysfunction
Lippincott® Illustrated Reviews: Pharmacology, 7e, 2019
Eg: empagliflozin (Jardiance),
dapagliflozin (Forxiga)
19. TYPE 1 DIABETES
• Effect of noninsulin treatment for Type 1 Diabetes:
• Pramlintide: approved for use in adults with type 1 diabetes. Modest reduction in A1C (0.3-0.4%)
and modest weight loss (~1 kg)
• Metformin: Small reductions in body weight, insulin dose, lipid levels but did not sustainably improve
A1C
• GLP-1 RAs: Modest A1C reduction (~0.4%), decrease in weight (~5 kg), reduction of insulin doses
• SGLT2 inhibitors: improvements in A1C, reduced body weight, improved blood pressure; however
increased rate of DKA
• The risks and benefits of noninsulin agents continue to be evaluated for treatment of type 1
diabetes, with consensus statements providing guidance on patient selection and precautions
20. TYPE 2 DIABETES
• A patient-centered shared decision-making approach should guide the choice of pharmacologic
agents for adults with type 2 diabetes. Factors that should be considered before initiating
regimen including:
• Cardiovascular & renal comorbidities
• SGLT2 inhibitors and/or GLP-1 RA are recommended for patients who have atherosclerotic
cardiovascular disease, HF, CKD (eGFR 20-60 ml/min/1.73 m2 )
• Hypoglycemia risk
• Impact on weight, cost, and access
• Risk for adverse reactions & tolerability
• Individual preferences
• Early combination therapy can be considered in adults with type 2 diabetes at treatment initiation
to shorten time to attainment of individualized treatment goals
• Medication therapy should be reevaluated at regular intervals (every 3-6 months) and adjusted
as needed
• GLP-1 RA, including a dual GIP and GLP-1 RA, is preferred to insulin
American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1)
25. CASE 1
A 62-year-old woman (50 kg, 160 cm) with a medical history significant for COPD
GOLD C, HF NYHA II was recently hospitalized for pneumonia. During her
hospitalization she was diagnosed with T2D. Her A1C today is 8.4% (personal
goal 7%). She denies any signs & symptoms of hypoglycemia. Her other lab
values are within normal limit. Her home medications include tiotropium 2.5 mcg,
metoprolol succinate 25 mg, telmisartan 40 mg and spironolactone 25 mg.
Which agent would be the best recommendation?
A. Lifestyle change with focus on nutrition therapy and exercise
B. Metformin 500 mg
C. Dapagliflozin10 mg
D. Pioglitazone15 mg
26. CASE 2
A 65-year-old man (60 kg, 165 cm) with a medical history of T2D & UC has
received insulin glargine 6 units SQ daily, metformin 1000 mg twice daily and
mesalamine 1000 mg four times daily. Due to his stressful job as an ICU nurse, he
drinks almost everyday when he is off-work and has moderate hepatic
impairment. He also admitted he occasionally forgets his insulin dose. His A1C
today is 7.8% (goal 7%). His morning FPG readings are consistently at goal (< 7
mmol/L); however, his postprandial glucose readings average 11-12 mmol/L.
Which would be most appropriate for this patient?
A. Increase metformin to 1000 mg three times daily
B. Add pramlintide 60 mcg SQ prior to major meals
C. Add acarbose 25 mg three times daily with each meal
D. Add sitagliptin 50 mg once daily
27. CASE 3
A 60-year-old female (70 kg, 170 cm) with uncontrolled T2D comes to a clinic for
medication therapy management. Her current A1C is 10.5%. Her medical history
is significant for recurrent UTI (4 times/year) and ischemic stroke last year, which
she was fully recovered. She is currently on metformin XR 1000 mg, insulin
glargine SQ 10 units, aspirin 81 mg, and rosuvastatin 20 mg
Which treatment is the most suitable for this patient?
A. Insulin aspart SQ 4 units before the biggest meal
B. Dulaglutide 0.75 mg
C. Gliclazide MR 60 mg
D. Dapagliflozin 10 mg
28. CASE 4
A 55-year-old man (80 kg, 165 cm) with T2D has been on metformin 1000 mg
twice daily and acarbose 100 mg three times daily for 3 years. His latest A1C is
7.5%. He recently suffered from MI a week ago and had 2 stents placed. As a
result, he received clopidogrel/aspirin 75/100 mg, rosuvastatin 20 mg, metoprolol
succinate 25 mg, lisinopril 5 mg daily
Which one of the following medications is best to add to his regimen?
A. Exenatide 2 mg
B. Pioglitazone 15 mg
C. Sitagliptin 50 mg
D. Empagliflozin10 mg
29. CASE 5
A 67-year-old woman (70 kg, 149 cm) with T2D, dislipidemia, and a stage 3 CKD
(45 ml/min/1.73 m2) have been on metformin XR 1000 mg 2 times daily, insulin
glargine 24 units daily for the past 2 years. Her current A1C is 8.5%. You want to
start GLP-1 RA for this patient.
Which one of the following is best to recommend for changing the patient’s
current insulin regimen to basal insulin/GLP-1 RA fixed –ratio combination?
A. Insulin degludec/liraglutide 10 units daily
B. Insulin degludec/liraglutide 16 units daily
C. Insulin glargine/lixisenatide 15 units daily
D. Insulin glargine/lixisenatide 30 units daily
30. SUMMARY
• Several medications can be used to control blood glucose but they are different
in efficacy and safety profiles
• Patient factors and potential medication side effects should be taken into
account prior to selecting an agent to prevent serious complications
• Updates on diabetes management 2024 reflect new evidences on CV benefits
of antidiabetics
