Block 3: T2DM Flashcards
1
Q
What are the PO medications fot T2DM?
A
- Biguanides (metformin)
- Incretin-mimetics (GLP-1 agonist, Rybelsus)
- Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitors
2
Q
What are the non-insulin injectables for diabetes?
A
- Incretin-mimetics (GLP-1 / GIP drugs)
- Amylin Analogs
3
Q
What are the insulin injectables?
A
- Basal Insulins (Glargine)
- Regular and NPH Insulins
- Bolus Insulins (Lispro)
4
Q
What are the major sites of action of antihyperglycemic agents?
A
5
Q
What are the non-pharms for diabetes?
A
Lifestyle modifications: diet and exercise
6
Q
What are the benefits of exercise?
A
- Improves blood glucose control
- Helps manage weight
- Reduces CV risk factors
- Improves overall health and well-being
7
Q
What are the treatment goals of diabetes?
A
- Non-pharm tx
- Stepwise and combinational pharmacological intervention
- Diabetes education is essential
8
Q
What are the pharmacological effects of metformin?
A
- Lowers glucose levels by decreasing hepatic glucose production (gluconeogenesis)
- Does not diretly effect beta-cells
- Improves insulin resistance (liver»_space;> muscle) without increasing insulin levels however does requires the presence of insulin to have effect
- Some patients can experience weight loss
9
Q
How much does metformin decrease A1c?
A
1.5-2%
10
Q
Metformin’s place in therapy?
A
- Monotherapy or Combination Therapy
- First-line therapy for management of type-2 diabetic patients and patients with “pre-diabetes
* Preferred in obese patients
* Approved in pediatric pathients at 10
11
Q
Metformin
Brand, Class, Metabolism, ADR, CI, DDI
A
Glucophage
Class: Biguanides
Metabolism: Renal elimination
ADR: GI upset, diarrhea, lactic acidosis (sx worsens at higher doses)
CI: Lactic acidosis causes complications for those with renal insufficienct, CHF, liver disease, and hypoxia
* Avoid with renal and hepatic problems
DDI: Contrast dyes
* Withhold metformin 48 hrs after procedure
12
Q
What are the thiazolidinediones?
A
Pioglitazone (Actos) and Rosiglitazone (Avandia)
13
Q
Pharmacology of TZDs?
A
- Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist
- Insulin sensitizer
- Lowers glucose levels by increases insulin sensitivity in muscle, fat, and lesser extent in liver
14
Q
Describe the MOA of glitazones?
A
- Glitazone binds to PPARy in the cytosol
- Forms a heterodimer with RXR and binds to DNA sequences, Peroxisome Proliferator Hormone Response Elements (PPREs)
- Regulates numerous genes including those associated with improving glucose uptake and disposal in muscle and fat tissues
15
Q
Describe the effectiveness of TZDs?
A
- Improves insulin resistance in muscle and fat»_space;> liver
- Improves HgbA1c by ~1-1.5%
- 4 week onset
- Lower risk of hypoglycemia
16
Q
Thiazolidinediones (TZDs)
Brand, Class, Indications, Metabolism, ADR, CI, DDI
A
Pioglitazone (Actos) or Rosiglitazone (Avandia)
Indications: T2DM
PK: extensive absorption, highly protein bound, hepatically metabolized, feces and urine
ADR: Hepatotoxicity, fluid retention, edema, CHF (Rosiglitazone or in combo with insulin)
CI: Severe CHF (Class III and IV)
DDI: Pioglitazone induces CYP3A4
17
Q
Types of 2nd gen sulfonylureas?
A
Glimepiride (Amaryl)
Glipizide (Glucotrol XL)
Glyburide (DiaBeta, Micronase)
Glyburide micronized (Glynase)
18
Q
Pharmacology/MOA of sulfonylureas?
A
- Lowers glucose levels by increasing basal and postprandial insulin secretion from beta cells
- Binds to the “sulfonylurea site” on the potassium channel of β-cells, closing the channel and depolarizing β-cell
- Requires functioning β-cells
Increase Insulin Secretion -> Secretagogues
19
Q
What are the first gen sulfonylureas?
A
- Tolbutamide
- Acetohexamide
- Chlorpropamide
- Tolazamide
All have been D/C’d
20
Q
Effectiveness of Sulfonylureas?
A
Decrease in HgA1c: 1.5-2%
21
Q
Sulfonylureas
Indications, Place in therapy, PK, ADR, CI, DDI
A
Indications: T2DM
P-in-T: Requires functioning β-cells, avoid in patients with hypoglycemic problems
PK: Increased half-life -> increased accumulation -> increased risk of hypoglycemia
* Glyburide (10 hour half-life)
* Glimepiride (9 hour half-life)
* Glipizide (2-5 hour half-life)
ADR: Hypoglycemia, weight gain
CI: G6PD deficiency (sulfa drugs), T1DM, elderly
DDI: Second-generation typically have fewer drug interactions due to mixed metabolism
22
Q
A
23
Q
What are the Short acting Insulin Secretagogues (Meglitinides)?
A
Nateglinide (Starlix) and Repaglinide (Prandin)
24
Q
MOA and Pharmacology of Meglitinides?
A
- Lowers glucose levels by increases insulin secretion from beta cells in the pancreas in the presence of glucose
- Binds to potassium channels on β-cells at different site than sulfonylurea
- Requires functioning b-cells
Increase Insulin Secretion -> Rapid Acting “Secretagogues”
25
Meglinitides
| Indications, Place in therapy, PK, CI, ADR, DDI
**Indications:** T2DM
**P-in-T:** Primarily used to decrease post-prandial glucose levels **Never combined with sulfonylureas)**
**PK:** Short half-life, high PB, hepatic metabolism, rapidly eliminated
**CI:** T1DM, hypersensitivity, liver dysfunction
**ADR:** Hypoglycemia, weight gain
**DDI:** Repaglinide/gemfibrozil
26
Describe the location of SGLT transporters?
SGLT1 is in the straight section of the proximal tubule (S3)
* 10% glucose absorption
SGLT2 is in the convoluted section on the proximal tubule (S1).
* 90% glucose absoprtion
27
What is the difference between SGLT1 and 2?
28
What are the types of SGLT2-I?
1. Bexaglifloxin (Brenzavvy)
1. Canagliflozin (Invokana)
1. Dapagliflozin (Farxiga)
1. Empagliflozin (Jardiance)
2. Ertugliflozin (Steglatro)
29
How does sotagloflozin differ from other SGLT2 inhibitors?
Dual inhibitor of SGLT1 (intestinal) and SGLT2 (renal).
30
What is the MOA of SGLT2 inhibitors?
Inhibits renal tubular Na-glucose co-transporter that reverses hyperglycemia -> reversal of gluco-tox
1. ↑ insulin sensitivity in muscle: ↑ GLUT4 translocation, ↑ insulin signaling
2. ↑ insulin sensitivity in liver: ↓ G6P
3. ↓ Gluconeogenesis
4. Improves beta cell function
31
Advantages of SGLT2 Is?
1. Lowers A1C around 0.6-0.8%
2. Lowers fasting glucose
3. Improved postprandial glucose levels
4. Weight loss (up to 3.5%)
5. Lower risk of hypoglycemia (<3.5%)
6. Improves cardiovascular and renal outcomes
32
how does SGLT-2 Inhibitors effect renal function?
SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfilt
33
SGLT-2 Inhibitors?
| Indications, PK, CI, DI
**Indications:** Adjunct to diet and exercise in T2DM, used in HF and kidney disease
**PK:** high PB, extensive hepatic metabolism via glucuronidation to inactive metabolites
**CI:** Ketoacidosis, severe renal dysfunction
**DI:** Diuretics, Insulin secretagogues (hypoglycemia), UGT Inducer (Canagliflozin)
34
SGLT-2 Inhibitor ADRs?
1. Fungal genital infections: Vulvovaginal candidiasis in women
2. Bacterial UTI with canagliflozin
3. Polyuria (>5%), hypoglycemia, DKA
4. Hyperkalemia
5. Dose-related increases in LDL-C
6. Symptomatic and orthostatic hypotension (hypovolemia)
7. Malignancies
35
What are the monitoring parameters of SGLT2-Inhibitors?
**Efficacy:** blood glucose levels, A1c
**Toxicity:** Renal function, Potassium, Magnesium, Phosphate levels, LDL, Genital infections, BP
36
What are the types of alpha-glucosidase inhibitors?
Acarbose (Precose) and Miglitol (Glyset)
37
MOA and pharmacology of Alpha-glucosidase Inhibitors?
1. Lowers glucose levels by Reversibly inhibiting glucosidases and Reversibly inhibiting glucosidases
2. Primarily used to control postprandial glucose
3. Delays absorption of glucose in the intestine, lowering the plasma peak.
38
Alpha-glucosidase Inhibitors
| Indications, Place in therapy, PK, ADR, CI, DDI, Dosing
**Indications:** T2DM
**Place in therapy:** Decreases postprandial blood glucose levels, Combo therapy
**PK**
* Metabolism: Acarbose is metabolized by GI amylases to inactive metabolites, Miglitol is not metabolized
* Excretion: acarbose is systemically absorbed, Miglitol is excreted unchanged in the urine
**ADR:** Flatulence, diarrhea, ab pain
**CI:** Treat hypoglycemia with glucose nor sucrose, Renal impariment, Cirrhosis, GI conditions
**DDI:** Effects absorption of some drugs in the GI tract
**DOsing:** start low, go slow
39
What is incretin?
Glucagon-like peptide-1 (GLP-1) gut hormone that helps with weight loss
1. Delays gastric emptying
2. Decreases glucogon excretion
3. Improves glycemic controly reducing fasting and postprandial glucose concentrations
4. Enhances glucose dependent insulin secretion
40
Describe the MOA and effectiveness of GLP-1 protein?
1. Rapidly released from ileal cells within 15 minutes of eating a meal: GLP1 receptor (Gs)
2. Induces insulin release only if blood glucose is >70-90 mg/dL
3. Lowers FBS 10-20 mg/dl, A1c ≈ 1%
4. Rapid metabolism in blood by dipeptidyl peptidase-IV (DPP-IV)
41
What are the types of incretin mimetics?
Exenatide (Byetta, Bydureon)
Liraglutide (Victoza, Saxenda)
Dulaglutide (Trulicity)
Lixisenatide (Adlyxin)
* Soliqua: Insulin Glargine and Lixisenatide
Semaglutide (Ozempic: inj and Rybelsus: PO)
42
Exenatide (Byetta)
| Dosage form, Administration
**MOA:** Synthetic form of exendin-4
**Admin:** SC BID
* 60-minutes before two main meals of the day
* Should not be administered after a meal
43
Exenatide (Bydureon BCise)
| Dosage form, Dosing, ADR
**Form:** Extended-release formulation of Byetta
**Dosing:** 2 mg weekly with or without food
**ADR:** thyroid tumors, pancreatitis
44
Effectiveness of Exenatide
Lowers hemoglobin A1c by 1.6% compared to 0.9% reduction for Byetta
45
Storage of Exenatide?
1. Regrigerate
2. A pen can be kept at a room temperature for 30 days
3. Do not freeze
4. Protect from light
5. Do not store with the needle attached
46
How does Liraglutide an improvement from Exenatide?
1. Lysine at 34 is replaced with arginine
2. Albumin binding
3. Self-association from SQ
4. Long plasma half-life
47
Liraglutide (Victoza)
| Dosing, Admin, Efficacy
**Dosing:** QW with or without food
**Admin:** SC
**Efficacy:** Lowers A1C by 1.0 to 1.5%, on average
48
How does Saxenda differ from Victoza?
Higher dose approved for weight loss
49
What is Xultophy?
| Dosing, Admin, Efficacy
insulin degludec (long-acting) and liraglutide
**Dosing:** Anytime, but at the same time each day
**Admin:** SC
**Efficacy:** Lowers A1C by 1.7%, on average
50
Describe the structure of Albiglutide?
Two copies of a modified human GLP-1, the alanine at position 2 is exchanged for glycine for DPP-4 resistance, remaining sequence is **albumin**
51
Albuigutide
| Brand, Dosing, Admin, Efficacy
Tanzeum
**Dosing:** Weekly SC
**Admin:** Allow pen to sit for 15 mins to 30 mins after reconstitution before injecting for complete mixing. Inject within 8 hours of reconstitution
**Efficacy:** Lowers A1C by 1.0%
52
Dulaglutide structure?
GLP-1 analog (7-37) covalently linked to an IgG4 Fc domain
53
Dulaglutide
| Brand, Dosing, Admin, Efficacy
Trulicity
**Dosing:** QW
**Admin:** SC
**Efficacy:** Lowers A1C by 1.3-1.5%
54
Lixisenatide
| Brand, Structure, Efficacy
Adlyxin
**Structure:** exendin-4 sequence
**Efficacy:** Lowers A1C by 0.5-0.7%
55
What is Soliqua?
Lixisenatide and insulin glargine
56
Semaglutide (Ozempic)
| Structure, Admin, Efficacy
**Structure:** The lysine at position 26 is acylated with stearic diacid, increasing plasma protein binding to albumin
**Dosing:** QW
**Admin:** SC
**Efficacy:** Lowers A1C by up to 1.5%
57
Semaglutide (Rybelsus)
| Dosing
Take RYBELSUS by mouth on an empty stomach when you first wake up with a sip of plain water
After 30 minutes, you can eat, drink, or take other medications
58
What is Wegovy?
QW semaglutide approved for weight loss
59
Tirzepatide
| Brand, MOA
Mounjaro
**MOA:** GIP (glucose- dependent insulinotropic polypeptide) and GLP-1 receptor
60
How does Tirzepatide differ from Ozempic?
Better reduction in HbA1C levels
61
Incretin mimetics
| Indications, I, PK, DDI, ADR, BBW
**Indications:** T2DM
**CI:** Hx of thyroid c-cell tumor, MENS2
**PK:** Excreted in the feces and urine
**DDI:** Medications that may be affected by a delay in gastric emptying
**ADR:** Nausea, GI upset, risk of pancreatitis, gastroparesis, and bowel obstruction
**BBW:** Thyroid C-cell tumors
62
What are the types of DPP4 inhibitors?
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
63
MOA of DPP-4 inhibitors?
1. Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down incretins (GLP-1) and Glucose-dependent insulinotropic peptide (GIP)
2. Increases incretin concentrations, prolonging anti-glycemic effects
64
DPP4 Inhibitors
| Indications, PK, CI, Effectiveness, Place in therapy, ADR
**Indications:** T2DM
**PK:** Minimally metabolized by CYP450, Excreted in the feces and urine
**CI:** T1DM
* Monitor renal function
**Effectiveness:** Decreases HbA1c 0.5-0.8%
**P-in-T:** Monotherapy, Combination Therapy
**ADR:** Respiratory infections, HA, Ab pain, N/D
65
What are the benefits of DPP-4 inhibitors and Metformin combos?
1. **Sitagliptin** improves beta-cell function and increases insulin synthesis and release.
2. **Sitagliptin** reduces HGO through suppression of glucagon from alpha cells.
3. **Metformin** has insulin- sensitizing properties.
4. **Metformin** decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.
66
CV Effects of DPP4 inhibitors
67
What is amylin?
1. Co-located and secreted with insulin from b-cels
2. Amylin deficiency accompanies insulin deficiency
68
Types of Synthetic Modified Amylin analog?
Pramlintide (Symlin)
69
MOA of Pramlinitide?
1. Slows gastric emptying
2. Inhibits glucagon secretion from pancreatic alpha cells
3. Reduces postprandial glucose. Reduces glucose fluctuations
4. **NO effect of pancreatic beta cells or insulin secretion**
5. Modest weight loss 1-2 kg
70
What are the action sites of Symlin?
**Liver:** Reduces hepatic glucose output by inhibiting glycogenolysis and glucose release
**CNS:** Promotes satiety and reduction of appetite
**Alpha cell:** Inhibits glucagon secretion
**Beta cell:** None
**Stomach:** Slow gastric emptying
71
Pramlinitide
| Indications, Dosing, ADR, BBW
**Indications:** T1DM, T2DM **can only be used in combo with insulin** to lower glucose in the 3 hr after meals
**Dosing:** before major meals
* Begin with the low starting dose and gradually titrate
* Differing doses based on type-1 or type-2 diabetes and nausea level
* When first starting reduce the amount of mealtime insulin by 50% to reduce the chance of hypoglycemia
**ADR:** Hypoglycemia
**BBW:** Must be able to monitor BG or is not considered suitable for drug due to hypoglycemia
* Do not mix in syringe with any type of insulin
72
Bile acid sequestrants for diabetes?
Colesevelam
73
MOA of Colsevelam?
Absorbs glucose for excretion in feces
74
Colesevelam
| Indication, Effectiveness, Place-in-therapy, ADR, DDI, CI,
**Indication:** T2DM
**Effectiveness:**
* Decreases HgA1c by ≤0.5% (0.32%)
* Decreases LDL
* Increases Triglycerides
**Place in therapy:** Combo not mono
**ADR:** N/C, ab pain, dyspepsia, hyperTG, pancreatitis
**DDI:** Separate by 4 hrs from drugs with narrow therapeutic index i.e., warfarin, phenytoin
* Decreases levels of levothyroxine, oral contraceptives
**CI:** TG >500, caution with >300
75
MOA of Bromocriptine?
Dopamine D2 receptor agonist that effects the **circadian neuronal activity** in the hypothalamus in **insulin-resistant patients**
76
Bromocriptine
| Brand, Indications, Place in therapy, ADR, CI, DDI
Cycloset
**Indications:** Reduce HbA1c and plasma triglyceride and FFA concentrations in type-2 diabetic patients
**Place in therapy:** Adjunctive therapy
* Decreases HgA1c by ~0.3%
* As monotherapy, has a very low risk of hypoglycemia
**PK:** CYP450 metabolism, high PB
**ADR:** Somnolence, Erythromelalgia and Raynaud’s phenomena
**CI:** T1DM, Lactation, renal/hepatic, hypersensitivity
**DDI:** Use of ergots (migraine medication) within 6 hours of bromocriptine is NOT recommended
77
What is the approaches for diabetis tx?
Treatment should **always** be directed at the **individual** patient and their underlying pathophysiology
78
Considerations in Pharmacologic Treatment of Type 2 Diabetes
1. Mechanisms of action of drugs
2. Impact on weight gain
3. Cost
79
Medications for postprandial hyperglycemia?
1. a-glucosidase inhibitor
2. short acting sulfonylurea,
3. meglitinides
4. short acting regular insulin or insulin analog
80
Medications for fasting hyperglycemia?
1. biguanide
2. long acting sulfonylurea
3. glitazone
4. long acting insulin or insulin analog
81
Medications for insulin resistance?
1. biguanide
2. glitazone
82
Medications for insulin deficiency?
1. Insulin
2. sulfonylurea
3. meglitinide
83
Why is it important to address insulin resistance?
Leads to atherosclerosis
84
Benefits of metformin + insulin combos
Improves insulin sensitivity at the liver and reduces hepatic glucose production
85
Benefits of glitazones + insulin combos
Improve insulin action in peripheral tissues and enhance glucose uptake
86
Benefits of a-glucosidase inhibitors + insulin combos
Decrease postprandial glucose absorption
87
Benefits of Sulfonylureas and Meglitinides
inhibitors + insulin combos
Increase levels of endogenous insulin and enhance meal-mediated insulin release
88
Benefits of GLP-1 agonists and DPP-4 inhibitors + insulin combos
Improve endogenous insulin release, reduce effects of glucagon, increase satiety
89
Benefits of SGLT-2 inhibitors + insulin combos
Block the reabsorption of filtered glucose in kidneys, resulting in increased urinary glucose excretion and an Insulin independent correction of hyperglycemia
