Diabetes Oral Agents and Non-insulin Injectables

What is the "Egregious Eleven" of diabetes?

1. Decreased insulin and increased glucagon secretion in pancreas (decreased beta and alpha cell function and mass)

2. Decreased incretin effect

3. Decreased GLP-1 secretion - altered microbiota, GI/biome

4. Decreased Amylin - increased rate of glucose absorption

5. Immune dysregulation/inflammation

6. Hyperglycemia

7. Neurotransmitter dysfunction

8. Increased renal glucose reabsorption

9. Increased lipolysis

10. Increased glucose production

11. Decreased glucose uptake

What drugs are preferred in T2DM therapy for patients with ASCVD or high risk?

SGLT2i or GLP-1 agonist

- if still above target, use the other drug type, then add pioglitazone if needed

What drugs are preferred in T2DM therapy for patients of ASCVD with heart failure?

SGLT2i

What does it mean to have CKD predomainance?

- eGFR < 60 mL/min

- ACR ≥ 3.0 mg/mmol (30 mg/g)

What drugs are preferred in T2DM therapy for patients with CKD predominance?

Max tolerated ACEi/ARB with SGLT2i or GLP-1 receptor agonist. Can add the other on if not at goal

For glycemic management, what is typically used?

Metformin or a combo

What 3 drugs/drug combos have a very high impact on glycemic control and result in a greater likelihood of achieving goals?

1. Dulaglutide (high dose), semaglutide, tirzepatide

2. Insulin

3. Combo oral + injectable GLP-1 RA/insulin

What 5 drugs/drug combos have a high impact on glycemic control and result in a good likelihood of achieving goals?

1. GLP-1 RA (other than dulaglutide, semaglutide, tirzepatide)

2. Metformin

3. SGLT2i

4. Sulfonylureas

5. TZD

What drugs have an intermediate impact on glycemic control and result in a likely chance of achieving goals?

DPP-4 inhibitors

Rank drugs by their weight loss efficacy, from very high to neutral

1. Terzepatide and semaglutide

2. Dulaglutide and liraglutide

3. GLP-1 RA not listed and SGLT2i

4. DPP-4i and metformin

What are the main GLP-1 physiologic actions?

1. Neuroprotection

2. Cardioprotection - improves endothelial function

3. Decreased glucose production

4. Increased glucose uptake and storage in muscle/adipose

5. Appetite suppression

6. Decreased gastric emptying

7. Increased insulin secretion

8. Decreased glucagon secretion

9. Increased beta cell proliferation

Expected A1c reduction from a GLP-1 RA

0.5-1.6%

Is there a hypoglycemia risk from being on a GLP-1 RA?

No

Describe the cardiovascular, heart failure, CKD benefits from being on a GLP-1 RA

- Cardiovascular benefits from dulaglutide, liraglutide, semaglutide

- Benefits to HF (HFpEF)

- Benefits to CKD when SGLT2i not tolerated

Can a GLP-1 RA be used in pregnancy?

There is not enough evidence to support it, avoid or stop 2 months before planning to become pregnant

What is an added benefit from Tirzepatide?

Improves obstructive sleep apnea, decreases dietary triglycerides, increases insulin sensitivity, increases glucagon

When would someone NOT be using a GLP-1 RA?

Metabolic associated liver disease (cirrhosis)

Which GLP-1 RA's should be avoided if CrCl < 30?

Exenatide

What should you NOT use in combo with insulin degludec/liraglutide (Xultophy)?

Do not use with basal insulin

Which GLP-1 RA should you avoid using with ESRD eGFR < 15 mL/min?

Lixisenatide (Adlyxin)

What complications can people see from taking a GLP-1 RA?

1. Diabetic retinopathy (dulaglutide, exenatide, semaglutide) - slow titration

2. GI (N/V/D)

3. Monitor for hypovolemia - maintain fluid intake

4. Hypoglycemia

5. Pancreatitis - severe abdominal pain that may radiate to back

GLP-1 RA's are contraindicated in...

- personal or family history of Medullary Thyroid Cancer (MTC)

- patients with Multiple Endocrine Neoplasia Syndrome (MEN2)

- Severe liver cirrhosis (ALT/AST <30)

Which GLP-1 RA's have no ASCVD or CKD benefit?

Exenatide and lixisenatide

What is the expected A1c reduction from tirzepatide?

2.3%

Describe the cardiovascular, heart failure, CKD benefits from being on tirzepatide (GLP-1/GIP agonist)

Under investigation or neutral

Where does tirzepatide stand for potential weight loss in comparison to GLP-1 RA's?

Potential for greater weight loss reduction due to:

- Increased insulin sensitivity, blood flow

- Decreased proinflammatory immune cells

- Decreased dietary triglycerides

- Decreases food intake

What are the main physiological effects of a Dipeptidyl Peptidase-4 inhibitor (Gliptins)?

- increases glucose dependent insulin secretion (enhances GLP-1 action)

- decreases glucagon secretion

What is the expected A1c reduction from being on a DPP-4i?

0.4-0.8%

Is there a hypoglycemia risk from being on a DPP-4i?

No

Describe the cardiovascular, heart failure, CKD, and weight management benefits from being on a DPP-4i

All neutral, potential HF risk in saxagliptin

Can a DPP-4i be taken in pregnancy?

Inadequate/inconclusive evidence, avoid

Which DPP-4i does NOT require renal dose adjustments?

Linagliptin

What are 8 DPP-4i adverse effects?

1. Angioedema (alogliptin, linagliptin)

2. HF (alogliptin, saxagliptin, sitagliptin)

3. Hepatic failure (alogliptin)

4. Acute pancreatitis (alogliptin, linagliptin, saxagliptin)

5. Hyperlipidemia (linagliptin)

6. Renal impairment (alogliptin, saxagliptin)

7. Joint pain

8. Bullous pemphigoid

What are 3 contraindications/warnings with DPP-4i's?

- History of serious hypersensitivity reaction with saxagliptin who have experienced anaphylaxis, angioedema, or serious exfoliative reactions

- History of bariatric surgery

- Caution in renal dysfunction (CrCl < 45)

With what drugs can DPP-4i's be used in combo?

Insulin or sulfonylureas, can decrease dose to avoid hypoglycemia

What drug should be avoided with a DPP-4i?

GLP-1 RA's

What effects do SGLT1i's have on the gut?

Inhibition of SGLT1 prevents glucose/galactose reabsorption within small intestine, causing large intestine elimination (diarrhea and dehydration possible)

What effects do SGLT2i's have on the kidneys?

- Increases glucosiuria

- Decreases glucotoxicity

Which 3 SGLT-2i have benefits towards the progression of Diabetic KD?

- Canagliflozin

- Empagliflozin

- Dapagliflozin

What is the expected A1c reduction from being on a SGLT-2i?

0.7-1%

Is there a hypoglycemic risk from being on a SGLT-2i?

No

Which SGLT-2i's have cardiovascular benefits?

Empagliflozin and canagliflozin, can decrease BP by 4-6 mmHg

Which SGLT-2i's have HF benefits?

Empagliflozin, canagliflozin, dapagliflozin

Which SGLT-2i's have CKD benefits?

Canagliflozin, empagliflozin, dapagliflozin

- decrease in urinary albumin excretion by 30-40% in patients with micro/macroalbuminuria with decreased glomerular pressure

Can SGLT-2i's be used in pregnancy?

No, potential risk to fetus when added during second and third trimesters

When considering SGLT-2i's, the lower the eGFR...

the less hyperglycemic benefits you may have. If you are already taking one and eGFR decreases, you can continue, just don't start one

What are 7 SGLT-2i adverse effects?

1. Hypotension

2. Potential for DKA

3. Yeast infections, UTI - increase water intake

4. Volume depletion

5. Hyperkalemia

6. Potential for leg/foot amputations, increase fracture risk

7. Necrotizing fasciitis

What are 3 contraindications and warnings for SGLT-2i's?

- NOT in severe renal impairment (dialysis)

- Assess for signs/symptoms of metabolic acidosis for ketoacidosis and volume status

SGLT-2i's are often used in combo with what drugs?

GLP-1 agonists, can be combined with basal insulin

SGLT-2i's are NOT recommended to combo with what drug?

DPP-4i

What is metformin's physiologic action?

- improves insulin sensitivity

- decreases hepatic glucose production

- decreases intestinal glucose production

- increases peripheral glucose uptake in muscles

What is the expected A1c reduction from being on Metformin?

1.5-2%

What is the hypoglycemic risk from being on metformin?

Low

Describe the cardiovascular, heart failure, CKD, and weight management benefits from being metformin

All neutral except ASCVD potential benefit

Can metformin be used in pregnanacy?

Yes, off-label use for gestational onset diabetes, does not cross placenta. Treats PCOS

Which metformin formulation is expensive and should rarely be used?

Fortamet, extended release

Why does metformin have to be stopped during the use of contrast media?

Increased risk of lactic acidosis and acute kidney injury

What are some adverse effects of metformin?

1. GI (N/D) - more so with immediate release, take with food consistently

2. Vitamin B-12 deficiency (on for over 5 years), fatigue

3. Lactic acidosis (rare)

4. Bradyarrhythmias

5. Respiratory distress

6. Hypothermia

7. Myalgias

8. Peripheral neuropathy

What are the contraindications to metformin?

- eGFR <30

- Acute or chronic metabolic acidosis, including diabetic ketoacidosis

- hypersensitivity

What are some lower cost options for glycemic management?

1. Metformin

2. Sulfonylureas

3. Thiazolidinediones (TZDs)

4. Human insulin

What is the expected A1c reduction from being on a TZD?

0.5-1.4%

Is there a hypoglycemic risk from being on a TZD?

No

Which TZD has a potential cardiovascular benefit?

Pioglitazone

Describe the impact of TZDs on heart failure?

Increased risk

Describe the impact of TZD on CKD and weight management

CKD - neutral

Can cause weight gain

Can TZDs be taken while pregnant?

No, can cross placenta

What are some warnings/contraindications for TZDs?

- Need liver function tests prior to therapy, not in active liver disease. D/C if ALT greater than 3x upper limit of normal

- Avoid in older adults

- NOT in NYHA Class III or IV HF (fluid retention)

What are some side effects associated with TZDs?

1. Increased LDL (ros)

2. HF

3. Edema

4. Hepatotoxicity (ros)

5. Hypoglycemia

6. Bladder cancer (pio)

7. Bone fracture risk

When are TZDs used in diabetes?

- Not used much due to HF risk with rosiglitazone

- Use with caution when adding additional agents (best for monotherapy)

- Pioglitazone is most used and may be cost effective (generic), but it is on Beers list

What is the expected A1c reduction from a sulfonylurea?

2nd gen: 1.5-2%

1st gen: 1-1.5%

Is there a hypoglycemic risk from being on a sulfonylurea?

Yes

Describe the potential cardiovascular, HF, CKD, and weight management benefits from being on a sulfonylurea

All neutral, exception is weight gain

Can you take a sulfonylurea while pregnant?

Not typically, crosses placenta, hypoglycemic risk to infants

When should you not take glyburide (a sulfonylurea)?

Hepatic impairment and renal failure (CrCl <60)

What are some adverse effects of sulfonylureas?

1. Weight gain

2. Elevated cardiovascular mortality (Tolbutamide)

3. N/V

4. Hypoglycemia

5. Increased Na excretion without free water clearance

6. Urticaria, pruritus, maculopapular eruptions, photosensitivity

What is a specific counseling point/limitation for sulfonylureas?

They loss efficacy over time and will likely be replaced with another agent eventually

Non-sulfonylurea Secretagogues (Glinides) MOA

Block ATP-sensitive K channels in pancreatic beta cell membrane. Similar to sulfonylureas, enhances insulin secretion

What is the expected A1c reduction from using a Non-sulfonylurea Secretagogues (Glinides)?

0.5-1.5%

Can a Non-sulfonylurea Secretagogues (Glinides) be used in pregnancy?

Low potential to cross placenta, limited data

What are the 2 Non-sulfonylurea Secretagogues?

Nateglinide and Repaglinide

How must Non-sulfonylurea Secretagogues (Glinides) be taken?

With FOOD, altered absorption with gastric bypass (increased hypoglycemia)

When are Non-sulfonylurea Secretagogues (Glinides) used in diabetes therapy?

- As initial treatment in place of sulfonylurea in those with sulfa allergy (repaglinide)

- Can interact with CYP2C8 inhibitors (gemfibrozil, trimethoprim) to increase concentration

- rarely used

What are the 2 alpha-Glucosidase inhibitors?

Acarbose and Miglitol

When should alpha-Glucosidases not be taken?

- SCr ≥ 25 mL/min (acarbose), SCr > 2 mg/dL (miglitol)

- Inflammatory bowel disease (IBS) or other GI issues

What are the main side effects of alpha-Glucosidases?

1. Flatulence due to increased fermentation of unabsorbed colonic bacteria

2. Diarrhea

3. Abdominal pain

Bromocriptine (Cycloset) MOA

Dopamine agonist, unknown MOA, thought to decrease sympathetic tone and output resulting in increased hepatic insulin sensitivity and decreased hepatic glucose output

What is the expected A1c reduction from taking Bromocriptine (Cycloset)?

0.5%

What are 2 side effects of Bromocriptine (Cycloset)?

Potential hypotension and nausea

Pramlintide (Symlin) MOA

Synthetic amylin analog that reduces glucagon secretion, decreases gastric emptying, and increases satiety

What is the expected A1c reduction from Pramlintide (Symlin)?

Type 1 DM: 0.4%

Type 2 DM: 0.6%, weight loss of 1.5 kg

What is the main side effect of Pramlintide (Symlin)?

Nausea

What are some medications that predispose to hypoglycemia?

1. Combining antidiabetics

2. Aspirin

3. Beta Blockers

4. Fluoroquinolone antibiotics

5. Fenugreek

6. Monoamine Oxidase inhibitors (phenelzine, procarbazine)

7. Psyllium

8. ACE inhibitors

9. NPH insulin, regular insulin

10. Sulfonylureas, meglitinides

What is the possible A1c reduction from using insulin?

Unlimited

Describe the potential cardiovascular, HF, CKD, and weight management benefits from being on insulin

All neutral, except possible weight gain

Can insulin be used during pregnancy?

Yes, recommended for T2 DM and gestational onset diabetes

When should insulin be started in T2DM?

- As the first injectable if there is catabolism, symptoms of hyperglycemia, when A1c > 10%, or blood glucose levels are 300 mg/dL, or T1DM is possible

- If patient is on GLP-1 RA or GIP/GLP-1 RA that is titrated and not at goal A1c

- If patient is unable to tolerate GLP-1 RA or GIP/GLP-1 RA and is not at goal A1c

Which basal insulins have the lowest risk of hypoglycemia?

1. Degludec (best)

2. Glargine U-300

3. Glargine U-100

4. NPH (not great)

When should an additional agent be considered to add to insulin in T2DM?

- If basal dose is > 0.5 u/kg/day

- Elevated bedtime to morning or post-prandial difference or high variability

What should be included in insulin patient education besides how to calculate dose (fixed dose)?

- Demonstrate insulin use (show pen, discuss injection)

- Verify insulin administration (inspect site, observe patient)

- Adherence confirmation (discuss storage, communicate with prescribers)

At what point during the day should prandial insulin be added if needed?

Before the largest meal of the day or greatest postprandial glucose excursion