RW Type 2 Diabetes

What is the incretin effect?

When food is ingested incretin hormones are released

Inc. insulin secretion

Dec. glucagon secretion

What is the Sodium-Dependent Glucose Transporter-2 (SGLT2)?

Reabsorbs glucose from the in kidney

What are the main differences in presentation of T2DM (vs. T1)?

Older age

Gradual onset

Positive family history

Obese or history of obesity

Metabolic syndrome common

Often asymptomatic

No ketones at diagnosis

Microvascular & macrovascular complications common

No autoantibodies

What are non-drug therapies for T2DM?

Diet - portion control, limit sugar and carbs

Weight loss

Physical activity

When is bariatric surgery recommended?

Any patient with BMI > 40 kg/m2

BMI between 35-40 kg/m2 with poor glucose control

When is weight management drug therapy indicated?

Drug therapy if BMI >30 kg/m2

OR< BMI >27 kg/m2 with one or more obesity related complication

What are drugs used for weight management?

Orlistat

Lorcaserin

Phentermine/topiramate

Naltrexone/bupropion

Liraglutide/Semaglutide/Tirzepatide

What is a normal fasting plasma glucose?

<100 mg/dL

What is a impaired (prediabetes) fasting plasma glucose?

100-125 mg/dL

What is a fasting plasma glucose in diabetes?

≥126 mg/dL

What is a normal 2hr postload plasma glucose?

<140 mg/dL

What is an impaired (prediabetes) 2hr postload plasma glucose?

140-199 mg/dL

What is a 2hr postload plasma glucose in diabetes?

≥200 mg/dL

What are diagnostic criteria for diabetes?

A1c ≥6.5%

FPG ≥126

2hr PPG ≥200

Random ≥200 w/symptoms of hyperglycemia

(Same for all types)

What is the A1c goal for diabetes?

≤7%

How often should A1c be monitored in diabetes patients?

Every 3 months if not at goal

Every 6 months if at goal

What is the FPG goal for diabetes?

80-130 mg/dl

What is the PPG goal for diabetes?

<180 mg/dl

How often should a diabetes patient test their BG?

Once per day if on oral agents or basal insulin

3-4 x/day if multiple daily insulin injections

What is the oral first drug of choice, in T2DM patients without CVD/HF/CKD?

Metformin

Why is metformin the 1st line agent in diabetes?

Effective (high A1c dec.)

Safe (no hypoglycemia)

Inexpensive

Widely available

What is the agent of choice in a patient whose goal is weight loss?

GLP-1s

What is the agent of choice in a patient with ASCVD or indicators of high CVD risk?

SGLT-2

In a patient with ASCVD/high risk, who is already on an SGLT-2, what can be added if additional therapy is needed?

GLP-1

Or pioglitazone (not as good as GLP-1)

What is the agent of choice in a patient with HF?

SGLT-2

What is the agent of choice in a patient with CKD?

SGLT-2

In a patient with CKD, who is already on an SGLT-2, what can be added if additional therapy is needed?

GLP-1

If a patient, who is newly diagnosed with T2DM, has an A1c of <8.5% what therapy is indicated?

Metformin

If a patient, who is newly diagnosed with T2DM, has an A1c of ≥8.5% what therapy is indicated?

Dual therapy

In pt.'s who's A1c is >1.5% above goal

In patients with A1c's >1.5% above goal (7%), what is indicated?

Dual therapy

If a patient, who is newly diagnosed with T2DM, has an A1c of >10% what therapy is indicated?

Early introduction of insulin

If a patient, who is newly diagnosed with T2DM, has BG levels >300 mg/dL what therapy is indicated?

Early introduction of insulin

When should insulin be introduced early (in newly diagnosed patients)?

Early introduction of insulin should be considered if there is evidence of:

ongoing catabolism (weight loss),

if symptoms of hyperglycemia are present,

When A1C levels (>10%) or blood glucose levels (>300 mg/dL) are very high

When injectable therapy is indicated, what is the best initial therapy for MOST patients?

GLP-1 or GIP/GLP-1

Used prior to insulin in most pt.'s

When should insulin be used as the first injectable therapy?

Symptoms of hyperglycemia are present

When A1c or blood glucose levels are very high (A1c >10% or BG ≥300 mg/dL)

When a diagnosis of Type 1 diabetes is a possibility

What type of insulin should be initiated first?

Basal insulin

Any basal insulin is appropriate for initial therapy

What is the initial dose of basal insulin?

10 units per day

OR 0.1-0.2 mg/kg per day

How should basal insulin be titrated?

2-4 units every 3-4 days

Until fasting blood sugars at goal

What is basal insulin titrated to?

Fasting blood glucose goal

How should a patient self-titrate if their blood sugar is >180 mg/dL?

Increase by 4 units

How should a patient self-titrate if their blood sugar is 130-180 mg/dL?

Increase by 2 units

How should a patient self-titrate if their blood sugar is 70-130 mg/dL?

Continue same dose

How should a patient self-titrate if their blood sugar is <70 mg/dL or they are experiencing hypoglycemia symptoms?

Decrease by 2 units

If a patient on basal insulin needs additional therapy, what is preffered?

GLP-1 or Tirzepatide (GLP-1/GIP)

Preferred over adding mealtime bolus insulin or switching to pre-mixed formulation

What combination injectable therapy is generally recommended?

Add GLP-1

OR, GLP-1/GIP

Why are GLP-1s and GLP-1/GIPs recommended for combination injectable therapy?

CV benefit

Weight loss

How should bolus insulin be added?

Add bolus at largest meal

Equivalent to using 3x/day

What is the difference between bolus dosing at largest meal and 3x/day dosing?

Equivalent effect on A1c

Multiple dialy injections improve A1c more rapidly

What are advantages of bolus insulin?

Easy to titrate (increase by 1-2 units every 3-4 days)

Well-tolerated

What are disadvantages of bolus insulin?

Hypoglycemia

Weight gain

Increased cost

Increased injections

Less convenient - timing with meals

What are advantages of GLP-1 Agonists?

Low risk of hypoglycemia

Weight loss or neutral

CV benefit

More convenient - once weekly or combination products

Can be administered regardless of meals

What are disadvantages of GLP-1 Agonists?

Increased cost

Tolerability

What are advantages of Basal insulin/GLP-1 combinations?

Decreased injection burden - one shot daily

Decreased cost - one copay

What are disadvantages of Basal insulin/GLP-1 combinations?

Need to titrate dose

Maximum dose of basal insulin due to GLP-1

What are pre-mixed combination insulins?

Fixed combinations of basal and bolus insulin

What is the initial dose of pre-mixed combination insulins based on?

Initial dose based on insulin dose

Divide 1/2 am and PM

OR, 2/3 am and 1/3 pm

What are advantages of pre-mixed combination insulin?

Less expensive - one copay or available OTC

Both basal and bolus insulin in one injection (2 injections vs. 4 for basal/bolus)

Less chance for dosing errors

What are disadvantages of pre-mixed combination insulin?

Has to be given with meals due to bolus insulin

Unable to titrate one insulin without adjusting the other

What is the initial dose of bolus insulin?

4 units per day

OR, 10% of basal dose

How should bolus insulin be titrated?

Increase by 1-2 units every 3-4 days

How should bolus insulin be adjusted if pre-lunch sugar is elevated?

Increase breakfast bolus insulin

How should bolus insulin be adjusted if pre-dinner sugar is elevated?

Increase lunch bolus insulin

How should bolus insulin be adjusted if pre-bedtime sugar is elevated?

Increase dinner bolus insulin

When looking at a patient's BG data, what issues should be addressed first?

Address hypoglycemia (by lowering most recent dose) first

Then can begin addressing highs

What are the relative potencies of diabetes drugs as monotherapies?

Which drugs have very high potency?

GLP-1s (dulaglutide, semaglutide)

Tirzepatide

Combination oral

Combination injectable

What is the approximate A1c decrease from very high potency drugs?

≥2%

Which drugs have high potency?

GLP-1s (other than dula/semaglutide)

Metformin

SGLT-2i's (-gliflozin)

Sulfonylurea (glipizide, glimepiride, glyburide)

TZD (pioglitazone)

What is the approximate A1c decrease from high potency drugs?

1.5-2%

Which drugs have intermediate potency?

DDP-4i

What is the approximate A1c decrease from intermediate potency drugs?

0.5-1%

What class is metformin?

Biguanide

What is the MOA of metformin?

Decreases insulin resistance

Decreases hepatic glucose output

Enhances peripheral glucose uptake

What A1c decrease does metformin cause?

High (1.5-2%)

Does metformin have a risk of hypoglycemia?

No

What is the effect of metformin on weight?

Neutral

What are the CV effects of metformin?

Neutral

Possible benefit on MACE

What is the main side effect of metformin?

GI

Manage by titrating up slowly or using ER form

What are side effects of metformin?

GI

May dec. Vit B12 levels

Concern for lactic acidosis in renal disease

C/I in hospitalized unstable congestive HF

How should the dec. in Vit B12 caused by metformin be managed?

Should be monitored at least yearly

How should metformin be used in renal disease?

Do not start if CrCl<45 ml/min

If patient already on therapy: can continue if CrCl 30-45 ml/min

Discontinue if CrCl<30 ml/min

If a patient has intravenous radiocontrast media, what should be done with their metformin?

Wait 48 hours for restart of metformin

What condition is metformin contraindicated in?

Contraindicated in unstable congestive heart failure requiring hospitalization

What are the names of the SGLT-2 inhibitors?

-gliflozin

Canagliflozin

Dapagliflozin

Empagliflozin

Ertugliflozin

How much do SGLT-2 inhibitors decrease A1c?

Intermediate to high

Less effective as GFR decreases (still used in CKD)

What makes SGLT-2 inhibitors less effective for decreasing A1c?

Decreased GFR

Less effective in CKD, but still used due to renal protective effects

Do SGLT-2 inhibitors have a risk of hypoglycemia?

No

What effect do SGLT-2 inhibitors have on weight?

Intermediate loss (2-3 kg)

Mainly water loss due to diuretic effect

(beneficial in HF)

What is the effect of SGLT-2 inhibitors on major cardiac adverse events (MACE)?

Beneficial

What is the effect of SGLT-2 inhibitors in heart failure?

Beneficial

What is the effect of SGLT-2 inhibitors in renal dysfunction?

Beneficial

Benefit when CrCl <60 ml/min or albuminuria

What are side effects of SGLT-2 inhibitors?

Euglycemic diabetic ketoacidosis

Dehydration/hypotension

Mycotic and genitourinary infections

(most common SE)

Fournier's gangrene

What is Euglycemic diabetic ketoacidosis, as a side effect of SGLT-2 inhibitors?

Presents like DKA (acidosis, N/V, fluid deficit)

But BG may be normal/not as high

How can Euglycemic diabetic ketoacidosis, a side effect of SGLT-2 inhibitors, be prevented?

Discontinue 3-4 days prior to planned surgeries, critical illness, prolonged fasting

What is Fournier's gangrene, as a side effect of SGLT-2 inhibitors?

Necrotizing fasciitis of the perineum

What classes of drugs are considered incretins?

GLP-1 receptor agonists (-tide's)

DDP4 Inhibitors (-gliptan)

GLP-1/GIP agonist (Tirzepatide)

Should two incretins be used together?

Generally, do not use the two classes of incretins together

Avoid combining GLP-1s, DDP4i's, and GLP-1/GIP

What are the names of the GLP-1 receptor agonists?

-tide's

Exenatide (Byetta, Bydureon)

Liraglutide (Victoza)

Dulaglutide (Trulicity)

Semaglutide (Injectable: Ozempic; Oral: Rybelsus)

Which GLP-1s are formulated as weekly injections?

Exenatide ER

Semaglutide

Dulaglutide

Tirzepatide (GLP-1/GIP)

Which GLP-1s are formulated as a daily oral tablet?

Semaglutide (Rybelsus)