Diabetes Topic Discussion

Definitions
Type I Diabetes
 Autoimmune B-cell destruction  insulin deficiency  loss of insulin production

Type II Diabetes
 Progressive loss of B-cell insulin secretion  insulin resistance  decreased insulin production over time
 Identify and treat other CV risk factors

Gestational Diabetes
 Develops during pregnancy
 Risk of macrosomia (high birth weight), hypoglycemia

Clinical Presentation
 Polyuria, polyphagia, polydipsia, blurred vision, fatigue

Screening
 Overweight + 1 additional risk factor
 Age 45 if no risk factors
 FPG, 2h plasma glucose after 75g oral glucose tolerance test, and A1C

Risk Factors/Complications
 First degree relatives
 High risk races/ethnicities
 Overweight (BMI ≥ 25 kg/m^2)
 Autoimmune disease (thyroid)
 Microvascular Complications: retinopathy, nephropathy, neuropathy
 Macrovascular Complications: CHD, CVD, and PAD
 Anxiety disorders, depression, eating disorders, mental illnesses
 HTN, Dyslipidemia
 Smoker

Prediabetes Diabetes Goals

FPG: 100-125 mg/dL FPG ≥ 126 mg/dL FPG: 80 – 130 mg/dL
2 hr glucose after 75g OGTT: 140-199 mg/dL 2 hr glucose after 75g OGTT ≥ 200 mg/dL PPG ≤ 126 mg/dL
A1C: 5.7 – 6.4% A1C ≥ 6.5% A1C ≤ 7% *
RPG ≥ 200 mg/dL

Non-Pharmacologic Measures
 Nutrition therapy (carbohydrate counting, omega 3 fatty acids. fiber)
 Limit saturated fat, cholesterol, trans fat, and sodium
 3500 kcal weekly reduction = 1 lb weight loss/week
 Waist circumference < 35 inches (females) and < 40 inches (males)
 Physical activity (30 min/day, 4-5x/week)
 Smoking cessation
Comprehensive Treatment
1. Primary Prevention  ASA 81 mg
- Men or women ≥ 50 years old with 1 additional risk factor
2. Secondary Prevention  ASA 81 mg
3. Blood Pressure Control  Thiazide, CCB, ACEi, ARB
4. Cholesterol Control  Mod/High Statin
5. Nephropathy
- Annual urine test screening for protein
- Urinary albumin excretion ≥ 30 mg/24 hours (kidney damage)  ACEi, ARB
6. Retinopathy
7. Neuropathy
- Foot and visual examinations

Drug Induced Hyperglycemia

 Atypical antipsychotics (olanzapine, clozapine, quetiapine)
 Beta blockers (carvedilol, propranolol)
 Cyclosporine, Tacrolimus
 Protease inhibitors
 Quinolones
 Corticosteroids (prednisone)
 Statins
 Thiazide and loop diuretics

Treatment Algorithm
Biguanides
MOA: Acts on liver to reduce hepatic glucose production, acts on intestine to enhance glucose uptake, acts on kidneys
to impair renal gluconeogenesis

Drug (Brand) Properties Adverse Effects Contraindications

Metformin (Glucophage,
Fortamet, Glumetza)
500 mg QD or BID w/food
Max = 2550mg QD
1-2% A1C Reduction Common: eGFR < 30 ml/min/1.73m^2
Reduces FPG GI Effects (N/V/D) Metabolic acidosis
Reduces TG Macrocytic Anemia  B12 Hypoxia
BBW: Lactic acidosis IV Iodinated Contrast
- Hold for 48h

Sulfonylureas
MOA: Stimulate insulin secretion from pancreatic beta cells

Drug (Brand) Properties Adverse Effects Contraindications

Second Generation 1-2% A1C Reduction Common: Severe hepatic disease
Glimepiride (Amaryl) Reduces FPG Hypoglycemia
1-8mg QD Reduces TG Weight gain Severe kidney disease
- Avoid Glyburide
Glipizide (Glucotrol) Precautions:
5-20mg BID Sulfa allergies
CV risk
Glyburide (Diabeta, Glynase)
2.5-10mg BID

GLP-1 Analogs
MOA: Pharmacological increase in incretin  glucose dependent increase in insulin, while inhibiting glucagon
 Restores first phase insulin response

Drug (Brand) Properties Adverse Effects Contraindications

Exenatide (Byetta) 0.8-1.9% A1C Reduction Common: Pancreatitis
5-10 mcg SQ BID Reduces PPG Nausea
Weight Loss CrCl < 30
- Avoid Byetta
- Avoid Bydureon
Exenatide ER (Bydurean) Reduces FPG Warnings:
2 mg SQ weekly Renal Dysfunction
Pancreatitis

Liraglutide (Victoza) BBW: Thyroid C-Cell Carcinoma

0.6-1.8 mg SQ QD - Only use Byetta

Albiglutide (Tanzeum)
30-50 mg SQ weekly

Dulaglutide (Trulicity)
0.75-1.5 mg SQ weekly
Thiazolidinediones (TZDs)
MOA: Act on PPAR gamma agonists (nuclear receptors) found in muscle, fat, and liver to induce gene expression
 Increase peripheral muscle and adipose tissue insulin sensitivity  decrease insulin resistance
 Slow onset and offset because they are dependent on gene expression changes
 Long lag time; max effect seen in 8-12 weeks

Drug (Brand) Properties Adverse Effects Contraindications

Rosiglitazone (Avandia) 0.8-1.5% A1C Reduction BBW: Heart Failure Exacerbation Class III/IV Heart Failure
1-2mg QD Increases HDLs
Max = 8mg Lowers TGs Common: Bladder Cancer
Decrease risk of CV events Weight Gain - Avoid pioglitazone
in patients w/o diabetes Fluid Retention (edema)

Pioglitazone (Actos) Warnings:

15-45 mg QD Fractures (women)
Induced ovulation PCOS
Hepatic failure (increased LFTs)

SGLT2 Inhibitors
MOA: Blocks early segment SGLT2 receptors in proximal tubule of kidneys, blocking reabsorption of glucose
 Results in excretion of glucose and salt/water loss
 Dapagliflozin works on kidney and pancreas therefore it can lead to increased levels of glucagon secretion

Drug (Brand) Properties Adverse Effects Contraindications

Canagliflozin (Invokana) 0.7-1.1% A1C Reduction BBW: Increased risk of eGFR < 30, ESRD, Dialysis
100-300mg QD b/f 1st meal leg/foot amputations
Mixed Effect - Avoid Canagliflozin

Dapagliflozin (Farxiga) Common:

5-10mg QD Genital mycotic infections
Hypotension
Weight loss

Empagiflozin (Jardiance) ** Warnings:

10-25mg QD Increased LDL
Ketoacidosis
DPP4 Inhibitors
MOA: Prolong t ½ of endogenous incretin, GLP1 and GIP, by inhibiting their inactivation of DPP4
 Glucose dependent increase in insulin
 Inhibition of glucagon

Drug (Brand) Properties Adverse Effects Contraindications

0.6-0.8% A1C Reduction Common: Renal Insufficiency
Sitagliptin (Januvia) Reduces PPG Nasopharyngitis (URTIs) Hx of Pancreatitis
UTIs
Warnings:
Dose reduce insulin or
Saxagliptin (Onglyza) Secretagogues
Acute pancreatitis
Arthralgia
Linagliptin (Tradjenta)
- No renal dose adjustment

Alogliptin (Nesina)

Meglitinides
MOA: Stimulate insulin secretion from pancreatic beta cells

Drug (Brand) Properties Adverse Effects Contraindications

Repaglinide (Prandin) 0.5-1.0% A1C Reduction Common: Hypoglycemic unawareness
Take 30 min before meals Reduces PPG Hypoglycemia Severe Kidney Disease
Weight gain Severe Liver Disease

Nateglinide (Starlix) Rare:

Take 30 min before meals Pancreatitis

Alpha Glucosidase Inhibitors

MOA: Competitive inhibition of intestinal alpha glucosidases that line the brush border of the small intestine
 Delays digestion, gastric emptying and absorption of complex carbs into glucose
 Use glucose tabs or gel for treatment of hypoglycemia, not sucrose (candy, table sugar, soda)

Drug (Brand) Properties Adverse Effects Contraindications

Acarbose (Precose) 0.5-1.0% A1C Reduction Common: IBD (Crohn’s, Colitis)
Taken with first bite of meal Reduces PPG Flatulence Colonic ulcerations
Abdominal discomfort Intestinal obstruction
Cirrhosis

Miglitol (Glyset)
Taken with first bite of meal
Amylin Analogs
MOA: Amylin is produced by pancreatic beta cells to control glucose. This is synthetic amylin that slows gastric
emptying leading to inhibition of glucagon secretion in a glucose dependent manner (no effect on insulin)

Drug (Brand) Properties Adverse Effects Contraindications

Pramlintide (Symlin) 0.5-0.7% A1C Reduction BBW: Must reduce mealtime Gastroparesis
Type 1 = 15 mcg SQ w/ meals Reduces PPG insulin dose by 50% to not Hypoglycemic unawareness
Type 2 = 60 mcg SQ w/ meals cause hypoglycemia with A1c > 9%
insulin

Common:
N/V
Weight loss

Bile Acid Sequestrant

MOA: By inhibiting bile acids, you prevent FXR activation and PEPCK upregulation, leading to decreased hepatic
glucose production

Drug (Brand) Properties Adverse Effects Contraindications

Colesevelam (Welchol) 0.4-0.6% A1C Reduction Common: Bowel obstruction
Taken with meals Reduces FPG Constipation TG > 500
Reduces LDL TG Increase Hx of HTG induced pancreatitis

Dopamine-2 Receptor Agonist

MOA: Resets aberrant central neurometabolic control of peripheral metabolism
 Other indications: Parkinson’s, Acromegaly, Hyperprolactinemia

Drug (Brand) Properties Adverse Effects Contraindications

Bromocriptine QR (Cycloset) 0.4-0.6% A1C Reduction Common: Ergot derivatives/dopamine
Taken w/ food to decrease N/V Reduces PPG N/V/C Lactation
Migraines
Insulin
Adverse Effects = hypoglycemia, hypokalemia, weight gain

Type I Diabetes (0.6 units/kg/day)

 Preferred: Utilize a rapid acting (bolus) + long acting (basal) approach
- 50% basal, 50% bolus dose divided among meals (TID)
 Other: NPH (2/3) and regular insulin (1/3)

Type II Diabetes (0.1 – 0.2 units/kg/day or 10 units/day)

 Initial basal insulin when patient fails to reach goal on multiple PO therapies
 Titrate by 10-15% or 2-4 units once or twice daily until FBG at goal

Conversions
 Can occur in a 1:1 (unit per unit) conversion of the total daily dose for most cases
 Dose Reduction Exceptions
- Twice daily NPH  once daily Glargine
- Use 80% of total daily NPH dose as initial insulin Glargine dose
- Once daily Toujeo  once daily Lantus or Basaglar
- Use 80% of total daily Toujeo dose as initial Lantus or Basaglar dose

Rapid Acting: Bolus Insulin Carbs: Rule of 500 Can mix with NPH
4 units or 0.1 u/kg before meals Correction Dose/Factor: Rule of 1800

Lispro (Humalog) Onset: 10-15 min

Aspart (NovoLog) Peak: 1-2 hrs
Glulisine (Apidra) Duration: 3-5 hrs

Inhaled (Afrezza)
- BBW: Do not use in
patients with asthma,
COPD, or smokers
Short Acting Carbs: Rule of 450 Can mix with NPH IV Use – DKA and
Regular (Humulin R, Novolin R) Correction Dose/Factor: Rule of 1500 Hyperkalemia
- Available w/o prescription
- Can be used IV Onset: 0.5-1 hr
Peak: 2-4 hrs
Duration: 4-8 hrs

Concentrated (Humulin R U-500)

- Used when patient needs >
200 units/d
Intermediate Acting Cloudy solution (protamine/insulin) Can mix with rapid/short
NPH (Humulin N, Novolin N)
- Available w/o prescription Onset: 1-3 hr
Peak: 4-10 hrs
Duration: 10-18 hrs

Long Acting: Basal Insulin CANNOT mix due to

10 units/d or 0.1-0.2 u/kg/d Peak: N/A acidity
Duration: 24+ hrs
Detemir (Levemir)
Glargine (Lantus, Toujeo)
Degludec (Tresiba)
Pre-Mixed: Short + Long
Novolog Mix 70/30
Humalog Mix 75/25
Humulin 70/30
Novolin 70/30
Ryzodeg
Hypoglycemia (blood glucose < 70 mg/dL)
- Symptoms = dizziness, hunger, shakiness, confusion
- Beta blockers may mask some symptoms
- Monitor glucose q15 minutes
- Treatment  15g of glucose (PO), 25 ml of D50 IV or Glucagon 1 mg by IM injection (NPO) Glucagon (unconscious)

Diabetic Ketoacidosis (blood glucose > 250 mg/dL)

- More common in type 1 diabetes
- Ketones present in urine, anion gap, metabolic acidosis, and dehydration
- Treatment  Fluids, Potassium, Regular Insulin IV

Hyperglycemia Hyperosmolar State (blood glucose > 600 mg/dL)

- More common in type 1I diabetes
- Symptoms = high serum osmolality, dehydration, no ketones
- Treatment  Fluids, Potassium, Regular insulin IV 0.1 unit/kg/hr

Sick Day Rules for Insulin Treated Patients

1. Do not stop basal insulin to prevent ketone production
2. May want to stop bolus (meal time) insulin
3. Check urine ketones
4. Vomiting = go to ER due to ketoacidosis