abnormal carbohydrate metabolism → hyperglycemia due to relative or absolute impairment of _insulin secretion_ due to peripheral resistance to the action of insulin

5-10% of pts absolute loss of insulin due to autoimmune beta cell destruction at time of diagnosis = 80-95% have been destroyed Complete insulin dependency Honeymoon period: Days to weeks after diagnosis experience remission Lasts weeks – months May need very low insulin supplementation DKA = initial presentation in 25% of adults genetic link: HLA-DR and HLA-DQ

_Diet_: counting carbs reducing trans fat; cholesterol intake \< 200mg/day protein – 15-20% of daily caloric intake (animal and vegetables) sodium: + CHF \<2g/day alcohol: NTE 2 drink/day; 1 drink = 12 oz of beer, 5oz wine, 1.5 oz of distilled alcohol _Exercise_: starting goal = 150 min/week

Diabetes Mellitus Oral Agents Flashcards by Gillian Collom

Definition of DM

abnormal carbohydrate metabolism → hyperglycemia
- due to relative or absolute impairment of insulin secretion
- due to peripheral resistance to the action of insulin

How well did you know this?

Not at all

Perfectly

What does the Pancreas Produce

insulin
amylin
glucagon

How well did you know this?

Not at all

Perfectly

Insulin resistance associated with CV risks such as?

abd obestiy
HTN
dyslipidemia
hypercoag
hyperinsulinemia

How well did you know this?

Not at all

Perfectly

What cells are located in the Islet of Langerhans?

Alpha Cells
- release glucagon
  - increases blood glucose
Beta Cells
- release insulin and amylin
  - decreases blood glucose

How well did you know this?

Not at all

Perfectly

Fasting stage: insulin levels

43-186pMol/L

How well did you know this?

Not at all

Perfectly

Type II DM definition

90% of patients
partial loss of insulin secretion
- variable degree of deficiency
peripheral insulin resistance
- mostly in skeletal muscles & liver
  - not responsive to glucose uptake
  - can’t stop hepatic glucose production
Present years before dx
often asymptomatic
hyperglycemia

How well did you know this?

Not at all

Perfectly

Type I DM

5-10% of pts
absolute loss of insulin
- due to autoimmune beta cell destruction
- at time of diagnosis = 80-95% have been destroyed
- Complete insulin dependency
Honeymoon period:
- Days to weeks after diagnosis experience remission
- Lasts weeks – months
- May need very low insulin supplementation
DKA = initial presentation in 25% of adults
genetic link: HLA-DR and HLA-DQ

How well did you know this?

Not at all

Perfectly

Vicious cycle of Type II DM

How well did you know this?

Not at all

Perfectly

Renal Glucose Threshold

180 mg/dL

How well did you know this?

Not at all

Perfectly

Diagnosis of Diabetes Mellitus WHO & ADA guidelines

How well did you know this?

Not at all

Perfectly

Medications that Affect Blood Glucose

How well did you know this?

Not at all

Perfectly

When to Screen for Type II DM: ADA guidelines

adults without risk factors:
- start at age 45
- repeat q 3 yrs
- more frequent if BMI ≥ 25 plus ≥ 1 risk factor
- Fasting plasma glucose and A1C preferred over OGTT
Children. at 10yo or onset of puberty with:
- BMI > 85th percentile for age and sex
- Wt for height > 85th percentile
- wt > 120% of ideal height
- plus ≥ risk factors
- Screen Q 2yrs

How well did you know this?

Not at all

Perfectly

Glycemic Goals for DM patients: ADA

A1C < 7% (normal 4-6%)
preprandial plasma gluc: 70-130 mg/dL
Postprandial plasma gluc: < 180mg/dL
BP < 130/80

How well did you know this?

Not at all

Perfectly

Non-Pharm Tx of DM

Diet:
- counting carbs
- reducing trans fat; cholesterol intake < 200mg/day
- protein – 15-20% of daily caloric intake (animal and vegetables)
- sodium: + CHF <2g/day
- alcohol: NTE 2 drink/day; 1 drink = 12 oz of beer, 5oz wine, 1.5 oz of distilled alcohol
Exercise:
- starting goal = 150 min/week

How well did you know this?

Not at all

Perfectly

Categories for Oral Antihyperglycemics for DM II & A1C reduction %

Biguanides: 1.5-2%
Sulfonylureas: 1-1.5%
Thiazolidinediones (TZD): 1-1.5%
Non-sulfonylurea Secretagogues: 0.8-1%
- (“Glinides” or Meglitinides)
SGLT2 inhibitor: 0.8-1%
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: 0.7-1%
Alpha-Glucosidase Inhibitors 0.3-1%
Bile Acid Sequestrant: 0.4% with metformin
Dopamine Receptor agonists: 0.1-0.4%

How well did you know this?

Not at all

Perfectly

Sulfonylureas MOA

Block the ATP-sensitive K channels on beta cells → insulin secretion

first class of PO antihyperglycemic agents approved in US
Cross sensitivity with sulfa allergy
all require renal adjustment, except tolbutamide
hepatic metabolism - 2C9
can’t stimulate insulin secretion at extremely high glucose levels (i.e. glucose toxicity)

Sulfonylureas 1st generation

Meds:
- Chlorpropamide (Diabinese)
  - Avoid in Renal dysfunction or elderly
- Tolazamide (Tolinase)
- Tolbutamide (Orinase)
SEs:
- Hypoglycemia
- weight gain
- reduce efficacy over time
- lower A1c by 1-1.5%
- Not preferred by ADA or AACE

Sulfonylureas 2nd Generation

Meds:
- Glyburide
  - more hypoglycemia
    - not recommended by ADA
- Glipizide
  - less weight gain than glyburide
- Glimepiride
  - less weight gain than glyburide
SEs:
- weight gain
- hypoglycemia
- 2^nd line tx (ADA) after metformin
- add on therapy
- inexpensive
- start low & slow in elderly

Non-Sulfonylurea Secretagogues (Glinides): Overview

block ATP-sensitive K channels
produce same effect as sulfonylureas,
- but shorter onset & duration
bind to receptor adjacent to the sulfonylureas receptor
cannot be used together with sulfonylureas
Advantage:
- reduce post-meal gluc level
**Lowers A1C 0.8-1%**
take 15-30min before meal

Non-Sulfonylurea Secretagogues (Glinides): Meds

Lowers A1C by 0.8-1%
Meds:
- Meglitinide
- Nateglinide (Starlix)
- Repaglinide (Prandin) + Metformin (PrandiMet)
  - more effective for lowering A1C than Starlix
SEs:
- weight neutral
- hypoglycemia
- 2nd line according to ADA
  - 1st line if metformin contraindicated
can use instead of sulfonylureas
used in combo with others

Biguanide

Metformin

lowers A1C by 1.5-2% and FBG by 60-80mg/dL

MOA:
- unclear
- decreases hepatic glucose production & increases insulin sensitivity → liver, fat, & muscles
- does not affect insulin release
used as monotherapy
reduced LDL by 18.7%; TG by 12%
- increased HDL by 1.2%
SEs:
- GI: N/Diarrhea (=most common)
  - decreased appetite
- Lactic Acidosis → rare
- inhibits mitochondrial oxidation of lactic acid
- Renal impairment elderly :
  - CrCl ≤ 30ml/min
  - hypoxemia, sepsis, dehydration
- interferes with B12 absorption
  - monitor B12 levels
Considerations:
- withhold tx when pt undergoes surgery or radiocontrast dye
- renal fxn: assess within 48 hours after procedure → normal → restart
- avoid in liver disease:
  - Check LFTs

Alpha-Glucosidase Inhibitors MOA & Meds

lowers A1C by 0.3-1%

MOA: delay absorption of carbohydrates (by inhibiting alpha-glucoside at the brush border of the small intestine)
- →reduce post-prandial BG
- act as osmotic to draw water into GI lumen
- pt can skip dose if they skip a meal/do not eat carbs
Meds:
- Acarbose (Precose)
  - not as effective as Miglitol
  - 3rd line – ADA
- Miglitol (Glyset)
- **GIVEN WITH MEALS** (BOTH)
SEs:
- GI:
  - flatulence, abd discomfort, diarrhea
contraindicated:
- short bowel syndrome
- irritable bowel syndrome
- SCr >2mg/dL
Wt neutral
take with Meals

Dosage of Metformin

500mg PO BID or 850mg Qday
Max: 2550 mg/day (Glucophage)
Max: 2000mg/day (Glucophage XR)

Thiazolidinediones: MOA, Considerations, SEs

lowers A1C by 1-1.5%; reduce FPG by 60-70mg/dL

aka TZDs or “glitazones”

MOA:
- stimulate peroxisome proliferator-activated receptor gamma (PPAR-gamma) → nuclear receptor
  - increase sensitivity to insulin
  - decrease plasma fatty acid levels
Onset: delayed → takes several weeks, up to 12 weeks for max effects
SEs:
- fluid retention
  - increased when combined with insulin tx
  - contraindicated in HF
- hepatotoxicity – reversible within weeks after d/c
  - check LFTs at baseline & PRN
  - if baseline ALT 2.5x UNL → do not start
  - if ALT 3x UNL after taking TZD → d/c
- Promotes ovulation → unwanted pregnancy
- increased incidence of upper & lower limb fracture
- increases risk of bladder cancer after 1 yr → dose related
  - contraindicated with h/o bladder cancer
- Weight gain
- low risk of hypoglycemia

Thiazolidinediones: Meds

**lowers A1C by 1-1.5%** * _Meds_: * **Pioglitazone** (Actos) * + metformin * + glimepiride * +alogliptin * **Rosiglitazone** (avandia) * + metformin * +glimepiride * greater risk of MI * **2nd line according to ADA** * _SEs_: * Fluid retention * increased ovulation * long bone fractures * hepatotoxicity * bladder cancer

Functions of GIP & GLP-1

* GLP-1: * increase insulin * *decrease glucagon* * decrease Beta cell apoptosis * increase beta cell proliferation * GIP: * increase insulin * *increase glucagon* * decrease beta cell apoptosis * increase beta cell proliferation * DDP-4 enzyme breaks down GLP-1 and GIP

DPP-4 Inhibitors (dipeptidyl peptidase-4 inhibitors): MOA, SEs, general info

**lowers A1C by 0.7-1%** * MOA: * inhibit DDP-4 therefore less GIP & GLP-1 is broken down and more is available * _General Info_: * less hypoglycemia * weight neutral * 2nd line tx * _SEs_: * HA * nasopharyngitis * pancreatitis??

DPP-4 Inhibitors: Meds

-gliptins **lowers A1C by 0.7-1%** * **Sitagliptin**: case report of acute pancreatitis, including hemorrhagic and necrotizing * **CrCl \<50 mL/min → max dose: 50mg/d** * **CrCl \<30 mL/min → max dose: 25mg/d** * **Saxagliptin**: * CrCl \<50 mL/min * **Strong 3A4 inhibitor** * **Linagliptin** * substrate of 3A4 * *no adjustment needed for renal/hepatic impairment* * **Alogliptin** * CrCl 30-59: 12.5 mg/day * CrCl \<30: 6.25mg/day

Dopamine Receptor Agonist and DM

**lowers A1C by 01-0.4%** * **Bromocriptine** (Cycloset) * unknown MOA * AM admin improves insulin sensitivity * **3rd line** tx * _SEs_: * rhinitis/sinusitis * HA/dizziness * syncope * nausea * hypotension * _Contraindications_ * **Lactation** * **Syncopal migraine**

Bile Acid Sequestrant and DM

**lowers A1C by 0.4%** when used with metformin * **Colesevelam** (Welchol) * binds to bile acid in GI lumen * unclear MOA for lowering glucose * lowers LDL by up to **20%** * _SEs_: * nausea/bloating/constipation * increased TGs * dyspepsia * _DDI_: * prevents absorption of: * levothyroxine, OC, phenytoin * warfarin, digoxin * \*\*separate by 4 hours\*\* * **Malabsorption of fat-soluble vitamins: A, D, E, K**

SGLT2 Inhibitor (Sodium-Glucose Co-transporter 2): MOA, general info, SEs

* _MOA_: * reduce reabsorption of filtered glucose * _benefits:_ * weight loss * BP reduction (slight) * less hypoglycemia * _general info_: * may increase LDL * expensive * only added onto metformin * _SEs_: * **renal dysfunction do not use** * fungal infx of genitals * **UTI** * **increased urination** * hypotension

SGLT2 Inhibitor: Meds

* **“if you use SGLT2 inhibitors you may sucCEED in losing weight"** * **Canagliflozin** (Invokana) * + Metformin (invokamet) * **Do Not Use if CrCl \<45 mL/min** * may increase risk of *stroke* * **Dapagliflozin** (Farxiga) * +Metformin (Xigduo XR) * **Do Not Use if CrCl \<60 mL/min** * **contraindicated with h/o bladder cancer** * may increase risk of bladder cancer * **Empagliflozin** (Jardiance) * +Linagliptin (Glyxambi) * +Metformin (Synjardy) * **Do Not Use if CrCl \<45 mL/min** * **Ertugliflozin** (Steglatro) * +sitagliptin (Steglujan) * +metformin (Segluromet) * **Do Not Use if CrCl \<30 mL/min**

Glycemic Goals of Tx in DM

* _Non-Pregnant_: * **A1C \<7%** * Preprandial BG: 80-130 mg/dL * Postprandial BG \<180 mg/dL * **May target A1C \<6.5%:** * DM2 tx with lifestyle mods or metformin only * long life expectancy * no significant CV disease * pregnancy (\<6% = optimal without hypoglycemia) * **May target A1C \< 8%** * H/o severe hypoglycemia * Limited life expectancy * Advanced micro or macrovascular * Complications extensive comorbidities * Long standing DM—difficult to achieve * Has been on appropriate doses on multiple agents and monitoring

Summary of Glucose Lowering Interventions (Chart)