Type II DM Flashcards
What is the pathology/presentation of DM type II?
Insulin resistance
Relative insulin deficiency
Gradual onset
Patient often obese or history of obesity
Often asymptomatic
Mico/macrovascular complications often present at diagnosis
What are the other physiologic issues in Type II DM?
Reduced circulating levels of Glucagon-like peptide (GLP-1)
GLP-1 released from distal ileum and colon in response to food containing carbs and fats
Loss of first-phase insulin response
Loss of Amylin
Amylin and insulin secreted from beta-cells
Absent in Type I; same fate as insulin in Type 2
How is type II diabetes diagnosed?
FPG >/= 126mg/dL (preferred test)
OR
Symptoms of diabetes + casual plasma glucose >/= 200 mg/dL
OR
Oral glucose tolerance test (OGTT):
2hr-postload glucose >/= 200 mg/dLWhat is the definition of Pre-Diabetes?
Impaired fasting glucose (IFG) = FPG 100-125 mg/dL
Impaired glucose tolerance (IGT) = 2-hr post-load glucose 140-199 mg/dL
IFG and IGT indicate a risk factor for diabetes and cardiovascular disease
Who should be screened for diabetes and how should it be done?
-Screening identifies asymptomatic patients who might have diabetes
-Consider in patients of any age if their BMI ≥ 25 kg/m2 and they have an additional risk factor for diabetes
-If no risk factors are present, begin at age 45
FPG (fasting plasma glucose) should be done initially
-Repeat screening every 3 years
When should you screen children for type II DM?
Overweight: BMI >85th percentile for age and sex, wt for height >85th percentile, or weight >120% of ideal for height
Plus 2 of the following
FH of type 2 diabetes in 1st or 2nd degree relative
Native American, African American, Latino, Asian American, Pacific Islander
Signs of insulin resistance ( acanthosis nigricans, hypertension, dyslipidemia, or PCOS)
Maternal history of diabetes or gestational diabetes
Start testing at age 10 or onset of puberty
Test FPG every 2 years
What are the three major metabolic abnormalities that contribute to hyperglyceemia in NIDDM?
Defective glucose-induced insulin secretion
Increased hepatic glucose output
Inability of insulin to stimulate glucose uptake in peripheral target tissues.
These abnormalities involve the cellular glucose transport in cells, liver, adipose tissue and skeletal muscle.
Also reduced sensitivity of fat and muscle cells to the effects of insulin (insulin resistance).
What are the other causes of insulin resistance?
Cushing’s Syndrome (excessive corticosteroids) Acromegaly (excessive growth hormone) Polycystic ovarian syndrome Hyperandrogenism Hirsutism Menstrual irregularities Obesity infertility
What are the microvascular complications of DM?
Retinopathy-occurs when microvasculature that supplies the retina becomes damaged
Nephropathy-most common complication reported in type II, pain, tingling, or numbness in the extremeties
Neuropathy
What are the macrovascular complications of DM?
Atherosclerotic Cardiovascular diagnosis
Dyslipidemia
What is the A1C goal for adults in general?
A1C goal for adults in general is < 7.0%
What is used for diabetes prevention in patients with IGT or IFG?
Weight loss (7% of body weight) and ↑ physical activity (150 min/week) Helps patients from progressing from pre-DM to DM. 14 g dietary fiber/1000 kcal Drugs studied for prevention Metformin Rosiglitazone Acarbose Troglitazone Orlistat
What is gestational diabetes mellitus (GDM)?
Glucose intolerance with onset or first detection during pregnancy
Associated with maternal morbidity
Fetal macrosomia
Higher rate of pre-eclampsia
Mother is then at risk for developing type 2 diabetes later on
Who is at very high risk for GDM?
Severe obesity Prior history of GDM or delivery of large-for-gestational age infant Presence of glycosuria Diagnosis of polycystic ovarian syndrome Strong family history
When should women be screened for GDM?
Women at very high risk should be screened as soon as possible after confirmation of pregnancy
All other women should be screened at 24-28 weeks of gestation
What diagnosis a woman with GDM?
Fasting ≥ 95 mg/dL 1h ≥ 180 mg/dL 2h ≥155 mg/dL 3 h ≥ 140 mg/dL Women with GDM should be screened for type 2 diabetes 6-12 weeks postpartum
What is the clinical management of diabetes?
Diet and exercise are the cornerstone of management of diabetes regardless of severity of symptoms.
>7% weight loss
150 min/wk exercise
14 g dietary fiber/1000 kcal
Therapeutic management must be highly individualized.
What is the goal of diabetes management?
Goal: To improve symptoms of hyperglycemia, reduce onset & progression of microvascular and macrovascular complications, reduce mortality & improve QOL.
What is the treatment of DM?
Improve sugars but aggressive management of traditional cardiovascular risk factors is required as well. Smoking cessation Lipid management Blood Pressure control Antiplatelet therapy
When should a patient with DM monitor blood glucose levels?
Self monitoring of blood glucose (SMBG)
At least 3 times/day if on insulin injections
If on orals, just use SMBG to help them achieve their glycemic goals
Use the data to make decisions on what therapy to add
When should a patients A1C be monitored?
At least twice a year in patients at goal
Every 3 months in patients whose therapy has changed or aren’t meeting treatment goals
Secretagogues Sulfonylureas- MOA
Direct stimulation of insulin release from viable pancreatic beta-cells thus reducing blood glucose levels (↑ insulin secretion)
Blocks ATP-sensitive K+ channels, resulting in depolarization and Ca++ influx->release of insulin
At higher doses these drugs also decrease hepatic glucose production
Decreased levels of glucagon
Derivatives of sulfonamides, but no antibacterial activity
Secretagogues Sulfonylureas- Efficacy
↓ A1C 1.5%
What are the drug names of the sulfonylureas?
Glyburide, Glipizide, Glimepiride (Amaryl®)
Glyburide, Glipizide, Glimepiride (Amaryl®)- clinical uses
Mild to moderate Type 2 diabetes
Ineffective in Type I diabetics and severe diabetics as the number of viable beta cells is very small.
Not used in gestational diabetes (not good for the baby)
Glyburide, Glipizide, Glimepiride (Amaryl®)- ADRs
HYPOGLYCEMIA --Elderly, hepatic/renal impairment; combo therapy WEIGHT GAIN Muscular weakness Dizziness Confusion Skin rash Photosensitivity Blood dyscrasias Cholestatic jaundice
Glyburide
Sulfonylureas
Administer with breakfast or first main meal
Greater risk of hypoglycemia than other sulfonylureas: longer half-life
Not recommended if CrCl < 50 ml/min (use a different sulfonylurea)
2009 guidelines do not recommend glyburide as a first line sulfonylurea
Glipizide
Sulfonylureas
Administer 30 min before first main meal
Not recommended if CrCl < 10 ml/min
Glimepiride
Administer with first main meal
Not recommended if CrCl < 22 ml/min
Response of sulfonylureas plateaus after half the max dose
Reduced GI absorption if blood glucose > 250 mg/dL
When should sulfonylureas be administered?
With a meal. Associated with a meal time dose.
Glyburide, Glipizide, Glimepiride (Amaryl®) (sulfonylureas)- Monitoring
FPG in two weeks
A1C in 3 months
Glyburide, Glipizide, Glimepiride (Amaryl®) (sulfonylureas)- Contraindications/cautions
Cross-sensitivity to sulfa
Higher risk w/hypoglycemia in patients w/renal or hepatic disease.
Avoid w/ETOH
Cross placenta and decrease fetal insulin->contraindicated in pregnancy
Glyburide, Glipizide, Glimepiride (Amaryl®) (sulfonylureas)- Drug interactions
may potentiate hypoglycemia via reduced hepatic metabolism, decreased urinary excretion or displacement from plasma proteins Sulfonamide antibacterials Propranolol Salicylates Phenylbutazone ETOH
Meglitinides- MOA
Short-acting secretagogues
Stimulate insulin release from pancreatic beta-cells
Shorter half life than sulfonylureas
Rapid release of insulin that only lasts 1-2 hours
Taken with meals- targets postprandial glucose levels
Meglitinides– efficacy
↓ A1C by 1.5%
Meglitinides- adverse effects
Hypoglycemia- less than with sulfonylureas
Weight gain
Meglitinides- Monitoring parameters
FPG at 2 weeks
Postprandial glucose at initiation
A1C at 3 months
What are the biguanides?
Metformin (Glucophage)
Metformin (Glucophage®)- MOA
Does not affect insulin secretion but requires the presence of insulin to be effective.
Decrease production of hepatic glucose production.
Decrease intestinal glucose absorption.
Incease peripheral glucose uptake.
Increase insulin sensitivity at sights of insulin uptake
Metformin (Glucophage®)- Efficacy
↓ A1C by 1.5%
Metformin (Glucophage®)- clinical uses
Works best in patients w/significant hyperglycemia
Often considered first-line therapy in the treatment of mild to moderate Type 2 overweight diabetics who demonstrate insulin resistance
Metformin (Glucophage®)- ADRs
GI symptoms (up to 50%)—less when taken w/food.
Diarrhea, abdominal bloating, nausea
Titrate dose at weekly intervals to minimize AEs
Give with meals
HAS THE ABILITY TO CAUSE LACTIC ACIDOSIS—very rare, but a greater potential w/:
renal failure- biggest one.
CHF
Hypoxemia
ETOH use
Metformin (Glucophage®)- Monitoring
SCr at baseline
FPG at 2 weeks
A1C at 3 months
Hypoglycemia is rare
How is lactic acidosis developed with metformin?
Increase production of lactate in the intestine leads to increased portal lactate which equals decreased liver pH leading to decreased lactate metabolism and lactate accumulation in the blood.
Metformin (Glucophage®)- Contraindications
Renal impairment
SCr >1.5 for men
SCr >1.4 for women
Acute or chronic metabolic acidosis- not DOC because risk of worsening this
Metformin (Glucophage®)- Precautions
Radiocontrast studies– Hold metformin for 48 hours. Important to remember
Age>80 unless normal GFR
Hypoxic states
Liver dysfunction
Alcoholism
Heart failure requiring pharmacologic therapy
What are the benefits or metformin?
No weight gain
No hypoglycemia as monotherapy
Inexpensive
Approved for use as monotherapy and in combination with other therapy
What are the thiazolidinediones (TZDs) insulin sensitizers?
Rosiglitazone (Avandia) and Pioglitazone (Actos)
Rosiglitazone (Avandia) and Pioglitazone (Actos)- Efficacy
↓ A1C by 0.5-1.4%
Rosiglitazone (Avandia) and Pioglitazone (Actos)- MOA
PPAR-gamma receptor activators (Peroxisome proliferator-activated receptors) which regulate glucose metabolism resulting in increased insulin sensitivity in adipose, liver and skeletal muscle
Biologic effect may not be seen for 4 weeks
Insulin required for action…doesn’t promote insulin release from pancreas due to acting at the tissues.
Don’t give exogenous insulin with Avandiaedema
Rosiglitazone (Avandia) and Pioglitazone (Actos) (TZDs)- Cardiovascular effects
Pioglitazone: Increased HDL; Decreased triglycerides
Rosiglitazone: Increased LDL and HDL
Change in LDL more buoyant and less atherogenic lipoproteins
Inhibit vascular smooth muscle proliferation in coronary and carotid vessels
Rosiglitazone (Avandia) and Pioglitazone (Actos) (TZDs)- Adverse effects
Fluid retention and peripheral edema Weight gain Fluid retention is major contributor Redistribution of adipose tissue New-onset heart failure <1% 2-3% when combined with insulin
Rosiglitazone (Avandia) and Pioglitazone (Actos) (TZDs)- Contraindications
Alcohol abuse Elevated liver enzymes Hepatotoxicity d/c liver enzymes rise 2-3 times the upper limit of normal Hepatic disease HF NYHA class III or IV
When are TZDs used in heart failure?
Use of TZDs in patients with NYHA class I or II HF May be used with initiation of treatment at lowest dosage (rosiglitazone 2mg daily or pioglitazone 15 mg daily) Observe for weight gain, edema or exacerbation of HF Do not use TZDs in patients with NYHA class III or IV HF
What are the alpha-glucosidase inhibitors?
Acarbose (Precose®)
Miglitol (Glyset®)
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)- MOA
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)-Delays intestinal carbohydrate absorption
Inhibits alpha-glucosidase found in the small intestinal brush border
Prevent glucose absorption and decreases post-prandial glucose levels
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)- Efficacy
↓ A1C 0.5-0.8%
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)- Adverse effects
Not well tolerated
In clinical trials 25-45% discontinuation
GI disturbances
Loose stools
Flatulence
Abd. Cramping
Minimize these effects by starting low, going slow
Can also be minimized by curtailment of carbohydrate consumption.
Usually transient effects
Does NOT cause wt. gain
Hypoglycemia does not occur
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)- Contraindications
Chronic intestinal disease
Cirrhosis
Acarbose (Precose®), Miglitol (Glyset®) (Alpha-glucosidase inhibitors)- monitoring
Post prandial glucose at initiation
A1C in 3 months
What are the Dipeptidyl peptidase-4 (DPP-4) inhibitors?
Sitagliptin (Januvia®)
Saxagliptin (Onglyza)
Sitagliptin (Januvia®), Saxagliptin (Onglyza) (DPP-4 inhibitors)- MOA
Prevent degradation of endogenous glucagon-like peptide-1 (GLP-1) and insulinotropic polypeptide (GIP)
Incretin hormones released in response to meal
Increase insulin synthesis and release from beta cells
Intracellular signaling
GLP-1 also lowers glucagon secretion from pancreatic alpha cells
Results in increased insulin release and decreased glucagon levels in circulation in glucose-dependent manner
Sitagliptin (Januvia®), Saxagliptin (Onglyza) (DPP-4 inhibitors)- efficacy
↓ A1C 0.5-0.7%
Dose adjusted for CrCl
Approved for monotherapy or combination therapy
Weight neutral
Sitagliptin (Januvia®), Saxagliptin (Onglyza) (DPP-4 inhibitors)- Adverse effects
Well tolerated
Similar to placebo
Few post-marketing
Sitagliptin (Januvia®), Saxagliptin (Onglyza) (DPP-4 inhibitors)- Contraindications
Haven’t been identified yet
Sitagliptin (Januvia®), Saxagliptin (Onglyza) (DPP-4 inhibitors)- monitoring
Renal function
A1C in 3 months.
Colesevelam (WelChol)- MOA
Bile acid sequestrant: received FDA indication in January 2008 for Type 2 diabetes as an adjunct to diet and exercise
Previously only approved for LDL reduction
Colesevelam (WelChol)- Efficacy
↓ A1C 0.4-0.8%
Not indicated as monotherapy
Colesevelam (WelChol)- Adverse effects
Constipation/nausea/indigestion
Increased triglycerides
Colesevelam (WelChol)- Contraindications
Bowel obstruction
History of hypertriglyceridemia-induced pancreatitis
Triglycerides >500 mg/dL
What are the oral therapies?
-Secretagogues sulfonylureas- Glyburide, Glipizide, Glimepiride (Amaryl®)
-Meglitinides- Repanglinide (Prandin) and Nateglinide (Starlix)
-Biguanides- Metformin
-Thiazolidinediones (TZDs)Insulin Sensitizers - Rosiglitazone (Avandia) and Pioglitazone (Actos)
-Alpha-Glucosidase Inhibitors-Acarbose (Precose®)
Miglitol (Glyset®)
-Dipeptidyl peptidase-4 (DPP-4) inhibitor- Sitagliptin (Januvia®), Saxagliptin (Onglyza)
-Colesevelam (WelChol)
What are the non-oral therapies?
Glucagon-like peptide 1 (GLP-1) agonists-Exenatide (Byetta)
Pramlintide (Symlin)
Repaglinide (Prandin)
Meglitinides- Short-Acting Secretagogues Approved for monotherapy or in combination w/metformin. Taken before meals 3 X/day Allergy to sulfas not an issue ADR hypoglycemia
Nateglinide (Starlix)
Meglitinides- Short-Acting Secretagogues
Phenylalanine derivative
Faster onset of action and shorter duration of action than repaglinide; less A1C reduction than repaglinide
Approved for monotherapy an combination w/metformin.
Taken 3X/d before meals
Exenatide (Byetta)- MOA
Glucagon-like Peptide 1 (GLP-1) agonists GLP-1 analog Incretin mimetic Resistant to degradation by DPP-4 Suppresses high glucagon levels Delays gastric emptying (can affect absorption of other meds)
Exenatide (Byetta)- Efficacy
↓ A1C 0.5-1%
Exenatide (Byetta)- indications
FDA approved for type 2 diabetes in patients on metformin, sulfonylurea, TZD, or a combination who are not at goal
Not yet approved for use with basal insulin
Exenatide (Byetta)- Adverse effects
N/V/D (30-45%0
Modest weight loss
Hypoglycemia wspecially in combination with sulfonylureas
Anti-exenatide antibodies
Exenatide (Byetta)- Monitoring
Renal function
A1C in 3 months
Exenatide (Byetta)- Contraindications
Type I DM
Exenatide (Byetta)- Precautions
ClCr <30 ml/min
Gastroparesis
Hypoglycemia
Pramlintide (Symlin)- indications
FDA approved for Type 1 or 2 diabetes in patients on optimal insulin therapy who are still not at goal
With or without metformin and/or sulfonylurea therapy
Pramlintide (Symlin)- Efficacy
↓ A1C ~0.1-0.4% in type 1; 0.3-0.7% in type 2
When is pramlintide administered?
In conjunction with mealtime insulin
What is the treatment of CHD is a patient with DM?
Should receive at least a daily aspirin unless contraindicated (81mg baby aspirin)
What is the treatment of Hyperlipidemia in a patient with DM?
Statin
What is the treatment of hypertension in a patient with DM?
ACEI or ARB 1st line in combination with a thiazide diuretic
What should you use to lower LDL in a patient with DM?
1st choice: Statin
Statin should be added (along with lifestyle intervention) regardless of lipid levels in diabetic patients with:
Overt CVD
Without CVD who are over the age of 40 and have one or more other CVD risk factors
In pts whose LDL goal can’t be achieved, a 30-40% reduction is acceptable
2nd choice: BAR- bile acid resin, niacin, or fibrate (non of these are first line)
What is hyperosmolar hyperglycemic state?
Hyperosmolar hyperglycemic state (HHS) is a life threatening condition similar to DKA
Extreme hyperglycemia and fluid deficits
Arises from inadequate insulin but occurs primarily in older type II patients
HHS lacks lipolysis, ketonemia, and acidosis (this is the difference of why its not DKA)
Illness often precipitates (usually have some sort of illness)
Patients with hyperglycemia and dehydration lasting several days to weeks are at greatest risk of developing HHS.
How is HHS diagnosed?
Plasma glucose > 600mg/dL
Serum osmolality of > 320 mOsm/kg
How is HHS treated?
Rehydration
Correction of electrolyte imbalances
Continuous insulin infusion
Reduce blood glucose levels gradually to avoid cerebral edema
