Diabetes Flashcards
Sarah is a 52 year old female with a medical history significant for hypertension, obesity (BMI = 31), and hyperlipidemia who was told she was “boarderline” diabetic 2 years ago at her last physical exam done by another physician. You order routine labs and find all are normal except for a fasting blood sugar of 160 mg/dL on two occasions and a hemoglobin A1C of 7.4%. Your best initial course of therapy is:
Best therapy: lifestyle changes + Metformin
**potential side effects: ** GI (gas, bloating, nausea), lactic acidosis (rare), vit B12 deficiency (not clincally sig.)
Robert is a 72 year old male with a history of coronary artery disease, congestive heart failure, chronic kidney disease, hypertension, hyperlipidemia, and glaucoma who presents to you for evaluation and treatment of his diabetes. He was diagnosed about a year ago and has been taking glyburide 5 mg once daily. He is not well controlled. His blood sugars at home are running around 190. His labs show a serum creatinine of 1.9 and a hemoglobin A1C of 8.7%. His exam shoes b/l lower extremity edema and he has crackles at his lung bases. What therapeutic changes should we make?
already taking sulfphonyurea
can’t give metformin b/c creatinine too high (>1.5)
edema so can’t give thiazolidinendiones
Therapy: try different sulphonyurea or swtich to GLP-1 analog/DPP-4 blocker
Metformin
MOA
Use
PK
side Effects
Contraindications
MOA:
- 1)Major: dec hepatic glucose prod.; Minor: dec intestinal absorp glucose, improve insulin sensitivity
- 2) antilipolytic—dec FFA conc.
- 3) activation of AMK
Use:
- -cornerstone of therapy, mono or in combo
- -prevent diabetes in pts w/ IGT
- -dec. A1c by 1-2%
- -mild wt loss
- -dec LDL and inc. HDL
- -dec CV disease
- -dec malignancy
PK:
- -rapidly absorbed in small intestine
- -not metabolized by liver
- -rapidly excreted unchanged in urine
- -takes 2 wks to achieve max effects
Side effects;
- -GI (most common); mild/transient
- -lactic acidosis (rare, fatal)
- -dec absorption vit B12 (rarely causes anemia)
Contraindications:
- -renal disease/dysfunction (creatinine >1.4F/1.5M)
- -active liver disease (lactic acidosis)
- -temporarily discontinue in pts undergoing imaging study with iodinated contrast
Sulphonyureas/Meglintinides
MOA
Use
PK
side Effects
Contraindications
**MOA: **
- -inhibit K-ATP channel→Calcium influx→release insulin
- -Meglintinides have same MOA but shorter half-life
Use:
- -lower A1c 1-2%
- -work quickly
- -mono or combo therapy
- -does not improve insulin resistance/assoc CV risks of metabolic syndrome
- long term failure in 30% of pts
**PK: **
-flat dose-response relationship: max response at half max dose
side Effects:
- -hypoglycemia (risks: impaired renal/hepatic function, exercise, missed meals, ethanol ingestion)
- -mild wt gain
- -dizziness, headache, nausea
Contraindications:
- -pts high risk hypoglycemia
- -sulfa allergy (meglintinides are OK)
Thiazolindinendiones
MOA
Use
PK
side Effects
Contraindications
MOA:
- Bind PPAR-gamma (reduces TNFa and FFA, raises adiponectin)
- improved insulin action, glucose metabolism, vascular function
- anti-inflammatory, antithrombotic, antiathrogenic
Use:
- mono or combo therapy
- lower A1c 0.5-1.4%
PK
- full clinical effect slow (2-4 months)
- metabolized by liver
side Effects
*unlikely to cause hypoglycemia
- fluid retention (edema)
- Wt gain
- dec. bone mineral density and inc fracture risk
- hepatotoxicity
- macular edema
Contraindications
-caution in pts with CHF
- Rosiglitazone assoc with inc. cardiac events and removed from market
- Pioglitizone assoc. with inc. risk bladder cancer
a-glucosidase inhibitors
MOA
Use
side Effects
MOA:
- -inhibit GI enzymes that break down complex polysacc.
- -slow absortion glucose, slower rise in post-prandial blood glucose
Use:
- -lower A1c by 0.5%
- -dose 3x day
- -start w/ low dose and inc. as tolerated
- **rarely used d/t weak glucose lowering and intolerable side effects
side Effects:
*low risk hypoglycemia
-GI (flatulence), diarrhea, nausea
GLP-1 analog
Exenatide
Liraglutide
MOA
Use
PK
side Effects
Contraindications
MOA:
- -Stimulate insulin secretion from b-cells and inhibit glucagon secretion by a-cells in glucose-dependent manner
- -slows gastric emptying
- -satiety
Use:
- -dec A1c 0.5-1.2%
- -5-10lb wt loss
PK
- minimal systemic metabolism
- proteolytic degrad.
- exenatide t1/2=2.4h (2xday)
- liraglutide t1/2=13hrs (1xday)
side Effects
- # 1 Nausea (vomiting, dyspepsia, diarrhea)
- jittery, dizzy, headache
- pancreatitis
- renal failure/insufficiency
- C-cell tumors in rats
Contraindications
- do not use in pts w/ creatinine clearance <30ml/min
- family hx of medullary thyroid cancer or MEN2A or MEN2B
Other:
- low rate hypoglycemia
- exenatide given once weekly injection
- liraglutide 1x day irrespective of meals
DPP-4 inhibitors
Sitagliptin
Linagliptin
MOA
Use
side effects
Other
MOA: Inhibits DPP-4 enzyme that breaks down GLP-1 and GIP
Use:
- -lower A1c 0.5-0.9%
- -5-10lb wt loss
side effects:
- -nasopharyngitis, URI, headache
- -hypersensitivity: stevens-johnson syndrome, anaphylaxis, angioedema
- -pancreatitis
Other:
- -low rate hypoglycemia
- -wt neutral
Pramlintide
MOA
USE
side effects
**MOA: **
- amylin analog
- inhibits glucagon secretion
- slows gastric emptying
- promotes satiety
USE:
- type 1 and type 2 insulin treated DM
- pts must dec. premeal insulin 50% to avoid hypoglycemia
- lowers A1c 0.5-0.6%
- mild wt reduction
side effects:
nausea (20%pts)
-hypoglycemia
Colesevalam
MOA
Use
PK
Side effects
MOA: Bile acid sequestrant; MOA unknown
Use: lowers A1c by 0.5%
PK: -pts must take 6 pills/day
Side effects: -GI—bloating, gas, diarrhea
Bromocriptine
MOA
Use
Side effects
MOA: Dopamine agonist; MOA unknown
Use: lowers A1c 0.4-0.5%; dec. cardiovascular disease
Side effects: -nausea, vomiting, fatigue, dizziness
chronic complications of diabetes…
1) microvascular: occur in 80% of all diabetcs
- retinopathy
- nephropathy
- neuropathy
2) macrovascular: diabetics at 2-6 fold increased risk
- coronary artery
- stroke
diabetes is leading cause of renal failure, blindness, and non-traumatic amputations
hyperglycemia caues tissue damage in 3 ways…
1) increased aldose reducatase activity leads to altered Na/K ATPase activity and accumulation of sorbitol in nerve tissue
2) inc. DAG and PKC activity lead to vascular smooth muscle dysfunction and altered endothelial cell permeability
3) accelerated glycosylation leads to activation of AGE-receptors which alter cell lipoproteins, basement membrane, and matrix
net result: inc. inflammatory cytokines leading to oxidative stress and damagge!
UKPDS: United Kingdom Prospective Diabetes Study
-Type 2 diabetics
- Intensive control group (A1c 7%) vs Conventional control group (A1c 7.9)
- Duration of 10 years in type 2 diabetics
- Intensive group had fewer microvascular complications
- Intensive control group did NOT show statistically significant improvement in macrovascular complications
- Landmark in demonstrating that improved glucose control improves microvascular outcomes in type 2 diabetics
DCCT Trial
- type 1 diabetics
- Intensive control (A1c 7.2%) vs conventional control (A1c 9.1%)
- Duration of 9 years in TYPE 1 DM
- Intensive control group had fewer microvascular complications
- Intensive control did NOT show statistically significant improvement in macrovascular complications
- Landmark in demonstrating that improved glucose control improves microvascular outcomes in type 1 diabetics
EDIC Trial
- type 1 DM
- An 11 year extension of the DCCT
- Landmark in demonstrating a concept called metabolic memory: The protective effects of intensive therapy persist over time even when the glycemic differences between the intensive group and the conventional group disappear
Diabetic complications: Eye disease (4)
- Retinopathy (Progresses from non-proliferative to pre-proliferative to proliferative)
- Cataracts: inc rate of age-related cataracts
- Refractory defects: hyerglycemia alters osmotic pressure of lens
- Glaucoma: inc. prevalence
Non-proliferative:
microaneurysms
small intra-retinal hemorrhages
hard exudates (lipid deposits around a leaking vessel)
*Left arrow is a blot hemorrhage. Right arrow is a hard exudate.
Pre-proliferative retinopathy:
- Development of retinal ischemia that appears as a cotton wool spot
- Venous changes appear as dilated loops
Proliferative retinopathy:
- Characterized by neovascularization that results from growth factors responding to retinal ischemia
- These new vessels are friable and lead to hemorrhage
- Fibrosis
- Retinal detachment
- Blindness
treatment is laser photocoagulation therapy
screening for diabetic eye disease…
dilated retinal exam:
- Type 1: 5 years after diagnosis, then yearly
- Type 2: at time of diagnosis, then yearly
Treating diabetic eye disease…
- Improve glucose control
- Transient worsening of retinopathy (and blurry vision) due to fluid shifts
- Laser photocoagulation therapy (For proliferative retinopathy)
- vitrectomy
- intravitreal glucocorticoids,
- VEGF inhibitors
Diabetic eye disease and pregnancy
Retinopathy tends to worsen during pregnancy
- Decreased systemic blood pressure
- Hormonal changes leading to ischemia and fluid shifts
- Should have frequent follow up but generally these changes are reversible
2 types of diabetic neuropathy…
1) Acute reversible neuropathy
- Associated with hyperglycemia or rapid correction of hyperglycemia
- Usually self limited
2) Chronic persistent neuropathy- many types
- Systemic polyneuropathy
- Autonomic neuropathy
- Other (mononeuropathies, pressure palsies, etc)
Diabetic Systemic polyneuropathy
- Most common type
- Classic peripheral “stocking glove” neuropathy
- Results from damage of sensory axons
- Can progress to loss of motor axons in severe cases
- Patients complain of burning or tingling in their feet
- Loss of sensation on monofilament testing
Diabetic Autnomic Neuropathy
- Neuropathy affecting smooth muscle
- Gastroparesis-results in slowed gastric emptying, nausea, vomiting
- Postural hypotension-results from abnormal cardiovascular response
- Bladder dysfunction- results in urinary incontinence or retention
- Erectile dysfunction- this is often multifactorial and often includes vascular disease as well
Screening for diabetic neuropathy
1) Peripheral polyneuropathy
- monofilament and vibration testing on feet
- All type 1 and type 2 diabetics at diagnosis, then yearly
2) Autonomic neuropathy:
- Evaluate for orthostatic hypotension
- All type 1 diabetics should be screened within 5 years of diagnosis
- All type 2 diabetics should be screened at diagnosis
Treatment of diabetic neuropathy
1) Optimize glycemic control
2) Only 2 medications FDA-approved for diabetic neuropathy
- Pregabalin (Lyrica®) –Binds to alpha2-delta subunit of voltage-gated calcium channels within the CNS, inhibiting excitatory neurotransmitter release
- Duloxetine (Cymbalta®)–Serotonin and norepinephrine reuptake inhibitor
diabetic foot Def?
Charcot arthropathy?
Diabetic foot: Diabetic neuropathy and peripheral vascular disease
Charcot arthropathy:
- Combination of neurapathy, mechanical force and vascular insufficiency that
- Leads to osteoarthropathy, destruction of bone in the foot
*
diabetic foot care
- Daily self-examination of their feet, especially if they have neuropathy
- ADA recommends annual foot exam
- Vibration, pressure, pain/temperature
- Monofilament test
diabetic nephropathy
Def?
Pathophys?
Clinical definition: renal impairment that starts with microalbuminuria (30 to 299mg/24hrs) and can progress to macroabluminuria (>300mg/24hrs)
Pathophy:
- Alterations in glomerular filtration barrier that result from Thickening of the glomerular basement membrane or Podocyte injury
- Results in increased flitration of proteins into urine
- Eventually leads to glomerulosclerosis and end stage renal disease
Stages of diabetic nephropathy
1) Hyperfiltration and renal hypertrophy due to expansion of tubular tissue of kidneys.
2) Microalbuminuria - > 30 mg/day
3) Glomerulosclerosis
Accelerated by hypertension
Occurence of diabetic nephropathy type 1 vs type 2
1) Occurrence in DM1-
- Usually presents within 15 years of diagnosis
- After 25 years, if no nephropathy has occurred, its rate of occurrence is only 1% per year
2) Occurrence in DM2
After 10 years from the diagnosis the prevalence is:
-Microalbuminuria 25%
-Macroalbuminuria 5%
-End stage renal disease requiring dialysis 0.8%
Screening for diabetic nephropathy
1) Urine albumin to creatinine ratio:
- Normal albumin/creatinine ratio is <30microg/mg
- Microabluminuria is a ratio 30-299microg/mg
- Macroabluminuria is a ratio of >300microg/mg
2) Serum creatinine and BUN
Can be normal even when there is microalbuminuria
Can be normal when there is macroalbuminuria
A rise in the serum creatinine level is seen in later stages
3) who and when to screen:
Urine albumin/creatinine ratio:
- Type 1 diabetics 5 years after diagnosis, then yearly.
- Type 2 diabetics at diagnosis, then yearly
Serum creatinine:
- Everyone yearly
Treatment of diabetic nephropathy
-Patients who have microalbuminuria
- Angiotensin converting enzyme inhibitors (ACE-I)
- Can use angiotensin receptor blocker (ARB) if cannot tolerate ACE-I (cough)
- Optimize glucose control
- Optimize blood pressure
Screening diabetics for macrovascular disease (CAD, Cerebralvascular disease)
ADA recommends
- Cardiac stress testing for diabetic patients with peripheral vascular disease or carotid artery disease
- This has led to improved identification of patients with CAD
- This has NOT lead to an improvement in morbidity or mortality
Treatment of macrovascular disease in diabetics
- risk reduction (glycemic control, BP, hyperlipidemia, smoking cessation, wt management)
- LDL goal: <70 for patients with DM and CAD
Hemoglobin A1c: Around 7% (not necessarily under)
ADA goals of therapy for diabetics
-A1c
- <7% for patients without CVD
- Around 7% for patients with CVD
- LDL <100, if CAD <70
- BP <130/<80
55yo female with 10 year history of impaired fasting glucose. Today random glucose test >200mg/dl. Diagnosis type 2 diabetes. Retinal exam reveals the following:
Dx?
Tx?
Dx: proliferative retinopathy (Characterized by neovascularization that results from growth factors responding to retinal ischemia)
Tx: laser photocoagulation
screening guidelines: dialted retinal exam at diagnosis, then yearly
66yo man with 10 year history of type 2 diabetes. Here for yearly exam…
What should you screen for?
What is it was a 17 yo with type 1 diabetes diagnosed 1 year ago?
1) dilated retinal exam: looking for retinopathy
2) neuropathy:
- peripheral polyneuropathy: monofilament and vibration testing
- autonomic neuropathy: orthostatic hypertension
3) nephropathy:
- urine albumin: creatinine ratio
- serum creatinine
17yo per guidelines:
- No retina exam
- peripheral polyneuropathy but not autonomic neuropathy
- nephropathy: only creatinine (no albumin creatinine ratio)
65yo male with 15 year history of type 2 diabetes. Poorly controlled with HbA1c 9.0%. Recently started to walk for exercise and has noticed trouble with foot. Hx of bilateral peripheral neuropathy in feet with monofilament testing. Foot exam reveals?
Dx?
Dx: charcot arthropathy: diabetic neuropathy, mechanical force and vascular insufficiency–>osteoarthropathy destruction of bone in foot
Tx: amputation ?
50yo female with 10 year history of type 2 diabetes. Results of lab work reveal albumin creatinine ratio of 150microg/mg
Dx?
Tx?
25% of type 2 diabetics have microalbuminuria 10 years after diagnosis.
Dx: microalbuminuria
Tx: ACE-I (or ARB)
