Exam 3 Flashcards
National Organ Transplant Act
Passed by congress in 1984 to address the nations critical donor shortage and improve the organ matching process.
Established OPTN
Indications for renal transplant (RTx)
End stage renal disease (ESRD) regardless of the cause.
Diabetes is the primary cause
Absolute contraindications to RTx
Severe cardiovascular or pulmonary disease
Chronic illness with short life expectancy
Active or recently treated cancer
Active sepsis or life threatening infectious disease
Active substance abuse
Poorly controlled mental illness
Relative contraindications to RTx
Current tobacco use BMI Age Dementia Lacking social support Non-Adherence Limited or no health insurance Pharmacologic
RTx- Donor evaluation
Must be at least 18 years old in good physical and mental health
Must be willing to donate (do not feel like you must)
Be well informed and have a good grasp on the risks and benefits.
Have a good support system
DBD: Donation after brain death
Death declared by physician (Not OPO)
Once, declared, OPO involved
Pt remains on ventilator throughout organ recovery which takes 3-4 hours
DCD: Donation after cardiac death
Family/NOK decide to withdrawal care Once decided, OPO involved Ventilator support withdrawn and death declared by physician 5 minutes after ceased circulation. Organ recovery in 1-2 hours Lack of blood flow may damage organs
Donor/ recipient Compatibility
- ) Blood type matching
- ) Tissue type matching
- ) Crossmatching
Blood type A matching
antibodies- anti-a
antigens-A
Compatible blood types- A and O
Blood Type B matching
Antibodies- anti B
Antigens- B
Compatible blood types- B or O
Blood Type AB matching
Antibodies- none
Antigens- A and B
Compatible blood types- A, B, AB, O
Blood Type O matching
Antibodies- anti-a, anti-b
antigens-none
compatible blood type- O
Tissue type matching
Determines the number of antigens the donor and recipient share
The more antigens matched, the more successful the transplant
Cross matching
Used to identify the presence of preformed antibodies against a donor (events: pregnancy, blood transfusion, prior transplant)
Panel Reactive Antibody (RBA)- recipient serum is tested against donor lymphocytes contained from a panel of about 100 donors.
%PRA=0= donor not sensitized, donor and recipient cells do not react together.
Desensitization
Process (plasmapheresis +/- medication therapy) to reduce harmful donor specific antibodies
Acute transplant rejection
Can occur at any time post-transplant and may lead to allograft loss.
Diagnosis: biopsy, decline in function, organ-specific factors
Kidney- rise in SCr
Liver- Elevated LFTs
Heart- no specific symptoms
Risk factors for rejection (kidney)
Number of HLA mismatches Younger recipient age Older donor age AA ethnicity Panel reactive antibody (>40%) Cold ischemia time >24 hours
General concepts of immunosuppressants
Lifelong immunosuppression is required after transplant
Risk of rejection is higher in the beginning
Induction immunosuppression- potent drugs given at time of transplant to quickly resolve immune response. Not always necessary
Maintenance immunosuppression- Started within the 1st week and continued long term. Higher doses in first 6-12 months
Infections are common
PTLD, tumors, and skin cancer common
BBW for most immunosuppressants
Increased risk of infection that may lead to hospitalization or death
May be associated with the development of malignancies that can lead to hospitalization or death
How to take immunosuppressants
No missed doses
Take on a fixed schedule
Take the same way each day (with or w/o food)
Must be up to date in vaccines prior to transplant, avoid live vaccines after transplant
The three signal model of T cell activation
Signal 1: Activation of T cell receptor (TCR)
- Located on T lymphocyte surface
- Recognizes foreign antigen presented by antigen-presenting cells
Signal 2: Co-Stimulation: Interaction between cell surface markers between the APC and T cell
Signal 3: Activation of IL-2 receptor on the T cell surface. Stimulates T cell proliferation
Classes of immunosuppressant drugs
Calcineurin inhibitors Costimulation inhibitors Antimetabolites m-TOR inhibitors Corticosteroids Monoclonal and polyclonal antibodies
Calcineurin inhibitors
Cyclosporine
Tacrolimus
Inhibit T cell activation by preventing the phosphatase enzyme calcineurin from acting on the nuclear factor of activated T cells (NFAT), the function of which is to upregulate the expression of IL-2
Cyclosporine varieties, absorption, and metabolism
Available in different dosage forms that are no bioequivalent.
Cyclosporine USP- oral and injectable
Cyclosporine USP modified- a microemulsion, oral only
Absorption-
Cyclosporine USP- poor and erratic, bile dependent
Cyclosporine modified- Improved not bile-dependent
Metabolism- Gut and hepatic CYP3A4, p-glycoprotein
Cyclosporine (CSA) major adverse events
Nephrotoxicity
- Acute- reversible and dose-dependent vasoconstriction of afferent arteriole
- chronic- irreversible damage to the nephrons
Neurotoxicity- tremor, HA, insomnia, confusion, PRES
Cosmetic effects- acne, hirsutism, gingival hyperplasia
Hyperkalemia
Hyperlipidemia
Hypertension
Cyclosporine dosing
Initial doses are weight-based and dosed Q12H
Titrated to achieve target trough levels of 100-400ng/mL
IV- 33-50% of oral dose as continuous infusions or in 2 divided doses
- Must be non-PCV bags.
- Associated with anaphylaxis and additional nephrotoxicity
Tacrolimus dosage forms, absorption, and metabolism
Calcineurin inhibitor
Available in different dosage forms-not bioequivalent
IR and ER formualtions
Absorption- variable, not bile-dependent, decreased by food (take consistently with regard to food)
Metabolism- CYP3A4 and p-glycoprotein
Tacrolimus AE
Same as cyclosporine, but more tolerable
More common- hyperglycemia, neurologic effects
Less common- HTN, hyperlipidemia, cosmetic effects
Additional AE- diarrhea, alopecia
Tacrolimus dosing
Initial doses are weight based and dosed Q12H
Titrated to achieve target trough values of 5-20ng/mL
IV- 25-33% PO dose as continuous infusion, must uses non-PCV bags, risk of anaphylaxis
Sublingual- open capsule contents under tongue and allow to dissolve. 50% PO dose.
Cyclosporine VS Tacrolimus
Study done in 1998
Three year graft and treatment failure significantly in the tacrolimus group
DDI with CNIs
Enzyme inducers lower CSA/TAC levels
- This increases the risk of rejection
- Phenytoin, carbamazepine, phenobarbitol, Rifampin, St. Johns wort
Enzymes inhibitors raise CSA/TAC levels
- Increases risk of toxicities
- Erythromycin, clarithromycin, azole antifungals, diltiazem, verapamil, nifedipine, metoclopramide, grape fruit juice
Trough levels
Whole blood concentrations drawn immediately before next dose
Belatacept
Costimulation inhibitor (Signal 2)
Binds CD80 ad CD86 receptors on APCs
-Blocks the binding to CD28 on T cells
Approved for kidney transplant only
IV infusion given monthly
Major benefit over CNIs- Decreased nephrotoxicity
Belatacept vs Cyclosporine
Belatacept is superior in kidney transplant
Antimetabolites
Azathioprine
Mycophenolate
Inhibit purine nucleotide synthesis which is necessary for T cell proliferation
Signal 3
Azathioprine
Prodrug, converted to 6-MP which competes with other purines to inhibit purine nucleotide synthesis
- prevents proliferation
- Acts within de novo and salvage pathways
6-MP is metabolized by several pathways, one of which is xanthine oxidase
Azathioprine AE
Hematologic- leukopenia, anemia, thrombocytopenia
N/V (take with food)
Alopecia, hepatotoxicity, pancreatitis
Azathioprine dosing
Oral- initial doses are weight based and dosed QD
Doses decrease with time away from transplant
IV=PO
Titrated to WBC count 3500-6000 (low-normal)
Mycophenolate
Mycophenolate mofetil (MMF) Enteric-coated mycophenolate sodium (EC-MPS)
Both are prodrugs for mycophenolic acid (MPA)
MMF is rapidly converted into MPA by 1st pass metabolism (desterification)
EC-MPS is released in small intestine
Mycophenolate MOA
MPA inhibits inosine monophosphate dehydrogenase (IMPDH)
-This inhibits lymphocyte proliferation
More specific than AZA for lymphocytes
Mycophenolate metabolism and elimination
After oral intake there is a rapid hydrolysis to MPA, seen as first peak concentration
MPA is converted back into MPAG in liver and some of it goes into enterohepatic recirculation appearing as a “second peak”
Complex metabolism=no trough levels
Excreted by the kidneys as either MPA or MPAG
Both metabolites may accumulate with renal insufficiency
Mycophenolate AR
GI: N/V/D, abdominal pain, peptic ulcers
-Take on an empty stomach (decreases Cmax with food) but food does not affect the overall AUC so you can take with or w/o food
Leukopenia, anemia
Mycophenolate dosing
Given BID, can split up more frequently prn for GI AE
MPA AUC equations are available
mTOR inhibitors
Sirolimus and Everolimus
Structurally related to macrolide abx and tacrolimus
-Diff MOA as TAC so can be used together
MOA: Inhibit mammalian target of rapamycin and inhibit vascular endothelial growth factor
Sirolimus
Poor absorption
Variably affected by food- take consistently with regard to food
Metabolism- CYP 3A4 and p-glycoprotein substrate
Mean 1/2 life of 60hrs
Time to steady state- 2 wks
Trough concentrations 1-2 weeks after dose changes
Sirolimus AE
Leukopenia, anemia, thrombocytopenia (dose related) Hyperlipidemia (particularly TGs) Delayed wound healing Mouth ulcers Interstitial pneumonitis Hepatic artery thrombosis after OLTXP Proteinuria
Sirolimus dose
Loading doses may be given if needed to get to therapeutic levels quickly
Dosed QD
Titrated to trough levels 5-25ng/mL
No IV formulations
Everolimus
2 types: kidney and liver transplant (tab), oncology (tabs and tabs for suspension)
Everolimus metabolism, ARE, dosing
Metabolism- Substrate of CYP3A4 and P-glycoprotein
1/2 life- 30 hours
Similar AE to sirolimus, but slightly better
Dosed BID
Titrated to trough levels 3-8ng/mL
Corticosteroids
Methylprednisolone and prednisone
Broad spectrum immunosuppressants
Decrease adhesion molecule synthesis
Inhibit transcription factors
Corticosteroids metabolism
Hepatic, active metabolite- prednisolone
Long biologic 1/2 life- give QD
Corticosteroids AE
Hyperglycemia, osteoporosis, cataracts, acne, CNS stimulation, HPA axis suppression, acid reflux, GI ulceration
Corticosteroids dose
Initially given in very high doses
Gradually tapered
Usual maintenance doses <10mg/day
Combination with other IS agents for lower doses
Monoclonal and Polyclonal antibodies
Target various immune cell surface markers, particularly on B and T lymphocytes
Indications vary- induction agents and acute rejection
Alemtuzumab
Mech- Anti-CD 52 monoclonal antibody
-causes antibody-dependent cellular-mediated lysis
Uses- B-cell chronic lymphocytic leukemia
Txp- induction therapy and acute rejection
Alemtuzumab dosing and AE
One dose IV injection on day of transplant
AE: neutropenia, anemia, thrombocytopenia, infusion reactions
Basiliximab
Chimeric- mouse-human monoclonal antibody Mechanism- IL-2receptor antagonist Use for induction therapy only Given IV x 2 doses AE- infusion reactions rare
Additional MABs used in kidney transplant
Rituximab-anti CD20 antibody, eliminates B lymphocytes
Use to treat rejection
Eculizumab- binds to compliment protein
Prevents compliment-mediated damage that can occur with rejection
Rabbit antithymocyte Globulin (rATG)
Polyclonal
Manufactured by introducing human lymphoid tissue into rabbits
Causes T cell depletion
Used in induction therapy and for tx of acute T cell-mediated rejection
Antithymocyte Globulin
Given in slow IV infusion for 3-14 days
AE: neutropenia, anemia, thrombocytopenia, infusion rxns, thrombophlebitis, serum sickness
ATG (equine) and IV immune globulin polyclonal antibodies
ATG- similar to rATG but less effective
IVIG0 multiple mechanisms to reduce circulating HLA antibody levels
Proteosome inhibitors
Bortezomib and Carfilzomib
Reversibly (B) or irreversibly (C) bind to intracellular proteasomes
Causes cell death in a variety of cell types that are dependent on proteasome function (plasma cells)
Elimination of plasma cells reduces antibody function
Hyperacute rejection
occurs minutes to hours after organ reperfusion
Requires preformed circulating antibodies
Crossmatch and blood matching techniques make this very rare
Acute rxn
3 subtypes: T cell-mediated (cellular), antibody mediated, or mixed
Can occur any time 1 week or longer
Diagnosed via biopsy
May or may not be reversible
Creating IS regimens
Combine drugs that act in different areas of the 3-signal model
+/- induction therapy- varies by organ
Maintenance therapy- CNA (CSA/TAC) or belatacept + antiproliferative (AZA, MMF, mTOR) + prednisone
Most common: TAC+ MMF+ Pred
Gluconeogenesis
Production of glucose from noncarbohydrate precursors
Glycogenesis
Conversion of glucose to glycogen for storage
Glycogenolysis
Breakdown of stored glycogen to glucose
Glycolysis
Breakdown of stored glycogen to glucose
Pancreatic islet cells
The pancreatic islet cells and their endocrine precursors:
alpha- glucagon
beta- insulin, amylin
delta- somastatin
The exocrine pancreas is involved in digestion
How does glucagon raise blood glucose
It stimulates glycogenolysis and gluconeogenesis
It also stimulates fat breakdown
How does insulin lower blood glucose?
Insulin is anabolic (a builder)
It stimulates glucose uptake
It suppresses glucose produced by the liver
It suppresses free fatty acids (FFA) release from fat cells. FFAs inhibit uptake of glucose and stimulate gluconeogenesis. Chronic FFa release will cause insulin resistance
Insulin suppresses glucagon release
Fasting state
Glucose-disposal
Non-insulin dependent tissues (75%)
Liver and muscle (25%)
Glucose production primarily in liver
Non-insulin dependent tissues
Beta cells Red blood cells Intestines Central nervous system Kidney
Fed state
Glucose disposal
Muscle- 80-85%
Adipocyte- 4-5%
Do mild physical activity after eating to stimulate glucose disposal
Pathogenesis of Type 1 Diabetes
Autoimmune disease with progressive beta cell destruction, resulting in physiologic dependence on exogenous insulin
Stage 1 Type 1 Diabetes
Characteristics- autoimmunity, normoglycemia, presymptomatic
Diagnostic criteria- Multiple antibodies, no IGT or IFG
Stage 2 Type 1 diabetes
Characteristics- autoimmunity, dysglycemia, presymptomatic
Diagnostic criteria- Multiple antibodies, Dysglycemia: IFG and/or IGT
FBG: 100-125mg/dL
A1C: 5.7-6.4% or greater than 10% increase
Stage 3 Type 1 Diabetes
Characteristics- New-onset hyperglycemia, symptomatic
Diagnostic criteria- Clinical symptoms, diabetes from normal criteria
Coexistent autoimmunity in type 1 diabetes
Celiac disease- have gluten free diet
Thyroid disease, generally hypothyroidism
Pathogenesis of Type 2 diabetes
Caused by multiple defects:
- Impaired insulin secretion
- Insulin resistance involving muscle, liver, and adipocytes
- Excess glucagon secretion
- Deficiency and resistance to insulin hormones
- Sodium0glucose cotransporter upregulation in the kidney
Insulin secretion
Glucose gets into the cells and closes the ATP-K channel, this opens the Ca channel and insulin is released
Insulin is not involved in glucose getting into beta cells
What phase of insulin response is impaired in T2DM?
Phase 1- insulin is not being stored completely
Impaired insulin secretion T2DM
Beta cell mass and function is reduced
This failure is progressive, there is a 5-7% loss of beta cells per year
-Caused by glucose toxicity, age, lipotoxicity, insulin resistance, genetics, incretin deficiency
Glucose toxicity
As glucose increases insulin increases. Glucose is toxic to beta cells and they can’t keep up with chronically high levels of glucose, causing loss of cells and function
Insulin Resistance T2DM
Liver- Hepatic glucose production increased in mild to moderate fasting hyperglycemia.
-Failure to suppress glucagon in response to a meal (two sources of glucose production in fed state)
Peripheral (skeletal muscle)- major site of postprandial glucose disposal. Onset of insulin action is delayed for about 40 minutes. Glucose uptake reduced by 50%
Peripheral (adipocyte)- Fasting plasma FFA levels increased and fail to suppress after glucose ingestion. FFAs stored as TGs in adipocytes and insulin is a potent inhibitor of lipolysis
Obesity and insulin resistance
Weight gain leads to insulin resistance
Visceral adipose tissue (VAT)
-fat cells located w/in abdominal cavity
-correlates with insulin resistance
-waste circumference is good marker
-Higher rate of lipolysis means increased FFA production
-Produces adipocytokines, increased FFA production
-Produces adipocytokines, causing insulin resistance, HTN, and hypercoagulability
Glucagon secretion T2DM
Failure to suppress glucagon after a meal
Paradoxical rise in glucagon levels because of insulin resistance and GLP-1 resistance
The incretin effect
Glucagon-like peptide-1 (GLP-1) is secreted by L cells
- Levels decreased in T2DM
- Stimulated insulin secretion and suppresses glucagon secretion.
- Slows gastric emptying
- Reduces food intake by increasing satiety
Glucose-dependent insulinotropic peptide (GIP)- secreted by K cells
- Insulin secretion during near-normal glucose levels
- insulin sensitizer in adipocytes
Characteristics of diagnosis for Type 1 Diabetes Age C-peptide ICA, GAD65, IA-2, IAA Circulating Insulin Time to requiring insulin
Age- <35 C-peptide- Very low ICA, GAD65, IA-2, IAA- Often positive Circulating Insulin- Rapidly deficient Time to requiring insulin- At onset
Characteristics of diagnosis for Type 2 Diabetes Age C-peptide ICA, GAD65, IA-2, IAA Circulating Insulin Time to requiring insulin
Age- >35
C-peptide- Normal to high
ICA, GAD65, IA-2, IAA- Negative
Circulating Insulin- Excessive and resistant
Time to requiring insulin- Can be many years
Characteristics of diagnosis for LADA Age C-peptide ICA, GAD65, IA-2, IAA Circulating Insulin Time to requiring insulin
Age- >/= 30 C-peptide- Low ICA, GAD65, IA-2, IAA- Can be positive Circulating Insulin- Gradually resistant Time to requiring insulin- Within 6 months (variable)
Gestational Diabetes Mellitus (GDM)
Any degree of glucose intolerance with on set or first recognition during pregnancy
- Test for GDM at 24-48 weeks of gestation in pregnant women not previously known to have diabetes (A)
- Test for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors (B)
If first trimester, it is T2DM not GDM
Second trimester, GDM unless clearly otherwise
Screening for GDM
75g glucose load, check fasting levels 1 hr and 2 hr after.
Diagnosis if fasting- 95mg/dL
1hr- 180mg/dL
2 hr- 155mg/dL
3hr- 140mg/dL
Long term risk of GDM
Strongest known predictor of T2DM- 50% diagnosed 10 years postpartum
Test women with GDM for prediabetes or diabetes at 4-12 weeks postpartum
2/3rds chance of GDM in future pregnancies
Increased lifetime risk of HTN and stroke
Medications related to hyperglycemia
Fluoroquinolones (cipro) Atypical antipsychotics (Risperidone, quetiapine, olanzapine) Beta-blockers Glucocorticoids Calcineurin inhibitors Protease inhibitors Thiazides and thiazide like diuretics
Criteria for diabetic testing in asymptomatic adults
Testing should be considered in overweight or obese adults who have one or more of the following risk factors: -1st degree relative with diabetes -History of CVD -HTN -Hyperhcolesterolemia -Women with PCOS - Physical inactivity -High risk ethnicity Begin testing at 45 for all patients Test q 3 years for women that have had GDM Prediabetics should be tested yearly All other patients should be tested q 3 years
Clinical presentation of diabetes
Polyuria Polydipsia Polyphagia Lethargy/fatigue Weight loss Blurred vision
Diagnostic criteria for diabetes
A1C- >/= 6.5%
FPG- >/= 126mg/dL
2-hr PG- >/= 200mg/dL during an OGTT
Classic symptoms of hyperglycemia and random PG >/= 200mg/dL
Diagnostic criteria for prediabetes
A1C- 5.7-6.4%
FBG- 100-125mg/dL
2-h PG- 140-199mg/dL
Hemoglobin A1C
Glucose enters erythrocytes and glycates amino terminals of hemoglobin
- Represents glycemic exposure over 2-3 months
- Does not require fasting
- Levels may vary with race/ethnicity
- Hemoglobinopathies/RBC turnover
Estimated average blood glucose (eAG) eqn
eAG= 28.7 x A1C -46.7
Strengths of A1C
Reflects chronic hyperglycemia
Less biologic variability than 1-2h glucose
Eliminates need for fasting
Unaffected by acute illness or recent activity
Used as a guide to adjust treatment
Better predictor of complications that fasting BG
Limitations of A1C
Certain conditions interfere with the interpretation of results (hemolytic anemia, recent transfusion, pregnancy, loss of blood)
Lack of standardization in other countries
Cost
Symptoms of hypoglycemia
Tremor, nervous/anxious, diaphoresis, tachycardia, hunger, lightheaded/HA, irritable, confusion, drowsiness
Hyperglycemic crisis
Type 1- diabetic ketoacidosis
Type 2- Hyperglycemic hyperosmolar state
Microvascular complications of diabetes
Retinopathy
Nephropathy
Peripheral neuropathy
Autonomic neuropathies (gastroparesis, erectile dysnfunction)
Macrovascular complications of diabetes
CAD, cerebrovascular disease, peripheral artery disease
DCCT trial
Intensive treatment of decreasing A1Cs decreases the risk of microvascular complications but not macrovascular
ADA glycemic targets
A1C- <7%
Preprandial- 80-130mg/dL
Peak postprandial PG- <180mg/dL
Monitoring for diabetes
Perform the A1C test at least 2 times a year in patients who are meeting treatment goals and who still have glycemic control
-Perform A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic control
Self-monitoring of blood glucose
Intensive insulin regimen- prior to meals/snacks, bedtime, occasionally postprandially, prior to exercise, when hypoglycemia expected, after treating hypoglycemia, prior to critical tasks (driving)
Continuous glucose monitoring
Measures interstitial glucose
Real-time CGM- continuously report glucose levels. Alarms for hypo and hyperglycemia
Intermittently scanning CGM (isCGM)- adult use only, no alarms, lower cost, does not communicate continuously
Limitations- Invasive, some require daily calibrations, requires very motivated pts
CGM- based targets
Goal target range 70-180 and be in this range >/= 70% of the time
Risks of uncontrolled diabetes in pregnancy
Spontaneous abortion Fetal anomalies Preeclampsia Fetal demise Macrosomia Neonatal hypoglycemia Neonatal hyperbilirubinemia
Pregnancy diabetes recommendations
A1C- <6.5%
Preconception counseling
Medication evaluation
Preeclampsia and aspirin
Women with type 1 and type 2 diabetes should be prescribed low dose aspirin from the end of the first trimester until the baby is born in order to lower risk of preeclampsia
Childrens and adolescents with diabetes
Mainly Type 1
Insulin doses may need to change based on sexual maturity and physical growth
Assess the ability to provide self-care
Supervision in childcare/school
Neurological vulnerability to hypoglycemia/hyperglycemia
Less stringent A1C goals than other pts due to risk of hypoglycemia
Older adults diabetes
Less stringent A1C goals
Cystic fibrosis related diabetes (CFRD)
Associated with worse nutritional status, more severe inflammatory lung disease, greater mortality.
Primary defect is insulin insufficiency related to partial fibrotic destruction of the islet mass
Annual screenings should begin at age 10 with OGTT
Do not use A1C
Patients should be treated with insulin!
Posttransplantation Diabetes Mellitus (PTDM)
Describes presence of diabetes in posttransplant setting irrespective of timing to diabetes onset
OGTT= gold standard test
Angioplasty
Damage of blood vessels
Microvascular disease
Damage to small blood vessels
Macrovascular disease
Damage to the arteries
Macrovascular complications of diabetes
Cerebrovascular disease, CAD, peripheral vascular disease
Microvascular complications of diabetes
Retinopathy, Nephropathy, autonomic neuropathy, peripheral neuropathy
What is the mechanism behind complications in diabetes?
Chronic exposure to hyperglycemia
-Interaction of glucose with proteins causes advanced glycosylation end products and leads to tissue damage and injury
-Accumulation of metabolic products of aldose reductase system affects cellular energy metabolism and contributes to cell injury and death
ASCVD
Acute coronary syndromes H/O MI Stable or unstable angina Coronary or other arterial revascularization Stroke Transient ischemic attack Peripheral arterial disease
ASCVD and HTN
HTN is a major risk factor for ASCVD and microvascular complications
Type 1 diabetes- often underlying nephropathy
Type 2 diabetes- coexists with other cardiometabolic risk factors
BP goals for diabetes patients
ACC/AHA- <130/ <80
ADA
Diabetes + HTN+ 10-year risk >15%- <130/<80
Diabetes + HTN + 10 year risk <15%- <140/<90
Diabetes + BP <160/100 treatment
Lifestyle management
Start with one agent
Albuminuria? Yes- ACE/ARB
No- ACE/ARB/CCB/Thiazide
Diabetes + BP >160/100 treatment
Lifestyle management
Start with 2 agents
Albuminuria? Start ACE or ARB + thiazide or CCB
no- Any 1st line agents
ASCVD lipid management
Increased prevalence of lipid abnormalities in T2DM
Low HDL associated with high TG
Use statin
Statin benefit groups
- ) Clinical ASCVD
- ) Primary elevation of LDL >190mg/dl
- ) 40-75 yo w/ diabetes w/ LDL 70-189mg/dL
- ) W/O clinical ASCVD or diabetes aged 40-75 w/ LDL 70-189mg/dL and 10 year risk >7.5%
What intensity statin should be recommended for statin benefit groups?
Moderate to high intensity
ADA statin recommendations primary prevention
40-75= moderate intensity statin
20-39 w/ ASCVD risk factors= may be reasonable Multiple ASCVD risk factors or 50-79= High-intensity statin
ASCVD risk >20% and LDL reduction <50%= add ezetimibe
ADA statin recommendations secondary prevention
High-intensity statin
Very high risk and LDL>70= add ezetimibe or PCSK9 inhibitor
ASCVD risk factors
LDL >100mg/dL HTN Smoking CKD Albuminuria Family h/o premature ASCVD
Vascepa
Icosapent ethyl (Vascepa)
FDA approval in 2019 for pts with controlled LDL on a statin but elevated TG (135-499)
REDUCE-IT trial
Fibrates and Niacin
Combination therapy with statin has not been shown to improve ASCVD outcomes or provide additional CV benefit and is generally not recommended
ASCVD antiplatelet agents
Everyone should be on an aspirin for secondary prevention
Primary prevention based on risk factors
Diabetic nretinopathy
Prevalence strongly related to duration of diabetes and glycemic control
Chronic hyperglycemia, nephropathy, HTN, dyslipidemia all increase risk
Nonproliferative diabetic retinopathy (NPDR)
Hyperglycemia contributes to changes in the integrity of blood vessels within the retina
Alterations in blood-retinal barrier and vascular permeability
Release of angiogenic factors related to hypoxia and ischemia
Occlusion of retinal capillaries
Proliferative diabetic retinopathy (PDR)
Neovascularization and accumulation of fluid within the retina (macular edema) contribute to vision impairment
Stages of diabetic retinopathy
Mild nonproliferative- microaneuryisms
Moderate nonproliferative- some blood vessels in retina become blocked
Severe nonproliferative- many blood vessels blocked. New blood vessels begin to form.
Proliferative- New BV have thin and weak walls and leak. This causes severe vision loss and potential blindness.
Screening for diabetic retinopathy
Type 1- at least w/in 5 years of onset
Type 2- at onset
After onset screen yearly
Diabetic nephropathy
Leading cause of ESRD
Caused by hemodynamic alterations in renal microcirculations and structural changes in glomerulus
Screening for diabetic nephropathy
Assess UACR and eGFR annually
Twice annually if UACR >30 and/or eGFR <60
Treatment for diabetic kidney disease
Glycemic and BP control
ACE/ARB not recommended for primary prevention
ACE/ARB recommended for UACR >30
Non-dialysis pts protein intake should be 0.8g/kg/day
Diabetic neuropathy
Distal symmetric polyneuropathy (DSPN)
other autonomic neuropathies
DSPN
Symptoms vary
small fibers- pain, burning, tingling
large fibers- numbness and loss of protective sensation
Screen annually
DSPN treatment
Pregabalin, duloxetine, gabapentin all 1st line
Diabetic foot care
Annual food exam
therapeutic footwear
screen for PAD
Do Ankle-brachial index testing
Ankle-brachial index testing (ABI)
Normal: 0.9-1.30 Mild obstruction- 0.7-0.9 Moderate obstruction- 0.40-0.69 Severe obstruction- <0.40 Poorly compressible >1.3
Peripheral artery disease
Needs to be on antiplatelet therapy (clopidogrel or aspirin)
Preventative foot care
Autonomic neuropathies
Cardiovascular autonomic neuropathy- resting tachycardia (>100bpm)
Orthostatic hypotension
GI- constipation, gastroparesis
GU- erectile and bladder dysfunction
Gastroparesis
Food stays in a diabetic pts stomach longer
Tx- small meals, low-fat, low-fiber, 4-5 times per day
Prokinetic agents- metoclopramide and erythromycin
Immunizations for diabetes pts
Influenza
Pneumoccocal
Hep B
