Definitions of the recommendation and evidence level grades (1A to 2C) are provided at the end of the "Major Recommendations" field.
A1C
Screen
Check hemoglobin A1C (A1C) 2 to 4 times a year as part of the scheduled medical visit, with frequency dependent upon revision of treatment program and the need to reinforce behavior changes. Increase frequency when therapy has changed and/or when glycemic goals are not met. Having the A1C result at the time of the visit can be useful in making timely treatment decisions. [1C]
A1C target goal should be individualized for each patient; aiming to achieve the lowest possible level may be modified based upon presence or absence of microvascular and/or macrovascular complications and life expectancy. [1A]
Goal
The true goal of care is to bring A1C as close to normal as safely possible. [1C]
A goal of < 7% is chosen as a practical level for most patients using medications that may cause hypoglycemia to avoid the risk of that complication. Achieving normal blood glucose is recommended if it can be done practically and safely. [1B]
Joslin's A1C goal is consistent with that of the American Diabetes Association (ADA). Other expert panels, such as American Association of Clinical Endocrinologists/International Diabetes Federation (AACE/IDF) suggested in August 2001 that the goal of treatment should be ≤ 6.5%.
Treatment
If A1C is > 7% and <8%, or above the individualized goal for 6 or more months:
- Review and clarify the management plan with the patient with attention to:
- Meal plan [1B]
- Activity program [1A]
- Medication administration schedule, technique and practices [1A]
- Self-monitoring blood glucose (SMBG) schedule and technique [1A]
- Treatment for hypoglycemia and hyperglycemia
- Sick day management practices
- Reassess goals and adjust medication as needed [1A]
- Communicate individualized glycemic goals to patient
- Consider referring patient to diabetes educator (DE) for evaluation, diabetes self-management education (DSME) and ongoing consultation [2A]
- Consider referring to registered dietitian (RD) for medical nutrition therapy (MNT) [2B]
- Schedule follow-up appointment within 3 to 4 months or more frequently as situation dictates
If A1C is ≥ 8%:
- Review and clarify the plan as previously noted [1B]
- Assess for psychosocial stress [1C]
- Refer patient to DE for evaluation, DSME and ongoing consultation. Document reason if no referral initiated. [1A]
- Intensify therapy
- Refer patient to RD for MNT [1B]
- Communicate individualized glycemic goals to patient
If history of severe hypoglycemia or hypoglycemia unawareness (a condition in which the patient is unable to recognize symptoms of hypoglycemia until they become severe):
- Assess for changes in daily routine such as decreased food intake or increased activity [1C]
- Refer to diabetes educator for evaluation, DSME and hypoglycemia prevention; encourage family/friend attendance
- Review use of glucagon
- Consider loosening A1C goal [2C]
- Communicate goals to patient
- Adjust medications accordingly
- If insulin-treated, consider use of a more physiologic insulin replacement program [1C]
- Consider and screen for other medical causes [1C]
- Consider referral for blood glucose awareness training, if available [1B]
- Schedule follow-up appointment within 1-2 months. If history of recent, severe hypoglycemia or change in pattern of hypoglycemia, recommend increase in frequency of communicating blood glucose levels to physician or diabetes educator. [1B]
Glucose Monitoring
Self-monitoring of blood glucose (SMBG) is an important component of the treatment program for all people with diabetes. Its use is to gauge treatment efficacy, help in treatment design, provide feedback on the impact of nutritional intake and activity, provide patterns that assist in medication selection, and for those on insulin, assist in daily dose adjustments. [1A]
The frequency of SMBG is highly individualized and should be based on such factors as glucose goals, medication changes and patient motivation. Most patients with type 1 diabetes should monitor at least 3 times per day [1A]; for patients with type 2 diabetes, the frequency of monitoring is dependent upon such factors as mode of treatment and level of glycemic control. [1C]
In order to obtain meaningful data for treatment decisions, it is helpful for the patient to monitor several days (e.g., 2 to 4) in a row. Often, obtaining readings 2 hours postprandially is useful, particularly during these periods of intensive monitoring, as postprandial hyperglycemia has been implicated in increased macrovascular risk. [1A]
It is recommended for patients who:
- Have an elevated A1C but fasting glucose is on target.
- Are starting new intensive insulin treatment regimens or who are experiencing problems with glycemic control.
- Are using glucose-lowering agents targeted at postprandial glucose such as repaglinide, nateglinide, exenatide or pramlintide.
- Are making dietary and exercise changes as an evaluation tool.
Encourage the patient to bring SMBG results (written record or meter for downloading) at each visit for review with provider/educator.
Hypoglycemia
Prompt action is recommended for the treatment of hypoglycemia. When possible, the patient should confirm symptoms with SMBG to document hypoglycemia. All patients with type 1 diabetes should ensure that a family member/companion/caregiver knows how to administer a glucagon injection in the event the patient is unable or unwilling to take carbohydrate orally. [1C]
Symptoms of hypoglycemia include: sweating, tremor, palpitations, dizziness, confusion, tiredness, inability to concentrate, difficulty speaking.
Treatment
- If patient is symptomatic or unable to confirm hypoglycemia with SMBG, or if blood glucose levels are <70 mg/dl (< 90 mg/dl at bedtime or overnight), treat it as mild-moderate hypoglycemia.
- Caution patient to avoid alternate site testing with blood glucose meter.
- For mild to moderate hypoglycemia (plasma glucose 51 to 70 mg/dl), begin with 15 to 20 grams carbohydrate (1/2 cup juice or regular soft drink, 3 to 4 glucose tabs, or 8 to 10 hard candies). If glucose level is ≤50 mg/dl, consume 20 to 30 grams carbohydrate. [1C]
- Recheck blood glucose after 15 minutes. [1B]
- Repeat hypoglycemia treatment if blood glucose does not return to normal range after 15 minutes. [1C]
- Follow with additional carbohydrate or snack if next meal is more than one hour away. [1C]
- If hypoglycemia persists after second treatment, patient or companion should be instructed to contact healthcare provider.
- In event of severe hypoglycemia (altered consciousness, unable to take carbohydrate orally, or requiring the assistance of another person) treat with glucagon and/or intravenous glucose. [1C]
- For patients with hypoglycemia unawareness, the threshold for treatment of hypoglycemia needs to be individualized. [2C]
Education
- Wear or carry diabetes identification.
- Inform patient of need to check blood glucose before driving, periodically during a long drive, and when operating heavy machinery. [1B]
- Instruct patient to carry treatment for hypoglycemia at all times.
- Identify possible causes of hypoglycemia in order to prevent it. [1C]
- Be clear in communicating modified treatment goals in individuals with hypoglycemia unawareness (see section in original guideline document on Hypoglycemia Unawareness). [1C]
Diabetes Self-Management Education (DSME)
Individuals with newly diagnosed diabetes should receive:
- DSME according to National Standards for Diabetes Self-Management Education [1A]
- Individualized Medical Nutrition Therapy (MNT) [1A]
- Multiple visits to evaluate progress towards goals [1A]
Individuals with existing diabetes should receive:
- An annual assessment of DSME and MNT, preferably by a trained Diabetes Educator [2B]
- Initial and ongoing assessment of psychosocial issues [1C]
Renal Disease and Macro-Micro Albuminuria
Screen
Measure serum creatinine at least annually to estimate glomerular filtration rate (GFR) regardless of degree of urine albumin excretion. (See the Joslin Diabetes Center & Joslin Clinic Guideline for Specialty Consultation/Referral). [1C]
Screen for micro/macro albuminuria by checking urine albumin/creatinine (A/C) ratio as follows:
- Type 1 patients 5 years after diagnosis and then yearly [1C]
- Type 2 patients at diagnosis (after glucose has been stabilized) and then yearly [1C]
- Annually in all patients up to age 70 years [2C]
- As clinically indicated in patients > 70 years of age
Micro/macro albuminuria is recognized as a major independent risk factor for coronary heart disease in patients with diabetes. Albuminuria may be measured with a spot or timed urine collection. Spot urine is preferred.
Continue use of routine urinalysis as clinically indicated. [2C]
Treatment
If A/C ratio < 30 mcg/mg or timed urine 30 mg/24 hr:
If A/C ratio 30-300 mcg/mg or timed urine 30-300 mg/24 hr:
- Confirm presence of microalbuminuria with at least 2 of 3 positive collections done within 3 to 6 months. In the process, rule out confounding factors that cause a false-positive such as urinary tract infection (UTI), pregnancy, excessive exercise, menses or severe hypoglycemic event. [1C] Consider testing first morning urine.
- Consider consult with nephrology team for blood pressure control, successive increases in microalbumin and other issues (i.e., GFR < 60 ml/min) [2C]
- Once confirmed:
- Evaluate blood pressure (BP) and initiate/modify aggressive blood pressure treatment to achieve a BP of < 130/80 mmHg [1A]
- Recommend patient self-monitor BP with portable cuff and maintain a record/log. The monitoring schedule should be determined with physician and is based on patient circumstance
- Strive to improve glycemic control with an optimal goal A1C of < 7% or as otherwise clinically indicated for individual patients [1A]
- Refer to diabetes educator for glucose management
- If microalbuminuria persists, initiate/ modify angiotensin converting enzyme (ACE) inhibitor or angiotensin II antagonist treatment. Check K+ and creatinine 1 to 2 weeks after making changes. [1A]
- Repeat A/C ratio at least every 6 months. Consider increase in frequency when changes in medication are made. [2C]
If A/C ratio > 300 mcg/mg (> 300 mg/24 hr) or proteinuria (positive dipstick for protein or ≥ 30 mg/dl):
- Follow all guidelines as stated for A/C ratio 30 to 300 mcg/mg
- Consider BP goal of < 125/75 mmHg [2B]
- Consult with nephrology if: [1C]
- Rapid rise in serum creatinine, abnormal sediment, or sudden increase in proteinuria
- Creatinine is elevated (> 1.8 mg/dl in women, > 2.0 mg/dl in men)
- Refinement of treatment program needed to prevent further deterioration
- Problems with ACE inhibitors, difficulties in management of high BP, or hyperkalemia
- If questioning etiology of nephropathy
- Creatinine clearance < 60 ml/min
- Difficulties in management of hyperphosphatemia
- Anemia due to renal disease
- Consider reducing protein in the diet [1B]
Cardiovascular Health
(Also see sections on Lipids, Blood Pressure, and Smoking)
Treatment
A daily enteric-coated aspirin (ASA) (75 to 325 mg) as a primary prevention strategy for everyone > 40 years of age [1A]; also for men and women ≥ 30 years of age [1C] with any ONE of the following risk factors:
- Family history of premature* coronary artery disease (CAD) or stroke
- Hypertension (HTN)
- Current cigarette smoker
- Micro/macro albuminuria
- Hyperlipidemia
*Premature – 1st degree male relatives younger than 55; 1st degree female relatives younger than 65
Recommend ASA (unless contraindicated) as a secondary prevention for everyone with: [1A]
- History of myocardial infarction; angina or documented CAD
- Vascular bypass
- Non-hemorrhagic stroke
- Transient ischemic attack (TIA)
- Peripheral vascular disease (PVD)
(Possible contraindications for ASA therapy may include allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding and clinically active hepatic disease). Eye disease is usually not a contraindication for ASA therapy.
Consider using beta-blocker in all patients with a history of MI or with documented CAD unless contraindicated. [1A]
Consider recommending aerobic exercise if not clinically contraindicated and a weight-loss program if overweight or obese. [1A]
Consider using ACE inhibitors (or angiotensin receptor blockers [ARBs] if ACE inhibitors not tolerated) in patients with known CAD or cardiovascular risk factors. [1A]
Lipids
Screen
Adults should be screened annually for lipid disorders with measurements of serum cholesterol, triglycerides, and low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, preferably fasting. [1C]
Lipid Goals (mg/dl)
LDL-cholesterol (LDL-C):
< 100 if no diagnosed cardiovascular disease (CVD) [1A]
< 70 if diagnosed CVD [1B]
HDL-cholesterol (HDL-C):
> 40 (men); >50 (women) [2C]
Triglycerides: < 150 (fasting) [2C]
Treatment
All patients should receive information about a meal plan designed to lower blood glucose and improve lipids, physical activity recommendations, and risk reduction strategies. Consultation with appropriate education discipline is preferred. [1A]
Institute therapy after abnormal values are confirmed.
For patients in whom CVD is not yet diagnosed
If LDL-C ≥100 mg/dl:
- Optimize glycemic control [1A]
- Refer to registered dietitian for intensive dietary modification; therapeutic lifestyle changes (TLC) [1A]
- Consider referral to exercise specialist or DE for exercise prescription
- Recheck lipids within 6 weeks
- If LDL-C remains >100, initiate medication with goal of lowering LDL-C by at least 30% or to < 100, whichever is lower, preferably with a statin [1A]
If LDL-C < 100 mg/dl:
Consider statin therapy if age > 40 yrs and one more CVD risk factor is present (hypertension, smoking, albuminuria or family history of premature CVD). [1A]
Patients with LDL-C < 100 mg/dl and fasting triglycerides ≥ 150 mg/dl or HDL-C ≤ 40 mg/dl:
- Optimize glycemic control [1A]
- Refer to RD for dietary modification; TLC [1A]
- Consider referral to exercise specialist for exercise prescription
- Recheck lipids within 6 weeks
- Consider medication if fasting triglycerides >200 mg/dl and/or HDL-C ≤ 40 mg/dl (fibrate preferred if fasting triglycerides > 500 mg/dl) [2C]
- In patients with fasting triglyceride levels 200-499 mg/dl, calculate non-HDL-C (total cholesterol minus HDL-C) and consider starting or titrating statin if non-HDL-C >130 [1C]
- Consider adding fibrate or niacin if fasting triglycerides > 200 and/or HDL-C ≤ 40 mg/dl, and LDL/non-HDL-C at goal. [2C]
- Initiate treatment with very low fat diet and fibrate if triglycerides > 1000 mg/dl for prophylaxis against acute pancreatitis; rule-out other secondary causes; reassess lipid status when triglycerides < 500 mg/dl. [1A]
Patients with cardiovascular disease (CVD)
If LDL-C ≥ 70 mg/dl:
- Optimize glycemic control [1A]
- Refer to RD for intensive dietary modification; TLC [1A]
- Consider referral to exercise specialist or DE for exercise prescription [1A]
- Consider starting lipid lowering agent (preferably statin) immediately if LDL-C is > 100. [1A]
- Recheck lipids within 6 weeks.
- If LDL-C remains > 70, initiate medication (preferably statin) with goal of lowering LDL-C to < 70. May require combination of statin with another lipid lowering agent to achieve this goal. [1B]
Blood Pressure
Screen
Check BP at all routine visits with patient sitting for 5 minutes. Use proper-sized cuff.
Postural BP should be checked initially as clinically indicated and if orthostatic, check at each follow-up visit. [1C]
- Orthostatic hypotension: defined as a fall in systolic BP (SBP) of 20 to 30 mmHg or diastolic BP (DBP) of 10 to 15 mmHg upon change in position
- Acute hypertension (>180/110 mmHg) warrants immediate attention [1C]
Goal
- BP goal for each patient >18 years old is <130/80 mmHg and modified for comorbidities [1B]
- BP goals for patients with proteinuria > 1 gm is < 125/75 mmHg [1C]
- Initial goal for patients with isolated systolic hypertension (SBP >180 mmHg & DBP < 80 mmHg) is a SBP <160 mmHg
- Initial goal for patients with SBP 160 to 179 mmHg is to lower SBP by 20 mmHg. If well tolerated, lower BP goals may be indicated. [1B]
- Strong evidence suggests significant benefits to be gained if BP < 130/80 mmHg [1B]
Treatment
If SBP 130-139 mmHg or DBP 80-89 mmHg, a 3-month trial of behavioral therapy is warranted, including: [1C]
- Counseling about meal plan, exercise, weight loss, sodium reduction, alcohol and stress reduction
- Consider referral to RD for MNT
- Encourage home BP monitoring
- Instruct patient to have BP checked on 3 separate occasions before next appointment
- Follow-up with healthcare provider within 2 to 4 weeks
- If BP remains above goals, initiate or adjust therapy with antihypertensive agents as clinically indicated
- Studies have shown that aggressive management and control of blood pressure may result in long-term benefits.
- If BP remains > 130/80 mmHg after 3 months of attempted lifestyle modification, or if BP > 140/90 mmHg at initial visit, add a pharmacological agent to behavioral modification.
Drug Therapy
- In choosing an initial anti-hypertensive drug, the most important thing is that it be efficacious. In that sense, any available antihypertensive drug can be an appropriate choice. However, other considerations (cost, presence of proteinuria, or co-existing CAD) dictate a preference for ACE inhibitors, ARBs, beta-blockers and diuretics. [1A]
- ACE inhibitors or ARBs are the drugs of choice for patients with evidence of nephropathy. These drugs require monitoring of serum creatinine and K+ within 1 week of starting therapy and periodically thereafter. [1A]
Smoking
Assess patient's smoking status on a routine basis.
Treatment (If patient smokes)
- Discuss rationale for and strongly recommend smoking cessation [1A]
- Review options available to assist in smoking cessation, including medications and cessation programs [1B]
Feet
Screen
Screening should include: (1) a foot evaluation for sensorimotor (monofilament), skin and soft tissues integrity, vascular sufficiency (pedal pulses) and biomechanic integrity, and (2) an examination of shoes for wear.
Frequency
- For healthy type 1 patients without complications: conduct foot screen at time of diagnosis and at least annually thereafter [1C]
- For type 2 patients without complications, check at baseline and at least annually thereafter [1C]
- For the "at-risk patients" check at all routine interval visits [1C]
"At-Risk Patients" includes patients who smoke, have vascular insufficiency, neuropathy, retinopathy, nephropathy, history of ulcers or amputations, structural deformities, infections, skin/nail abnormality, are on anticoagulation therapy or who cannot see, feel or reach their feet.
Treatment
For patients with acute problems or who are "at risk":
- Refer to podiatrist for routine care and evaluation [1B]
- Refer to diabetes educator for foot care training* [1C]
*Foot care training will include information about:
- Avoidance of foot trauma
- Daily foot inspection
- Proper footwear
- Impact of loss of protective sensation on morbidity
- Need to stop smoking
- Action to take when problems arise
For current ulcer or infection: mild** [1C]
**Mild Infection or Ulcer: superficial (no foul odor), no significant ischemia, no bone or joint involvement, no systemic toxicity, minimal or no cellulitis (< 2 cm):
- Instruct non-weight bearing
- Apply local dressings
- Consider baseline x-ray to evaluate for bone integrity and possible osteomyelitis
- Consider systemic antibiotic therapy
- Refer to podiatrist for debridement or further treatment
- Refer for foot care training
- Ensure follow-up appointments are kept
For limb-threatening*** ulcer or infection: [1C]
***Limb-threatening: deep ulcer, bone or joint involvement, gangrene, lymphangitis, >2 cm cellulitis, systemic toxicity, significant ischemia, no social support system, immunocompromised, foul odor in ulcer, and osteomyelitis presumed to be present if probed to the bone.
- Consider hospitalization and refer to a podiatrist and vascular surgeon for immediate evaluation and treatment
- Ensure appointments are kept and prevention strategies are implemented
Eyes
Exam Schedule
Refer patient for comprehensive dilated eye exam or validated retinal color imaging to determine level of retinopathy.
- Type 1: initial eye exam within 3 years after diagnosis of diabetes once patient is 9 years or older. Exams annually thereafter. [1B]
- Type 2: at diagnosis and annually thereafter [1B]
- Pregnancy in pre-existing diabetes: prior to conception and during first trimester; follow-up as determined by first trimester exam [1B]
For intensive insulin therapy (pump therapy or multiple daily injections) -consult with patient's eye doctor prior to and 2 to 4 months after initiating therapy.
Treatment
Aggressively treat known medical risk factors for retinopathy: [1A]
- Strive to improve glycemic control with optimal A1C goal of < 7%
- Monitor eye disease carefully when intensifying glycemic control
- Strive for BP <130/80 mmHg
- Treat micro/macro albuminuria
- Strive to maintain total cholesterol, LDL, HDL and triglyceride levels as per the recommendations outlined in the Lipids Section of the original guideline document
- Treat anemia
Revise activity program depending on the level of retinopathy. Consider consultation with exercise physiologist.
Reinforce follow-up with eye care provider for any level of retinopathy including no retinopathy. The frequency of follow-up is dependent upon the level of retinopathy and is determined by the eye care provider.
- For high-risk proliferative diabetic retinopathy, scatter (panretinal) photocoagulation is indicated promptly [1A]
- For clinically significant macular edema (CSME) - focal laser is generally indicated regardless of level of retinopathy [1A]
- The level of diabetic retinopathy and diabetic macular edema (DME) generally determines follow-up: [1A]
If Mild Nonproliferative Diabetic Retinopathy
- Without DME 12 months
- With DME* 3 to 4 months
If Moderate Nonproliferative Diabetic Retinopathy
- Without DME 6 to 9 months
- With DME* 3 to 4 months
If Severe – Very Severe Nonproliferative Diabetic Retinopathy
- Without DME** 3 to 4 months
- With DME* 3 months
If Proliferative Diabetic Retinopathy less than High-Risk
- Without DME** 1 to 4 months
- With DME* 1 to 3 months
If High-Risk Proliferative Diabetic Retinopathy
- With or without DME – scatter laser surgery with follow-up in 3 months
*Focal laser surgery is generally indicated for CSME
**Scatter laser surgery may be indicated, especially for type 2 diabetes or type 1 diabetes of long duration
Intravitreal and periorbital steroid injections are sometimes used in clinical practice to treat macular edema despite no definitive studies on their effectiveness or safety to date. These modalities are currently under rigorous investigation to further define their role.
Immunizations
Recommend the following vaccines:
- Influenza vaccine - yearly for all adult patients with diabetes [1B]
- Pneumococcal vaccine – once for all patients with diabetes. [1B]
- People ≥ 65 years of age should receive a second dose of pneumococcal vaccine if:
- They received the previous dose ≥ 5 years earlier and
- They were < 65 years of age when they received the previous dose
Women's Health
- Women with the potential for conception should receive information about contraception use and relation to blood glucose control and fetal development [1C]
- Refer to the Joslin Diabetes Center & Joslin Clinic Guideline for Detection and Management of Diabetes in Pregnancy for more details
- Follow appropriate guidelines for pap/pelvic and mammography screening for primary care patients [1A]
- Individualize approach to bone health for women with risk factors for osteoporosis, including surgical and natural menopause [1B]
- If sexual dysfunction exists, assess for infections or hormonal, psychological, or structural etiologies. Refer to specialist as indicated. [1C]
Men's Health
At initial & annual visit, discuss sexual function. If dysfunction exists, assess for hormonal, psychological, or structural etiologies. Refer to specialist as indicated. [1C]
Dental Care
At initial visit and annually, discuss need for dental exams at least every six months. If evidence of gingivitis, may need dental evaluation/treatment every 3 to 4 months.
Refer to dental specialist if oral symptoms such as sore, swollen, or bleeding gums, loose teeth or persistent mouth ulcers occur. [1C]
Definitions:
| Grade of Recommendation |
Clarity of Risk/Benefit |
Quality of Supporting Evidence |
1A
Strong recommendation
High quality of evidence
|
Benefits clearly outweigh risk and vice versa. |
Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk. |
1B
Strong recommendation
Moderate quality of evidence
|
Benefits clearly outweigh risk and burdens, or vice versa. |
Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design. Further research is likely to have an impact on our confidence in the estimate of the benefit and risk and may change the estimate. |
1C
Strong recommendation
Low quality of evidence
|
Benefits outweigh risk and burdens, or vice versa. |
Evidence from observational studies, unsystematic clinical experience, or from randomized controlled trials with serious flaws. Any estimate of effect is uncertain. |
2A
Weak recommendation
High quality of evidence
|
Benefits closely balanced with risks and burdens. |
Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk. |
2B
Weak recommendation
Moderate quality of evidence
|
Benefits closely balanced with risks and burdens; some uncertainty in the estimates of benefits, risks, and burdens. |
Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design. Further research is unlikely to have an impact on our confidence in the estimate of the benefit and risk and may change the estimate. |
2C
Weak recommendation
Low quality of evidence
|
Uncertainty in the estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdens. |
Evidence from observational studies, unsystematic clinical experience, or from randomized controlled trials with serious flaws. Any estimate of effect is uncertain. |
