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Internal Medicine 08: 55-year-old male with chronic disease management

User: Beatriz Duque

Email: [email protected] Date: October 2, 2020 10:29PM

Learning Objectives

The student should be able to:

List the major causes of morbidity and mortality in diabetes mellitus.

Recognize the basic management of hypertension and hyperlipidemia in the diabetic patient. Perform a diabetic foot exam.

Counsel patient on behavior change.

Recognize value of a team approach to the management of diabetes.

Appreciate the impact diabetes mellitus has on a patient’s quality of life, well-being, ability to work, and the family.

Knowledge

Hypoglycemia

It is important at each visit to ask diabetic patients if they have experienced any hypoglycemic symptoms or events that required the assistance of another person.

Often times, when a patient is hypoglycemic, he does not write it down because he is preoccupied treating the hypoglycemia.

Diabetic Neuropathies

It is estimated that 50% of patients with diabetes will eventually struggle with one or more neuropathies related to their diabetes.

Axonal loss and atrophy are responsible for the majority of clinical symptoms and loss of function in patients with neuropathy. There can also be evidence of demyelination and remyelination, with the actual number of large nerve fibers being reduced, while small nerve fibers increase.

Distal polyneuropathy

Distal polyneuropathy is the most common type of diabetic neuropathy. It is the progressive loss of sensation in the classic stocking/glove distribution. Diabetic foot ulcer incidence is greatly increased in patients with distal polyneuropathy.

Autonomic neuropathy

Autonomic neuropathy can take many forms and affect one or many organs. Specific types include:

cardiovascular (orthostatic hypotension, resting sinus tachycardia, postprandial hypotension) gastrointestinal (gastroparesis, chronic constipation, esophageal motility disorders) genitourinary (sexual dysfunction, neurogenic bladder) abnormal pupillary responses and disorders of hidrosis

Diabetic Retinopathy

Diabetic retinopathy, a microvascular diabetic complication, is the leading cause of preventable blindness in the developed world.

Prevention

Two large prospective trials (DCCT with Type 1 diabetics and UKPDS with Type 2 diabetics) revealed that intensive glucose management resulted in prevention or delayed onset and progression of diabetic retinopathy.

Coexisting hypertension, nephropathy, and tobacco abuse also contribute to retinopathy onset and progression.

Two types of diabetic retinopathy

1.  Non-proliferative diabetic retinopathy

Involves cotton wool spots, hard exudates, microaneurysms, and retinal hemorrhages.

Vision loss usually results from severe macular edema, a thickening of the retina with resultant edema of the macula.

2.  Proliferative diabetic retinopathy

Involves neovascularization of the retinal vessels or optic disc, retinal hemorrhage (dot-blot, flame), retinal fibrosis with traction detachment, and vitreous hemorrhage. Macular edema can occur as well.

Image of proliferative retinopathy with neovascularization

Onset

Development of diabetic retinopathy is directly related to disease duration and is generally not seen in patients who have had diabetes less than five years. The exception is Type 2 diabetic patients who were likely hyperglycemic more than five years prior to their diabetes diagnosis.

Screening

Annual dilated eye exams by an ophthalmologist are recommended for all Type 1 diabetic patients within five years of diagnosis and shortly after diagnosis in patients with Type 2 diabetes. Patients with progressive retinopathy are often seen quarterly or biannually.

Panretinal Treatment

Panretinal laser photocoagulation is the treatment of choice for proliferative diabetic retinopathy and severe cases of nonproliferative retinopathy. Screening is done aggressively due to the well-documented efficacy of laser photocoagulation in the prevention of vision loss. Ranibizumab, an anti-vascular endothelial growth factor, injected into the vitreous showed noninferiority to laser therapy and can also be used.

Diabetic Nephropathy

Epidemiology

Diabetic nephropathy occurs in 20% to 40% of diabetic patients and is the most common etiology of end-stage renal disease in the U.S.

Risk factors associated with the progression of diabetic nephropathy include: obesity, increasing age, African American race, and tobacco abuse.

Pathogenesis

Kidney insult appears to originate with glomerular hypertension and hyperfiltration. Chronic hyperglycemia leads to mesangial expansion, deposition of matrix, increased amount of VEG-F and other cytokines, local inflammation, and activation of protein kinase C.

Prevention / Treatment

Two large prospective trials (DCCT with type 1 diabetics and UKPDS with Type 2 diabetics) revealed that intensive glucose management resulted in prevention or delayed onset and progression of diabetic nephropathy.

Aggressive blood pressure lowering is critical for treatment of increased urinary albumin excretion. In patients with hypertension with increased urinary albumin excretion, an ACE inhibitor or ARB therapy is recommended to delay the onset and decrease progression of diabetic nephropathy.

Referral

Referral to nephrology is appropriate if the cause of kidney disease is not certain, and or there are challenging management issues present, such as resistant hypertension or electrolyte derangement. The threshold for referral to nephrology varies across providers; however, nephrology should be consulted if Stage 4 or greater chronic kidney disease (GFR < 30 ml/min per 1.73 m2) develops since this has been found to reduce cost, improve quality of care, and keep people off dialysis longer.

Diabetes Patient Resources in Spanish

The ADA website has excellent resources for Spanish-speaking patients and their families.

When to Perform the Diabetic Foot Exam

It is important to do a thorough foot exam in a diabetic patient on an annual basis for low-risk patients and more often in patients at high risk for foot ulcer formation.

Patients at High Risk for foot Ulcer Formation

Patients with known diabetic polyneuropathy, sensory or vascular deficits, patients who smoke, and patients with a prior history of diabetic foot ulcer or amputation.

Foot Exam in Patients with Diabetes

Visually inspect the feet for callus formation, ulceration, nail infections, and bony deformities.

Assess skin integrity, especially between toes and under metatarsal heads.

Palpate the dorsalis pedis and posterior tibialis pulses to screen for peripheral vascular disease and look for signs of peripheral

Clinical Skills

vascular disease, such as hair loss.

Check sensation using a 128 Hz tuning fork (vibration) and a cool metal object, potentially the same tuning fork (temperature).

Check pressure sensation using a 10-g monofilament:

Show the monofilament to the patient and try it on their hand to show them it will not hurt.

Ask the patient to close their eyes or look at the ceiling and tell you each time they feel the monofilament touch their foot.

Randomly place the end of the monofilament on the 9 different areas of the foot (see image to the right) with enough pressure to bend the monofilament.

If the patient does not say "yes" at a particular site, continue to the next site and re-test that site at the end.

Check Achilles reflexes.

Effectiveness of Intravenous Insulin for Blood Glucose Control

Blood sugar control in critically ill patients has been the subject of considerable investigation. Previous research suggested that tight control (80-120 mg/dL) was desirable, but more recent research shows that aggressive blood sugar control can be associated with higher mortality.

Hypoglycemia (serum glucose concentration <70 mg/dL), with rates as high as 40% in some studies, is associated with tight glycemic control. A meta-analysis of 29 controlled trials involving more than 8,000 adult ICU patients showed no difference in inhospital mortality between the group assigned to tight glucose control versus usual care.

The current recommended blood glucose target for most hospitalized patients is 140 to 180 mg/dL.

Thiazolidinediones

Pioglitazone (D), a member of the class of drugs known as thiazolidinediones (TZD), is not recommended for use in patients who have newly developed heart failure and in those with known NYHA Class III and IV heart failure. The same is true for rosiglitazone, another TZD that has been associated with an increased risk of cardiovascular disease.

Management

Diabetes Chronic Disease Management

Evaluate for and optimize prevention of diabetic complications

Macrovascular complications:

Cardiovascular disease

Cerebrovascular disease

Microvascular complications:

Retinopathy

Nephropathy

Neuropathy

In particular, cardiovascular disease is the No. 1 cause of mortality for people with diabetes, and one of the top causes of morbidity.

Hypoglycemia, infections, foot ulcers, and amputations are additional causes of morbidity and mortality in patients with diabetes.

The American Diabetes Association publishes annual guidelines to assist in the management of a patient with diabetes.

Remember the large role that the psychosocial aspects of a diabetes diagnosis play in management

Non-adherence with medical recommendations could be due to economic, work-related, religious, social, or linguistic barriers to care. Care must be taken to assess the psychosocial status of each person with diabetes at each clinic visit to ensure that barriers to successful diabetes care are minimized.

ADA Recommendations to Minimize the Risk of Cardiovascular Disease in Patients with Diabetes

Smoking cessation, daily aspirin, blood pressure control, and lipid control are all recommended to reduce the risk of cardiovascular disease.

Please note that as of 2018, ADA recommendations were published with the older definition of hypertension (140/90). It always takes time before multiple different organizations agree on the same thresholds.

Daily low dose aspirin is recommended for primary prevention of cardiovascular disease in diabetic patients with a 10-year risk of atherosclerotic cardiovascular disease of >10%. It is also recommended for secondary prevention of all diabetic patients with a history of atherosclerotic disease.

Reduction of cardiovascular risk is achieved with a goal of optimal glycemic control, as well as control of many other health factors that raise cardiovascular risk, such as tobacco use, obesity, poorly controlled hypertension, and hypercholesterolemia.

Mechanism of action: TZDs are peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists.

Effects: TZDs decrease insulin resistance, increase glucose uptake in peripheral tissue, decrease hepatic glucose production, decrease vascular inflammation, redistribute visceral adipose tissue peripherally, and preserve beta cell function. Overall, they cause the A1c to decrease by 1% to 1.5%. Hypoglycemia is not associated with this medication class. TZDs have differing effects on lipids. Pioglitazone slightly reduces LDL levels and raises HDL. Rosiglitazone can increase LDL levels.

Side effects: The receptors that TZDs activate are ubiquitous and are abundant in the cells within the renal collecting tubules. Hence, TZDs increase sodium reabsorption, leading to increased water retention. Compared to placebo, all TZDs are associated with a statistically significant increase in edema and weight.

Warnings: Care should be used with these agents in patients with liver disease. Serum transaminases greater than 2.5 times the upper limit of normal is a contraindication to initiation of these agents, and a rise to greater than three times the upper limit of normal should lead to their discontinuation. Liver tests should be measured at baseline and periodically while the patient is on this class of medication.

Contraindications: The FDA has added a warning to the label of pioglitazone noting an increased risk of bladder cancer after more than one year of treatment. Pioglitazone is now contraindicated in patients with a history of bladder cancer or active bladder cancer. Patients should be counseled to tell their physician if they notice blood in their urine or a red tint to their urine.

When to Refer Patients with Diabetes to an Endocrinologist

If a patient is having recurrent or severe hypoglycemia (seizure, coma, or impairment that requires the aid of another person), an endocrinologist should be consulted. Hypoglycemia is defined as a blood glucose <70 mg/dL.

Primary care physicians' threshold for referral varies across providers. Other conditions that would warrant referral are when a patient's A1c is 8% more than twice in a 12-month period, despite intensive treatment; for initiation of a complex multiple daily injection insulin regimen; or for initiation of continuous infusion insulin pump therapy.

Self-Monitoring Glucose: Indications & Effectiveness

Effectiveness of Self-Monitoring Blood Glucose

Patients should be advised to check their blood sugar if they feel "low" because it is well recognized that people are not able to accurately detect hypoglycemia (blood glucose of < 70 mg/dL) by symptoms alone. Eating high carbohydrate food to treat perceived hypoglycemia rather than actual hypoglycemia leads to worsened overall glycemic control.

Clinical studies have shown that self-monitoring of blood glucose (SMBG) may improve glycemic control, although for some patients self-monitoring increases depression and anxiety. It is important to evaluate patients' abilities to use SMBG techniques to ensure they are using accurate data to evaluate their response to therapy and their degree of success in reaching blood-glucose targets. After receiving education, patients can use SMBG data to adjust their activity level, food intake and choice, as well as drug therapy to achieve optimal glycemic control.

When to Self-Monitor Blood Glucose

In patients on less frequent insulin injections, SMBG may be useful in achieving glycemic goals.

Patients on an insulin pump and those using multiple daily insulin injections should self-monitor blood glucose at the following times:

before each meal at bedtime

when they have symptoms of hyper- or hypoglycemia after treating hypoglycemia to ensure return of euglycemia before exercise

before critical activities, such as driving

Blood Glucose Goals

Healthy Adults

*Medically Complex

Adults

**Very Medically Complex

Adults

fasting and before meals

80-130 mg/dL (3.9-7.2 mmol/L)

90-150 mg/dL

100-180 md/dL

one to two hours after a meal

< 180 mg/dL (10.0 mmol/L)

before bed

100-130 mg/dL (5.6-7.2 mmol/L)

100-180 mg/dL

110-200 mg/dL

*Medically complex adults have multiple coexisting chronic illnesses, two or more ADL impairments, or mild to moderate cognitive impairment.

**Very medically complex adults or adults in poor health have long term care or end-stage chronic illnesses, moderate to severe cognitive impairment, or two or more ADL dependencies.

Foot Care for Patients with Diabetes

It is important to review and provide information about foot self-care with diabetic patients.

Patients should be instructed to check the dorsal and plantar surfaces of their feet everyday for cuts, sores, redness, and swelling.

See the associated reference ranges in conventional and SI units.

Body Weight Management in Patients with Diabetes

Classification

BMI in kg/m2

Normal

19-24

Overweight

25-29

Obese

30-39

Morbidly obese

40+

Maintenance of a healthy body weight is essential in the management of patients with diabetes. However, for some patients, attainment of an ideal body weight is too large a goal, especially if they are morbidly obese. Studies have shown that a modest weight loss of approximately 5-10% of the current weight can lead to significant improvement in glycemic control, blood pressure control, and lipid parameters.

Multidisciplinary Approach to Diabetes Care

The care of the patient with diabetes is a team endeavor. Through a multidisciplinary approach, patients can be offered the very best chance of optimizing their blood glucose control and reducing their risks of morbidity and mortality.

Refer to a registered nutritionist for medical nutrition therapy regarding daily food choices and portion sizes. Refer to an accredited diabetes care center for diabetes management self-education, both in group and one-on-one settings. Numerous studies have shown that diabetes management self-education is effective in improving patients' selfcare behaviors, lowering their A1c, improving their knowledge of diabetes and enhancing their quality of life.

Office-based counseling of basic ADA recommendations for diet and exercise can be reviewed with the patient. For example, patients can be taught how to monitor his carbohydrate intake through carbohydrate counting, food exchanges, or selfreflection. Thirty minutes of moderately intense exercise, more days than not, may be a good recommendation for many patients. Less than 10% of daily calories should be from fat.

Patient education materials are a useful adjunct to office-based counseling, and can be found at the ADA website section on diet/exercise.

Blood Pressure Goal for Patients with Diabetes

There is ample, well-validated evidence that blood pressure control is one way of lowering a diabetic patient's cardiovascular risk. According to the ADA, the optimal blood pressure goal in patients with diabetes is less than 140/90 mmHg. Younger, healthier patients who can be treated without increasing the treatment burden may have a lower systolic target, such as less than 130. It is important to remember that an individual patient's blood pressure goal may be higher or lower based on his/her response to therapy and personal characteristics. Note: Other organizations recommend different blood pressure goals for patients with diabetes, such as the ACC/AHA, which recommends treatment in people with diabetes who have blood pressure greater than or equal to 130/80 mmHg, with a goal blood pressure of less than 130/80 mmHg.

The ACC/AHA guidelines on hypertension published in late 2017 suggested lower numbers for a definition of HTN; now anything over 130/80 is considered hypertension per ACC/AHA. Other organizations - like ADA - have not yet updated their guidelines to reflect this change.

Pharmaceutical management

Most diabetic patients require multiple agents to reach and maintain their individual blood pressure goal. ACE inhibitor and ARB therapy are first-line treatment options because they also delay the onset and decrease the progression of diabetic nephropathy. Diuretics and calcium channel blockers can be used to attain blood pressure goals.

Reasons for uncontrolled blood pressure

There are multiple reasons why a patient may have uncontrolled blood pressure. Blood pressure may be uncontrolled in patients needing increased dosages of their medications or additional agents. It may be elevated secondary to medications (e.g. NSAIDs) or alcohol. Or patients may not be taking their medications regularly, may not have taken their medications on the day of the office visit, or may have run out of their medication prior to the visit.

Before adding another medication or increasing the dose of existing medication, it is critical that nonadherence be explored first as a possible cause of uncontrolled hypertension.

If the patient is unable to view his entire foot by himself, then a caregiver should be asked to do it for him.

Feet should be washed daily and dried well.

Remind patients to use their forearm to check water temperature to prevent burns.

Patients should keep the skin of their feet smooth and soft with lotion.

Toenails should be trimmed weekly or as needed.

Patients should be encouraged to wear white socks, as these will show any drainage from a previously unknown sore, and well-fitting, comfortable shoes.

Shoes and socks should be worn at all times.

There is no robust evidence to warrant the recommendation that all patients with diabetes be fitted with special shoes to prevent diabetic foot ulcers.

High-risk patients should be referred to a podiatrist for comprehensive foot care.

Smoking Cessation in the Setting of Diabetes

Complete smoking cessation is the goal in all patients, and smoking cessation counseling should be part of every clinic visit. Merely asking if the patient is considering smoking cessation increases the chance that the patient will quit. Patients who have already cut down should be congratulated on accomplishing that hard task, then they should be encouraged to build on this success and quit completely.

Studies have shown that diabetic smokers suffer far more cardiovascular comorbidity than patients without diabetes who smoke and that smoking cessation leads to decreased progression of retinopathy and nephropathy.

Vaccinations for Patients with Diabetes

Diabetic patients should receive a pneumococcal vaccination and should be immunized for influenza annually. They should also receive the Hepatitis B vaccine series if they are between 19 and 59 years old.

Dental Care for Patients with Diabetes

Diabetic patients should be seen by a dentist regularly; the recommendation is twice a year.

Metformin Contraindications

Metformin is not recommended for patients with reduced ejection fraction requiring pharmacologic therapy, in particular patients with unstable or acute heart failure. It is likely safe in patients with well-compensated, stable CHF. It is prudent to stop a patient's metformin in the setting of a recent heart failure diagnosis but it may also be reasonable to restart it in the future should their symptoms stabilize.

Metformin is also contraindicated in patients with a GFR of < 30 mL/min/1.73m2. In addition, it shouldn't be started in patients with a GFR of 30 to 45 mL/min/1.73m2 though can be continued at a reduced dose with a GFR in this range in patients started on the medication when kidney function was normal. It is also contraindicated in patients with alcohol abuse or marked liver disease. These contraindications exist due to the increased risk of lactic acidosis in these patients. Metformin should be routinely discontinued when patients are hospitalized due to the increased risk of dehydration and opportunity for IV contrast dye use, which could reduce renal function.

Injectable Medications for Type 2 Diabetes

Insulin

Different types of insulin are used to manage diabetes.

The ADA Standards of Medical Care in Diabetes state, "consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed Type 2 diabetes who are symptomatic and/or have A1c 10% or greater and/or blood glucose levels

300 mg/dL or greater."

Evidence is accumulating that earlier use of insulin in the treatment of patients with uncontrolled Type 2 diabetes results in better long-term glycemic control. In a patient with an A1c value 9% or greater, oral hypoglycemic and non-insulin injectable medications as monotherapy are unlikely to bring the patient's A1c to goal, and dual therapy is recommended.

When insulin is used, typically a basal insulin, such as glargine or detemir, is initiated first, with continuation of one or more oral medications (usually metformin, unless there is a contraindication). The regimen is then escalated every three to six months until the A1c goal is attained.

In patients on a single oral agent whose A1c is within one percentage point of goal, adding another oral agent or non-insulin injectable should be considered. A well-known meta-analysis found that for each non-insulin agent added from a different class, the A1c could be expected to decrease 0.9-1.1%.

For a comprehensive list of available insulins refer to table 8.2: Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes

Glucagon-like peptide-1 receptor agonists

Mechanism of action: There are several GLP-1 receptor agonists available, commonly prescribed agents include exenatide and liraglutide. These agents increase insulin secretion in a blood glucose dependent manner. They also decrease

postprandial glucagon secretion, slow gastric emptying, centrally increase satiety, and decrease appetite.

Administration: These agents are all delivery by subcutaneous injection. There are monthly, weekly, daily and twice daily formulations. They can be used in combination with most oral medications and with basal insulin.

Side effects: The most common side effect is nausea, which can be significant, accompanied by emesis.

Effects: A1c decreases of approximately 1% and statistically significant weight loss are associated with use.

Contraindications: There have been post marketing reports of exenatide-induced pancreatitis, so its use in patients with a history of pancreatitis should be avoided. Tumors of the C-cells have been reported.

Studies

Chronic Diabetes Evaluation

Hemoglobin A1c

Hemoglobin A1c should be ordered every six months in patients who are meeting their individualized treatment goals, and every three months if they are not or if therapy is changing.

An HbA1c goal of < 7% is generally a reasonable goal for a nonpregnant, otherwise healthy adult patient. More stringent A1c goals (< 6.5%) may be appropriate in some patients, with shorter disease duration, long life expectancy, and no significant cardiovascular disease, if it can be attained without significant hypoglycemia.

The ADA Standards of Medical Care in Diabetes state, "less stringent A1c goals (such as < 8%) may be appropriate for patients with history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom a stringent goal is difficult to attain." For patients who have limited resources and a poor support system, and/or are unable to prioritize self-care due to social, economic or psychological stressors, a less stringent A1c goal may also be appropriate.

Remember that HbA1c levels are unreliable in patients with hemoglobin variants, such as sickle cell disease; with end-stage kidney failure/on dialysis, and who have recently had blood transfusions or large blood loss. Individuated Hemoglobin A1c Goals

Healthy Nonpregnant Adults, without severe recurrent hypoglycemia/hypoglycemic unawareness

< 7%

Medically Complex Adults, with history of severe hypoglycemia and/or longstanding diabetes

< 8%

Medically Complex Adults/Adults in Poor Health, with severe recurrent hypoglycemia/hypoglycemic unawareness

< 8.5%

Fasting lipid profile

The ADA and the AHA/ACC are overall in agreement regarding lipid management in diabetic patients.

The AHA/ACC guidelines are:

Lifestyle modification (weight loss, increased physical activity, reduced fat intake) should be recommended for all patients with diabetes, where appropriate.

All patients with diabetes and cardiovascular disease, regardless of age, should be on a high intensity statin.

All patients aged 40 to 75 with diabetes should be on a moderate-intensity statin. If ASCVD risk is >7.5%, they should be on a high-intensity statin.

For patients aged <40 or >70 with diabetes, consider statin therapy depending on risks/benefits and patient preferences. The ACC/AHA does not recommend lipid goals at this point.

See the Aquifer Cholesterol Guidelines for more information about this.

Liver function profile

Indicated if the patient takes a TZD. When patients take this class of medication, liver tests should be monitored periodically.

Basic metabolic profile

Indicated to monitor renal function if the patient takes metformin and in patients with diabetes in general.

Spot urine albumin/creatinine ratio

Indicated annually in patients with Type 2 diabetes without evidence of increased urinary albumin excretion (<30 mcg albumin/mg creatinine) and more often to assess for progression and effect of therapy in patients with established increased urinary albumin excretion (30 mcg albumin/mg creatinine or greater). A diagnosis of increased urinary albumin excretion is made when two of three specimens collected within a 3- to 6-month period are 30 mcg/mg creatinine or greater. Remember that vigorous exercise within the last 24 hours, menstruation, illness, fever, markedly elevated blood pressure, CHF exacerbation, and acute hyperglycemia can cause false-positive results.

Urine dipstick measurements are not used to diagnose or follow increased urinary albumin excretion because of the insensitivity of the method for detecting the initial small increases in protein excretion. Protein excretion must exceed 300 mcg per day to turn the dipstick positive.

Estimated GFR based on the serum creatinine should also be used to assess for chronic kidney disease, at least annually, looking at declining GFR as another marker of kidney disease progression.

See the associated reference ranges in conventional and SI units.

References

American Diabetes Association Standards Of Medical Care In Diabetes-2016. The Journal of Applied Research and Education. January 2016, Volume 39, Supplement 1. http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-ofCare.pdf.. Accessed March 13, 2020.

American Diabetes Association Standards Of Medical Care In Diabetes-2018. Diabetes Care. 2018 Jan; 41 (Supplement 1): S1-S2. http://care.diabetesjournals.org/content/41/Supplement_1. Accessed March 13, 2020.

Economic Costs of Diabetes in the U.S. in 2012. American Diabetes Association. Diabetes Care. April 2013; 36(4):1033-1046. http://care.diabetesjournals.org/content/36/4/1033. Accessed March 13, 2020.

Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.