Endocrinology: Diabetes

Endocrinology: Diabetes
Courses in Therapeutics and Disease State Management

Epidemiology Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia that affects over 29 million Americans. Results from defects in insulin secretion, insulin sensitivity, or both Diabetes contributes to microvascular and macrovascular complications, and is the leading cause of kidney failure in the U.S. In 2012, the burden of diabetes exceeded $245 billion in direct and indirect costs Diabetes is a complex metabolic disorder of carbohydrate, protein, fat and lipid metabolism that is marked by excess glucose in the blood, also known as hyperglycemia. This can be due to a deficiency of insulin caused by defects in pancreatic insulin secretion, a lack of response to insulin due to insulin resistance in the cells and sometimes a combination of both. Diabetes is a highly prevalent disease in the U.S. affecting over 29 million Americans which around 10% of the population. Of those with diabetes, one third have not been diagnosed yet. We will be discussing strategies to correct these defects in insulin secretion and sensitivity and identify the thresholds used clinically to detect diabetes.

Classification Characteristic Type 1 DM (5% of all cases)*
Typical age at onset Youth, adolescence Adulthood Speed of onset Rapid Slow Response to lifestyle modifications Poor Good Frequency of DKA High Low Personal or Family history of autoimmune disease Common Uncommon Body habitus Lean Overweight, obese, central adiposity C-Peptide Levels Undetectable to low Normal to high Evidence of β-cell autoimmunity Present Absent Gestational diabetes (GDM) and other forms make up the remaining 5% of cases. See Table 57-1 in Pharmacotherapy for additional classifications and Table 20.1 in Patient Assessment Diabetes is generally categorized into one of 2 groups, type 1 or type 2 diabetes. Your text for the course has additional detailed information on the other forms of diabetes that are less commonly seen. This table identifies several of the differentiating charactertistics between Type1 and Type 2 DM. Generally, Type 1 is characterized by a lack of insulin production as a result of autoimmune destruction of pancreatic beta cells that typically presents in childhood or adolescence. These patients are likely to have antibodies present and because of the lack of insulin that would otherwise suppress ketosis, these patients often present or experience DKA. Type 2 DM is more likely to present in adults, although this is changing due to the obesity epidemic among our nation’s youth. Generally, patients in early type 2 dm have normal or excess insulin however the body’s cells are not able to effectively use it due to insulin resistance. Patients with type 2 dm may also have defects with incretin deficiency and glucagon excess. Over time, Type 2 Dm can progress to a mixed picture of both insulin resistance and deficiency as beta cell function declines. Obesity and a sedentary lifestyle contributes to insulin resistance seen in type 2.

Screening Symptomatic Asymptomatic
Patients presenting with Diabetic Ketoacidosis or Hyperosmolar Hyperglycemic State Generally Type 1 DM or longstanding Type 2 DM Asymptomatic All adults >45 years old Any adult with a BMI ≥ 25kg/m2 (≥23kg/m2 for Asian Americans) with ≥1 diabetes risk factor Recheck at a minimum of every 3 years Patients who do present in a symptomatic state and are subsequently diagnosed with diabetes are generally those with type 1 dm (keep in mind the rapid onset) or patients with longstanding type 2 who may already have development of diabetes related complications. Screening of asymptomatic, healthy adults without diabetes risk factors is generally recommended beginning at age 45. Testing should begin sooner for younger patients if they are overweight or obese and have any diabetes risk factors. For the purposes of screening Asian Americans, a BMI greater than 23 meets the threshold for screening due to an increased risk for diabetes at lower BMI in this high risk ethnic group. Testing should be repeated every 3 years and sooner in those with pre-diabetes or multiple risk factors. Risk factors identified by the American Diabetes Association are listed on the next slide.

Diabetes Risk Factors (Slide 1 of 2)
Physical inactivity First degree relative with diabetes African American, Latino, Native American, Asian American, Pacific Islander Women with PCOS, a history of GDM or delivering a baby weighing >9lbs Hypertension, HDL <35mg/dL, or triglycerides >250mg/dL A1c ≥ 5.7%, impaired glucose tolerance or impaired fasting glucose Conditions associated with insulin resistance Cardiovascular disease Some risk factors for diabetes can be modified, others cannot. Conducting a thorough review of an individual patient’s personal and family history is important to ascertain the presence of these risk factors. Examples of conditions associated with insulin resistance include severe obesity (BMI >40) or acanthosis nigricans, a skin thickening and hyperpigmentation seen in body folds and creases, most notably the back of the neck.

Diabetes Risk Factors (Slide 2 of 2)
Physical inactivity First degree relative with diabetes African American, Latino, Native American, Asian American, Pacific Islander Women with PCOS, a history of GDM or delivering a baby weighing >9lbs Hypertension, HDL <35mg/dL, or triglycerides >250mg/dL A1c ≥ 5.7%, impaired glucose tolerance or impaired fasting glucose Conditions associated with insulin resistance Link: Figure of acanthosis nigricans, with typical hyperpigmented plaques on a velvet-like, verrucous surface on the neck. Cardiovascular disease Some risk factors for diabetes can be modified, others cannot. Conducting a thorough review of an individual patient’s personal and family history is important to ascertain the presence of these risk factors. Examples of conditions associated with insulin resistance include severe obesity (BMI >40) or acanthosis nigricans, a skin thickening and hyperpigmentation seen in body folds and creases, most notably the back of the neck.

Diagnosis Pre-Diabetes Diabetes HbA1c 5.7%-6.4%
Fasting plasma glucose mg/dL IFG=Impaired Fasting Glucose 2-hour plasma glucose mg/dL during an OGTT IGT=Impaired Glucose Tolerance HbA1c ≥6.5% Fasting plasma glucose ≥126 mg/dL (Fasting is defined as no caloric intake for at least 8 hours) 2-hour plasma glucose ≥200 mg/dL during an OGTT In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose concentration ≥200 mg/dL The choice of which test to use may be determined by cost, convenience, or the need for fasting. Fasting is defined as no caloric intake for at least 8 hours which may can be a barrier to testing for some patients, which may be overcome by the use of the Hemoglobin a1c. The oral glucose tolerance test or OGTT tends to be the most costly and time consuming but may be preferable as a follow up test in some patients with equivocal results. The cutpoints for diagnosis of both prediabetes and overt diabetes are listed on the slide.

Concept Review (Slide 1 of 2)
GC is 24 year-old, obese, white female seen in family medicine clinic to establish care. She has a history of polycystic ovarian syndrome. Her family history is unknown. She denies tobacco and alcohol use. Endorses polydipsia with polyuria and oligomenorrhea with moderate to heavy menstrual bleeding. Height: 5 ft 7in Weight: 300lbs BMI: 47 kg/m2 BP: 140/101 Is GC a candidate for diabetes screening? Before we discuss treatment, lets review the concepts we have learned so far with a patient case. While GC is not old enough to begin routine testing being under the age of 45 years old, she does meet the criteria for testing based on her obesity and the presence of PCOS. Her elevated blood pressure and severe obesity are additional risk factors that would warrant screening. Polydipsia and polyuria are also symptoms of hyperglycemia that could prompt testing.

Concept Review (Slide 2 of 2)
GC is ordered screening labs based on her BMI and diabetes risk factors. Her results: HbA1c 10.6% Plasma Glucose (non-fasting) 325mg/dL What diagnosis, if any, can be made today? Link: Table of a list of other assessments that should be completed at the initial visit. How should we approach treatment? Based on the Hba1c GC clearly has hyperglycemia at a level that is considered Diabetes as it is above 6.5%. The plasma glucose is not a fasting measurement. However, in light of her classic hyperglycemia symptoms with the increased thirst and urination this random plasma glucose over 200 would also place her at a level where a diagnosis can be made. We will now discuss the approaches to treating diabetes once a diagnosis has been made.

Goals of Treatment Prevent Acute Complications
Prevent Chronic Complications Alleviate Symptoms of Complications Minimize/Avoid Drug Related Problems The approach to diabetes treatment must take into account the complications of diabetes and those that may arise due to drug treatment. Most complications can be prevented and sometimes managed through improved glycemic control. We will start with the measures used to assess glycemic control.

Glycemic Control Self-Monitoring of Blood Glucose (SMBG) HbA1c
Part of the patient’s self-management strategy Pre-prandial is the primary target Symptoms of hypo-/hyperglycemia Individualized for the needs and goals of the patient HbA1c Glycosylated hemoglobin on RBCs Every 3 months “average blood glucose” Target to prevent complications SMBG, also referred to as home BG monitoring or fingersticks is an important part of the patient’s self managing of their diabetes. The timing and frequency of testing is going to vary depending on the patient’s use of hypoglycemia causing medications and their overall management plan. Pre-prandial, or before meal, readings are generally the primary target. Post-prandial readings are typically used to help fine-tune the insulin dose for patients on meal time insulin regimens. Patients should also test any time they have symptoms they believe to be caused by a high or low blood sugar. The SMBGs can be thought of as a “snapshot in time” The HbA1c on the other hand provides more of a 3 month average of blood glucose during that time frame. The RBC’s when exposed to glucose become irreversibly glycosylated. This measure is also useful for making drug therapy decisions as achieving specific targets is known to reduce microvascular complications.

SMBG (Slide 1 of 2) Measured using blood glucose meter
Link: Video on Home Blood Glucose Monitoring Link: Video on Preventing Infections When Monitoring Blood Glucose ADA recommendations Preprandial Goal mg/dL Postprandial Goal <180mg/dL Hypoglycemia Any value <70mg/dL Herrier RN, Apgar DA, Boyce RW, Foster SL. Herrier R.N., Apgar D.A., Boyce R.W., Foster S.L. Herrier, Richard N., et al.Diabetes Mellitus. In: Herrier RN, Apgar DA, Boyce RW, Foster SL. Herrier R.N., Apgar D.A., Boyce R.W., Foster S.L. Eds. Richard N. Herrier, et al.eds. Patient Assessment in Pharmacy. New York, NY: McGraw-Hill; Accessed November 05, 2016.

SMBG (Slide 2 of 2) Non-intensive regimens
Patients using multiple insulin injections per day Non-intensive regimens Before meals and snacks Occasionally postprandially At bedtime Prior to exercise or performing critical tasks When suspect the presence of, and after treating hypoglycemia Oral agents only Monitoring for hypoglycemia May help guide treatment decisions Basal Insulin Fasting SMBG for titration of basal insulin dose The decision of how often to test is a very individualized one. Patient’s should be trained on what to do with the values they receive and should not test more frequently than what is necessary to avoid the cost and pain associated with SMBG. Patients on MDI WILL need to test their BS more frequently, atleast 4 or 5 times per day. However, patients on agents that do not pose a risk for hypoglycemia may only need to test a few days week or once a day. As the risk for hypoglycemia increases then the need for more frequent testing may arise. If SMBG values are being used to titrate a medication or evaluate therapy, the patient can test more frequently for a few days and then return back to their normal schedule.

HbA1c A1C is influenced by both the fasting glucose and post-prandial levels Estimated Average Glucose eAG= 28.7 X A1C – 46.7 Link: eAG/A1C Conversion Calculator Link: Infographic on A1C Goals Measured every 3-6 months Goal for most patients is <7% More stringent goals (<6.5%) can be considered if: Hypoglycemia can be avoided Short duration of diabetes Long life expectancy No significant CVD Less stringent goals (<8%) can be considered if: Severe hypoglycemia Limited life expectancy Advanced complications/Longstanding disease Extensive comorbidities Because the A1c represents an average, it is influenced by both the fasting and posprandial blood glucose levels. The ADA has a calculator that can be used to provide patients with an estimated “average” blood glucose since they are more familiar with blood glucose values from their SMBG testing. Testing usually occurs every 3 months in patients when treatment adjustments are being made or if the previous A1c was not at goal. Stable patients, meeting goals can be checked every 6 months instead. Landmark diabetes trials such as the UKPDS and DCCT have shown that when patients are treated to achieve intensive glycemic control, the risks for chronic microvascular complications neuropathy, retinopathy, and nephropathy are significantly reduced. Therefore, the goal for MOST patients is an A1c of below 7%. Younger patients with a longer life expectancy and low risk for adverse effects from medications are likely to benefit by more aggressive therapy aimed at reducing the A1c to less than 6.5%. This is the target A1c for all patients in the AACE guidelines. Older patients at greater risk for adverse effects or with extensive comorbidities and complications are not as likely to see a benefit from more aggressive therapy. The A1c targets in these patients is increased to <8%, a level at which acute symptoms of hyperglycemia are typically avoided.

Concept Review GC is 24 year-old, obese, white female
History of polycystic ovarian syndrome. Family history is unknown. Denies tobacco and alcohol use. Endorses polydipsia with polyuria and oligomenorrhea with moderate to heavy menstrual bleeding. Vitals/Labs Height: 5 ft 7in Weight: 300lbs BMI: 47 kg/m2 BP: 140/101 HbA1c 10.6% Plasma Glucose (non-fasting) 325mg/dL What glycemic targets would you recommend for GC? Link: Table on Treatment Goals for Adults with Diabetes Let’s revisit our patient case. Recall that our patient is young and does not have any established complications or comorbidities that would shorten her life expectancy. Her A1c target would definitely be less than 7% and most likely less than 6.5% depending on how she tolerates drug therapy. Her pre-prandial blood glucose values should be between mg/dl. She isn’t a candidate for post-prandial testing since she is not on mealtime insulin, yet.

Comprehensive Assessment
Link: Table of Guidelines on for Ongoing, Comprehensive Medical Care for Patients with Diabetes Medical History Physical Exam Laboratory Evaluation Referrals

Acute Complications Symptoms of Hyperglycemia
Include: Drugs that cause hyperglycemia Polyuria Corticosteroids Polydipsia Niacin Atypical Antipsychotics Polyphagia Protease inhibitors Dry Skin Sympathomimetics Nausea Treatment Fatigue/Drowsiness Blurred vision Additional insulin Moderation of carbohydrate intake May be caused by: Physical activity Too much food Too little insulin/medication Illness, stress Link: Table on Medications that may Affect Glycemic Control While achieving glycemic control helps in the prevention of many complications associated with diabetes, there are other interventions or targets that are specific to other complications. Many patients with significantly elevated blood glucose levels will experience symptoms of hyperglycemia. The overlap between some of these and symptoms of hypoglycemia highlight the iprotance of SMBG testing when patients believe their blood sugar to be high or low. Patients who are generally meeting glycemic targets will likely be able to avoid these symptoms, however, excess food or not enough diabetes medication can cause these symptoms to present. Periods of stress or illness may also cause a rise in blood glucose levels. Pharmacists must recognize medications that can contribute to or worsen hyperglycemia and identify when it is recommended to monitor for hyperglycemia in patients taking them, particulary corticosteroids and atypical antipsychotics. In addition to maintaining adherence to the prescribed diabetes medications, patients may also require short term supplemental insulin, especially during hospitalizations or severe illness. Patients with type 2 DM may also be able to reduce the blood glucose through increased physical activity and moderation of carbohydrate intake. Patients with Type 1 DM may need to adjust their insulin:carbohydrate ratios, a concept we will discuss in more detail later.

Acute Complications Impaired Wound Healing and Infection
Vaginal candidiasis Urinary tract Skin infections Causes Foot Infections Increased susceptibility Treatment Decreased healing Prevention through foot care Glycemic control Referral to podiatry Prevention Link: Video on Diabetic Foot Exam Immunizations Link: Algorithm covering pathophysiology of the diabetic foot Influenza-yearly Infection Pneumococcal Tetanus Skin Hepatitis B vaccine Oral Genitourinary Complications related to infections and impaired wound healing can largely be prevented through immunizations, appropriate foot and skin care and glycemic control. Neuropathy, another complication of diabetes that we will discuss later, poor circulation and delays in wound healing can put patients with diabetes at risk for serious foot infections. Women are particularly at risk for genitourinary complications due to the proximity of the urethra and vagina. Glucose spilled into the urine provides a nutrient rich environment in which fungi and bacteria may thrive. Individuals with diabetes should be encouraged to receive an annual influenza vaccine, stay up to date on tetanus boosters and become candidates to receive vaccines against Hepatitis B and Pneumococcal disease as a result of their diagnosis.

Hyperglycemic Crises (Slide 1 of 2)
Diabetic ketoacidosis (DKA) Hyperosmolar hyperglycemic state (HHS) Causes Decreased insulin Increased counter-regulatory hormone Release of free fatty acids (lipolysis) that are oxidized to ketone bodies Results in metabolic acidosis Presentation Acute presentation (<24 hours) Can occur with BG >250 Usually Type 1 DM, can be precipitated in Type 2 by infection/stress or drugs Causes Inadequate insulin levels to utilize glucose Enough insulin to prevent lipolysis Glycosuria leads to osmotic diuresis Presentation Evolves over several days to weeks Occurs with BG >600 Type 2 DM The most severe acute complications related to hyperglycemia are DKA and HHS. Both require urgent treatment and can be life threatening. DKA typically presents in patients with Type 1 DM, although some subsets of DM may be more prone to DKA. The lack of insulin results in ketosis and lipolysis creating a metabolic acidosis. In HHS on the other hand, enough insulin is present to suppress lipolysis but the spilling of glucose into the urine creates an osmotic diuresis leading to dehydration.

Hyperglycemic Crises (Slide 2 of 2)
Symptoms Hyperglycemia Vomiting Weight loss Dehydration Weakness Clouding of sensorial Coma Tachycardia Hypotension Abdominal pain (DKA only) Symptoms of both DKA and HHS are listed on the slide. The diagnosis and treatment of hyperglycemic crisis are beyond the scope of this course. At this level, students should be able to recognize symptoms of hyperglycemic crises and which patients are likely to experience.

Chronic Complications Microvascular (Slide of 1 of 6)
Retinopathy Leading cause of new blindness Edema Non-proliferative diabetic retinopathy-microaneurysms, hemorrhages Proliferative diabetic retinopathy-growth of new blood vessels into optic nerve and macula; hemorrhage, retinal detachment Prevention Glycemic control Blood pressure control Fundoscopic Eye Exam Type 1- initial exam or within 5 years after disease onset, annually thereafter Type 2- initial exam shortly after the diagnosis of diabetes, annually thereafter Laser treatment to prevent vision loss, intravitreal anti-VEGF agents Link: Figure of a patient has neovascular vessels proliferating from the optic disc Diabetic peripheral retinopathy is the leading cause of new blindness in the U.S. and a complication that can be prevented through good glycemic control and blood pressure management. Patients with retinopathy will usually be classified as proliferative or non-proliferative retionopathy with the former being the more serious of the two and characterized by the growth of blood vessels into the retina. Screening for retinopathy is done with a fundoscopic (dilated) eye exam and the ADA recommends different intervals for screening based on the type of dm. Treatment includes photocoagulation of new vessels and the use of ocular injections of antivascular endothelia growth factors.

Chronic Complications Microvascular (Slide 2 of 6)
Nephropathy Leading cause of ESRD Link: Algorithm for screening for microalbuminuria Annual urine microalbumin/creatinine ratio Annual serum creatinine (even patients without kidney damage) Prevention Glycemic control Blood pressure control Compelling indication for use of ACEI or ARB Treatment ACEI prevents CVD events AND slows the decline in renal function ARB prevents progression of albuminuria Link: Figure on time course of development of diabetic nephropathy Can use either ACEI or ARB in normotensive patients with elevated urinary albumin An additional microvascular complication is nephropathy. Diabetes is the leading cause of end stage renal disease. Screening should be conducted yearly by measuring a urine microalbumin/creatinine ratio. Any ratio above 30mcg/mg (not due to other causes) is considered albuminuria, and an indication to begin angiotensin blocking agents, even in normotensive patients. ACE inhibitors or ARBs should be selected as first-line antihypertensive therapy in patients with dm and hypertension due to the renal protective effects afforded by these agents. Most clinicians will use ACE inhibitors first due to lower costs, reserving ARBs for patients intolerable to ACE inhibitors due to cough or angioedema.

Chronic Complications Microvascular (Slide 3 of 6)
Neuropathy Vibration using 128-Hz tuning fork, OR, pinprick sensation, OR ankle reflexes, OR vibration perception Autonomic Orthostatic BP measurements Erectile Dysfunction A fall in systolic blood pressure >20 mmHg upon standing without an appropriate heart rate response Link: Chapter on ED on AccessPharmacy Cardiac Resting tachycardia Heart rate measurements (>100bpm) Orthostasis Treatment Gastroparesis Erectile dysfunction Link: Chapter on Nausea and Vomiting on AccessPharmacy Link: Algorithm for selecting treatment for erectile dysfunction Sensory Diabetic Peripheral Neuropathy phosphodiesterase type 5 inhibitors Numbness, tingling, burning, loss of sensation esp. in extremities intracorporeal or intraurethral prostaglandins Screening vacuum devices Foot exam at each visit Link: Video on Diabetic Foot Exam Erythromycin Metoclopramide Pulses (dorsal pedal and post tibial) Diabetic Peripheral Neuropathy (DPN) Monofilament testing (loss of protective sensation) Link: Table on Pharmacologic Management of Chronic Noncancer Pain Neuropathy is the most common complication of diabetes and has several manifestations in many parts of the body. Damage to the autonomic nervous system can result in erectile dysfunction, cardiac autonomic dysfunction, and gastroparesis. Screening for these should be conducted routinely and treatment targeted towards the clinical manifestations, which may be limited due to comorbid conditions and concomitant drug therapy. Patients with erectile dysfunction can be treated, if no contraindications exist, following the algorithm in Figure Gastroparesis will present with nausea, vomiting, and early satiety and is a contraindication to the diabetes treatments affecting gastrointestinal motility. Metoclopramide and erythromycin are the traditional first line therapy for this complication. Diabetic peripheral neuropathy can manifest as pain, tingling, and numbness in the hands and feet. Improving glycemic control can help to reduce this symptom, but many patients will require treatment with agents targeting neuropathic pain such as the tricyclic antidepressants, anticonvulsants and their derivatives, and topical agent capsaicin.

Chronic Complications Macrovascular (Slide 4 of 6)
Blood Pressure Checked at each visit Link: Table on Blood Pressure Technique ADA 2016 Standards JNC8 Systolic Goal <140mmHg (<130mmHg may be appropriate in younger patients; those with albuminuria; additional ASCVD risk factors. If achieved without undue treatment burden.) <140mmHg Diastolic Goal <90mmHg (< 80mmHg may be appropriate in younger patients; those with albuminuria; additional ASCVD risk factors. If achieved without undue treatment burden.) < 90mmHg Drug Therapy ACEI or ARB for all patients with diabetes Administer 1 or more antihypertensive meds at HS Add on amlodipine, HCTZ or chlorthalidone CKD: ACEI or ARB Nonblack persons: ACEI, ARB, Thiazide, or CCB Black persons: Thiazide or CCB The next category of chronic complications are the macrovascular or large vessel disease, usually synonymous with ASCVD. To reduce risk of ASCVD, patients with diabetes should have bp measured regularly at each appointment and more often if necessary. There are several hypertension guidilines to consider in the approach to a patient with diabetes and hypertension. Most clinicians will use the approach recommended by the ADA which endorses a systolic goal of <140mmHg unless the patient is able to tolerate a lower target of 130mmHg. More aggressive BP lowering may be appropriate in younger patients and those with multiple ASCVD risk factors such as tobacco use, family history, albumuria, and dyslipidemia. Similarly, the diastolic goal is <90mmHg for most patients with the option of <90mmg in patients likely to have benefits outweighing the risks. The JNC * recommendations are provided for comparison. As discussed previously, the ADA recommends ACEI or ARB therapy as first line in patients with DM and HTN. Controlled trials among patients with DM have demonstrated additional cardiovascular benefits when 1 or more of the antihypertensive agents are taken at bedtime compared with AM dosing only. Typical add on therapy will include dihydropyridine CCBs or thiazide diuretics.

Lipids Lipid panel at least annually Link: Figure on Four Major Statin Benefit Groups Moderate intensity statin if age with diabetes (Level of evidence: A) High intensity statin if age with diabetes and a ≥7.5% 10 year ASCVD risk. (Level of evidence: E) Evaluate benefit vs risk in patients <40 and >75 with diabetes (Level of evidence: E) 10-Year Risk can be calculated using the ASCVD Pooled Cohort Equations CV Risk Calculator Link: Algorithm covering major recommendations for statin therapy for atherosclerotic cardiovascular disease (ASCVD) prevention Link: Figure on intensity levels of statins The ACC/AHA 2013 Guidelines shifted the focus of lipid treatment from a “target” based approach to one based on “risk”. Diabetes is one of the 4 “Statin Benefit Groups” outlined in the guidelines. Patients with diabetes should be screened annually and statin therapy initiated for most over the age of 40 years. The American college of cardiology has a CV risk calculator that can be used to determine a patient’s ASCVD risk % for a primary event. Essentially, the recommendation from the ACC/AHA is that all patients with diabetes between the ages of 40 and 75 are candidates for primary prevention with at least moderate intensity statin therapy. The choice of statin and dose should be guided by the patient’s ASCVD risk with high intensity statins recommended for patients with ASCVD risk >7.5%. Any patient with diabetes and overt CAD is recommended to receive high intensity statin therapy.

Antiplatelet therapy Aspirin mg/day Primary Prevention MEN and WOMEN > 50 with at least 1 additional major risk factor family history of CVD, hypertension, smoking, dyslipidemia, albuminuria Secondary prevention Recommended for ALL patients with previous MI or stroke Smoking Cessation Pharmacotherapy and Support programs—“The 5 A’s” Similarly, ADA and USPSTF guidelines recommend aspirin as primary prevention for patients with diabetes over the age of 50 with ASCVD risk factors, including albuminuria. Patients with over CAD are candidates to receive aspirin as secondary prevention. The usual dosage in the US is 81mg.

Medical Nutrition Therapy (Slide 1 of 3)
Carbohydrates in diabetes management The carbohydrate amount in meals and available insulin are usually the most important factors influencing glycemic response after eating and should be considered when developing the eating plan. Includes carbohydrate from fruits, vegetables, whole grains, legumes, and low-fat milk (sucrose- containing foods in place of other carbohydrates should not displace nutrient dense food choices. Monitoring carbohydrate, whether by carbohydrate counting, exchanges, or experienced-based estimation, remains a key strategy in achieving glycemic control. For example: 200 grams of carbohydrates per day grams per meal; grams for snacks Avoid excess calories (adjust to maintain desirable weight or prevent weight gain) Consume a variety of fiber containing foods (20-30 grams of dietary fiber per day) People with diabetes or pre-diabetes should limit/avoid intake of sugar-sweetened beverages to reduce risk for weight gain and worsening of cardio-metabolic risk. Sugar alcohols and nonnutritive sweeteners are safe within recommended daily intake levels While all patients with diabetes should receive meal planning education by trained dieticians, pharmacists can assist patients with basic lifestyle education to promote weight loss and improved glycemic control. The ADA stresses in their recommendation that there is not an ideal percentage of calories from carbohydrate, protein, and fat for all people with diabetes; therefore, macronutrient distribution should be based on individualized assessment of current eating patterns, preferences, and metabolic goals. However, there are some general principles to follow. Moderation of carbohydrate intake is the key strategy to help patients achieve glycemic targets, especially the postprandial response. Patients should strive to obtain the majority of their daily carbohydrate intake from the nutrient dense sources listed on the slide and to avoid the empty calories that come from sugar sweetened beverages. While monitoring carbohydrate intake will often lead to a reduction in caloric intake, patients should be reminded to avoid excess calories in order to prevent weight gain or to promote weight loss.

Fat and cholesterol in diabetes management Limit saturated fat to <7% of total calories Minimize intake of trans fat and reduce dietary cholesterol to <200 mg/day Two or more servings of fish per week provide n-3 polyunsaturated fatty acids Protein in diabetes management If normal renal function, no need to restrict usual protein intake Protein should not be used to treat acute or prevent nighttime hypoglycemia To prevent macrovascular complications, patients should also be encouraged to reduce saturated fats in the diet. Protein typically does not need to be restricted unless the patient has renal impairment. However, protent should not be used to treat acute or prevent nighttime hypoglycemia as it increases the insulin response without increase blood glucose concentrations.

Alcohol in diabetes management Limit daily intake to one drink per day or less for women and two drinks per day or less for men Alcohol may increase risk for hypoglycemia, especially if taking insulin or insulin secretagogues Sodium Reduce sodium to < 2,300 mg/day; for individuals with both diabetes and hypertension, further reduction in sodium intake should be individualized The recommendations for alcohol intake in patients with diabetes mirror those set forth by other guidelines. The use of alcohol is not recommended in patients on insulin or medications which increase insulin secretion as the presence of alcohol increases the risk for severe hypoglycemia as it blunts the effect of glucagon in the presence of hypoglycemia. Alcohol, when consumed, should be done so with a meal.

Insulin, Basil (Background Insulin)
Intermediate Long acting Ultra Long Acting NPH (Humulin N®, and Novolin N®) Glargine U-100 (Lantus®, Basaglar®) Glargine U-300 (Toujeo®) Detemir (Levemir®) Degludec (Tresiba®) 100units/ml and 200units/ml Can be dosed QD at dinner or HS; or BID (at breakfast and dinner or HS) Daily at same time Dosed once daily at any time of day (must separate by >8 hours) Cloudy Clear Can be mixed with R or Rapid acting insulin by patient or premixed Cannot be mixed with other insulin Characteristics of the basal insulin products currently on the U.S. Market are listed. Discuss differences between. Link: Table on Available Injectable and Insulin Preparations Link: Table on Pharmacokinetics of Various Insulins Administered Subcutaneously

Insulin, Bolus (Mealtime Insulin)
Short Acting Rapid Acting Regular (Humulin R®, Novolin R®) Lispro (Humalog®) Aspart (Novolog®) Glulisine (Apidra®) Clear Humulin 70/30®; Novolin 70/30® (70% NPH; 30% Regular) Humalog Mix 50/50® (50% NPH; 50% Lispro); Humalog Mix 75/25® (75% NPH; 25% Lispro) NovoLog Mix 70/30® (70% NPH; 30% Aspart); Ryzodeg® (70% degludec/30% Aspart), Can be mixed with NPH Characteristics of the meal time insulin products currently on the U.S. Market are listed. Discuss differences between. It is important to note that the rapid acting agents should generally be injected within 5-10 minutes prior to the start of a meal to prevent hypoglycemia. Link: Table on Available Injectable and Insulin Preparations Link: Table on Pharmacokinetics of Various Insulins Administered Subcutaneously Link: Graphic on insulin action

Injecting Insulin Link: Video on Drawing and Preparation of Diabetic Injections Subcutaneous Injection sites Abdomen (most predictable) Outer upper arm Buttocks Hip Front and side of the thigh (most likely affected by exercise Insulin can be delivered via pen devices or using vial and syringe. The video demonstrates how these devices are typically used. It is important for patients to rotate injections within a site to prevent insulin hypertrophy. Image obtained from:

Pharmacotherapy in Type 1 Diabetes
Intermediate or Long-acting Basal Insulin AND Pre-meal Rapid or Short Acting Insulin Continuous Subcutaneous Insulin Infusion (CSII) aka “Insulin Pump” Link: Figure on relationship between insulin and glucose over the course of a day and how various insulin and amylinomimetic regimens could be given. Link: Chapter on Pancreatic Hormones & Antidiabetic Drugs Because the primary defect in Type 1 DM is insulin deficiency, treatment is focused on insulin replacement which will include both a basal and bolus component to meet the patients fasting and post-prandial insulin needs.

Insulin Regimen Profiles
Commonly used insulin regimens. Panel A shows administration of a long-acting insulin like glargine (detemir could also be used but often requires twice-daily administration) to provide basal insulin and a pre-meal short-acting insulin analog. Panel B shows a less intensive insulin regimen with BID injection of NPH insulin providing basal insulin and regular insulin or an insulin analog providing meal-time insulin coverage. Only 1 type of shorting-acting insulin would be used. Panel C shows the insulin level attained following subcutaneous insulin (short-acting insulin analog) by an insulin pump programmed to deliver different basal rates. At each meal, an insulin bolus is delivered. B, breakfast; L, lunch; S, supper; HS, bedtime. Upward arrow shows insulin administration at mealtime. This figure shows how the kinetic profile of the insulin used, its timing, and the mode of delivery (CSII vs SQ injection) can be used to cover a patient’s insulin needs throughout the day.

Initiating Insulin in Type 1 Diabetes (Slide 1 of 2)
Use an empiric dose (best “estimate” based on actual weight) Initial U/kg/day [Total Daily Dose (TDD)] May drop to U/kg/day during “honeymoon phase” as glucose toxicity resolves May increase to U/kg/day during illness or growth Since patients with Type 1 diabetes need a regimen of BASAL and BOLUS insulin, the TDD needs to be split. Usually start with a Basal-to-Bolus ratio of 50:50. Newly diagnosed Type 1 diabetic weighing 114 lbs. What is a reasonable initial total daily dose (TDD) of insulin? Using the TDD calculated above, what doses of basal and bolus insulin would the patient be started on?

Initiating Insulin in Type 1 Diabetes (Slide 2 of 2)
114 lbs ÷ 2.2 lbs/kg = 52 kg TDD = U/kg/day = units Using 26 units as the TDD 50% Basal = ~14 units QD 50% Bolus = 3 units breakfast, lunch, 4 units dinner These are estimated starting doses with room for adjustments.

Adjusting Insulin Doses
Fixed Dose Approach Look for patterns/trends in SMBG and patient characteristics to adjust and provide patient with a fixed prandial insulin dose. Dose adjustments by 1-2 units every few days Patient must be consistent in carbohydrate amounts at each meal Flexible Meal Dosing Approach Patients can have more flexibility from meal to meal by injecting per sliding scale to correct an elevation (correction dose) and provide coverage for carbohydrates in the meal. Amount of insulin to inject depends on insulin sensitivity and amount of carbs in the meal Correction dose calculated from patient’s insulin sensitivity (ranges from 1 U per 25mg/dL to 1 U per >60mg/dL). A conservative correction factor is 1 U per 50mg/dL. (measured blood glucose mg/dL – goal blood glucose mg/dL) ÷ Correction factor mg/dL/U = Correction dose Patients will also estimate pre-meal insulin requirements based on anticipated carbohydrates in meal (ranges 1 U for every 6 g of CHO up to 20 g of CHO). 1 U per 15 g CHO is good starting place Carbohydrates in meal g ÷ insulin:carb ratio = Units of insulin The goal is to match prandial insulin to carbohydrate intake, premeal glucose, and anticipated physical activity. Can be done using a fixed dose approach or flexible meal dosing

Pharmacotherapy in Type 2 Diabetes (Slide 1 of 2)
Lifestyle modifications Oral agents Non-insulin injectables Insulin Treatment for type 2 diabetes focuses on the primary defect of insulin resistance and excess glucagon and includes the addition of insulin in patients with defects in insulin secretion. Newer agents target other defects including glucagon-like peptide-1 (GLP-1) deficiency and upregulation of sodium glucose transport in the kidney.

Pharmacotherapy in Type 2 Diabetes (Slide 2 of 2)
Link: Infographic from the ADA 2017 Guidelines covering general recommendations for Antihyperglycemic therapy in Type 2 Diabetes. The ADA recommends in their 2017 consensus algorithm recommends that all patients diagnosed with diabetes engage in lifestyle modification that includes a healthy diet, weight loss, physical activity and diabetes education. Metformin is typically the first line therapy for most patients without contraindications.

Metformin (Slide 1 of 2) Biguanide
Primarily decreases hepatic glucose production; also increases peripheral insulin sensitivity Initial dose 500mg QD-BID with food. Titrated to maximum effective daily dose of 2000mg. Contraindicated at eGFR<30ml/min; not recommended to start when eGFR 30-45ml/min. Hold for 48 hours following iodinated contrast imaging if eGFR<60ml/min, or if liver disease, alcoholism, or heart failure Metformin’s utility in Type 2 diabetes is tied to its mechanism of improving insulin sensitivity and suppressing gluconeogenesis. To avoid GI upset, start patients on a low dose of 500mg once or twice a day with food and titrated as tolerated to the target dose of 2000mg per day. An extended release form is available and may help to reduce some of the GI upset seen with metformin when used BID. The FDA revised the labeling for metformin related to renal function in The previous recommendation of avoiding use below specific creatinine levels was modified to better reflect renal function by using the eGFR as a threshold. Lactic acidosis is rare when metformin is used within these guidelines.

Metformin (Slide 2 of 2) Monitoring Advantages
Diarrhea and abdominal cramping Lactic acidosis (rare) CBC/B12 levels Initial dose 500mg QD-BID with food. Titrated to maximum effective daily dose of 2000mg. Advantages Low risk for hypoglycemia as monotherapy Weight loss/weight neutral Long term safety record Low cost Efficacious

Concept Review GC is 24 year-old, obese, white female with a new diagnosis of Type 2 Diabetes and a history of polycystic ovarian syndrome. Her family history is unknown. She denies tobacco and alcohol use. Height: 5 ft 7in Weight: 300lbs BMI: 47 kg/m2 BP: 140/101 HbA1c 10.6% Plasma Glucose (non-fasting) 325mg/dL Creatinine 0.8mg/dL How should we approach treatment? Recall our patient GC. She is newly diagnosed with Type 2 diabetes and has a history of PCOS. Metformin is the drug of choice for this patient along with diabetes education and lifestyle changes. She will be initiated on 500mg once or twice a day with food a titrated to a target dose of 1000mg BID. Metformin also has benefits towards PCOS.

Selecting Add-on Therapy
Efficacy Weight Mechanism of action Blood pressure Cost Link: Table on Oral Agents for the Treatment of Type 2 Diabetes Mellitus Safety Contraindications Adverse effect profile Risk for hypoglycemia Extraglycemic effects Lipids When selecting add-on therapy there are several factors to consider as listed on the slide.

Patient Centered Considerations
Avoiding Hypoglycemia Avoiding Weight Gain Lower Costs Metformin Thiazolidinediones SGLT-2 Inhibitors Sulfonylureas GLP-1 Agonists DPP-IV Inhibitors Basal Insulin (NPH) In addition to its efficacy, Metformin’s side effect profile makes it an ideal first line agent and also prevents or avoids many of the adverse effects that can be problematic for some patients. When selecting an add-on agent, efficacy, safety, cost and patient preferences must be taken into account. For patients where hypoglycemia is a significant concern (elderly, beta blocker therapy, hypoglycemia unawareness, irregular eating habits) therapy can be driven towards these add-on therapies. Avoiding weight gain (or promoting weight loss) is a concern for most patients with type 2 Diabetes. These add-on therapies are weight neutral or produce modest weight loss. Costs are often a concern for patients on Medicare and the underinsured and uninsured. Even patients with insurance, may have significant out of pocket drug costs due to their comorbid conditions. The therapies listed here are typically less expensive than other options.

Sulfonylureas (Slide 1 of 2)
Enhance insulin secretion Glimepiride (Amaryl®) Initial: 1-2mg QD with breakfast; then 1-4mg QD. Max: 8mg QD Glipizide (Glucotrol®, Glucotrol XL®) Initial: 5mg QD 30 minutes before breakfast and titrate by 2.5-5mg Max: 20mg BID XL Initial: 5mg QD with breakfast. Max: 20mg QD Glyburide (Diabeta®, Micronase®) +metformin (Glucovance®) Initial: 2.5mg QD with breakfast and titrate by 2.5mg q week. Max: 20mg QD; Do not use in eGFR below 60ml/min The textbook reviews both first and second generation sulfonylureas, the latter of which are almost exclusively used in practice today due to a more favorable pharmacologic and kinetic profile that reduces the risk for hypoglycemia.

Sulfonylureas (Slide 2 of 2)
Interact with CYP2C9 inducers and inhibitors Monitoring Hypoglycemia Weight gain Advantages Long term safety record Low cost Efficacious

Meglitinides (Slide 1 of 2)
Stimulate insulin secretion Repaglinide (Prandin®) Initial: 0.5mg TID within minutes before the start of each meal. Titrate by doubling dose every week Max: 16mg a day Nateglinide (Starlix®) 120mg TID within 30 minutes before the start of each meal While not listed specifically in the ADA algorithm, the meglitinides may be used as an alternative to sulfonylureas in patients with irregular eating patterns or hypoglycemia as their faster onset and shorter duration provide for better coverage of the meal and less hypoglycemia.

Meglitinides (Slide 2 of 2)
Interact with CYP2C8 and CYP3A4 inducers and inhibitors Monitoring Hypoglycemia Weight gain Advantages More flexible dosing and less hypoglycemia compared to sulfonylureas

Thiazolidinediones Increase peripheral insulin sensitivity; decrease hepatic glucose Pioglitazone (Actos®) +metformin (ActosPlusMet®) Initial: 15-30mg QD; titrate to 45mg QD in 3-4 weeks Max: 45mg QD Interact with CYP2C8 and CYP3A4 inducers and inhibitors Monitoring Weight gain/edema AST/ALT Heart Failure Fractures Advantages No hypoglycemia A second TZD, rosiglitazone is marketed in the U.S. however its use has fallen out of favor due to an increased risk of myocardial infarctions in patients using it. TZDS should NOT be used in patient’s with NYHA 3-4 stage HF or in patients with elevated liver transaminases.

DPP-IV Inhibitors (Slide 1 of 2)
Reduce glucagon and improve insulin response to hyperglycemia Sitagliptin (Januvia®) +metformin (JanuMET®) Initial/typical: 100mg QD; Renal dosing: CrCl 30-50ml/min: 50mg QD; CrCl <30ml/min:25mg Saxagliptin (Onglyza®) +metformin (Kombiglyze®) Initial/typical: mg once daily; Renal dosing: CrCl <50ml/min: 2.5mg; CYP3A4/5 (-): 2.5mg Linagliptin (Tradjenta®) +metformin (Jentadueto®) Initial/typical: 5 mg QD Alogliptin (Nesina®) +metformin (Kazano®) Initial/typical: 25 mg QD Renal dose: CrCl ml/min: 12.5mg; <30 ml/min: 6.25mg

DPP-IV Inhibitors (Slide 2 of 2)
Monitoring Urticaria Angioedema Pancreatitis Worsening of heart failure Advantages Low risk for hypoglycemia Weight neutral

SGLT2 Inhibitors (Slide 1 of 2)
Increase urinary excretion of glucose Canagliflozin (Invokana®); +metformin (Invokamet®) Initial/typical: 100mg QAM, titrate 300mg QD Renal dose 100mg eGFR<60. Do not use below 45ml/min Dapagliflozin (Farxiga®); +metformin (Xigduo XR®) Initial/typical: 5mg QAM, titrate 10mg QD Do not use in eGFR below 60ml/min Empagliflozin (Jardiance®); +metformin (Synjardy®); +linagliptin (Glyxambi®) Initial/typical: 10mg QAM, titrated to 25mg QAM

SGLT2 Inhibitors (Slide 2 of 2)
Monitoring Genital mycotic infections Urinary tract infections Orthostatic hypotension DKA Advantages No hypoglycemia Weight loss Convenient, daily dosing, in the morning The most common adverse effects genital mycotic infections or urinary tract infections in women and uncircumcised men. Females are more likely to develop mycotic infections if they have had a previous episode.

GLP-1 Agonists (Slide 1 of 2)
Enhance insulin secretion (glucose-dependent), reduce postprandial glucagon secretion and increase satiety and slow gastric emptying Exenatide (Byetta®) Initial: 5mcg BID, 10mcg BID after 1 month. Give 60min before meals Exenatide ER (Bydureon®) Initial: 2mg SQ weekly Liraglutide (Victoza®) Initial: 0.6 mg QD AC for 1 week; then 1.2 mg QD; Max: 1.8 mg QD Dulaglutide (Trulicity®) Initial: 0.75mg SQ weekly, can increase to 1.5mg Albiglutide (Tanzeum®) Initial: 30mg SQ weekly, can increase to 50mg

GLP-1 Agonists (Slide 2 of 2)
Monitoring GI upset (contraindicated in gastroparesis) Injection site reactions Gall bladder disease Pancreatitis Advantages No hypoglycemia Weight loss Efficacious

Basal insulin Most effective add-on therapy
Titrated to bring AM fasting SMBG in range Mealtime bolus insulin added if A1c not at goal and/or as TDD approaches 0.5 units/kg/day Link: Insulin algorithm for type 2 diabetes mellitus in children and adults; initiation of once-daily therapy Hypoglycemia and injection site reactions Adding basal insulin (NPH, glargine, detemir, or degludec) is the most effective add-on agent at reducing the A1c and is typically started after metformin when the a1c remains above 9% as other agents are not likely to bring the a1c to goal at that level. The fasting AM BG becomes the primary target for making adjustments to the basal insulin dose. Insulin therapy can be progressed to a basal-bolus regimen when fasting targets are met but the A1c remains elevated. Total daily doses of basal insulin approaching 0.5 units/kg/day also typically require the addition of mealtime insulin. Hypoglycemia is the most common adverse effect. Injection site reactions can occur if sites are not rotated.

Concept Review GC returns for a follow-up 3 months later and is tolerating metformin at 1000mg BID. Blood glucose readings after dinner ’s. Has not met with dietician yet, but plans to in near future. Prior to appointment, patient has labs drawn: HbA1c 8.3% Glucose (non fasting) 192mg/dL What options are available as add-on therapy for GC’s diabetes management? How would the options change if she: Was 74 with an eGFR < 50ml/min? Was an uncircumcised male with a history of balanitis? Had a history of irritable bowel syndrome? Was 65 with an ejection fraction of 35% on diuretics? Had difficulty affording her medications? GC has been titrated to the target dose of Metformin yet her diabetes is not at goal. While any of the 6 add on therapies in the ADA algorithm would be appropriate for GC, the team may want to avoid the use of agents that contribute to weight gain given her obesity. This would eliminate the Sulfonylureas/glinides, insulin, and pioglitazone as options. A GLP1 agonist may be of particular interest as she would likely experience weight loss with these agents. Students can discuss the alternatives given the various scenarios.

Treatment Pre-Diabetes
Patients with IGT, IFG, or an A1c % Intensive lifestyle modification is most effective (~58% reduction in 3 years) 7% weight loss 150 min/week of moderate intensity physical activity Drug therapy (not as effective as lifestyle) Metformin Those with BMI >35kg/m2 Aged less than 60 years old Women with history of GDM Assessment and management of cardiovascular risk factors Obesity Hypertension Hyperlipidemia Smoking cessation As the number of adults with pre-diabetes increases and screening programs make identification of these individuals possible, pharmacists will be faced with more questions on how to prevent or delay the progression of pre-diabetes to diabetes. The DPP trial demonstrated that lifestyle modifications are most effective in most patients. Patients who were likely to benefit from drug therapy were women with GDM, younger patients and those with BMI’s >35kg/m2. Early identification of individuals with pre-diabetes also provides an opportunity for management of other risk factors related to diabetes and complications.

Preventing and Avoiding Drug Related Problems
Hypoglycemia Regular assessment Identify causes Education Appropriate treatment Medication Safety Heart failure Impaired renal function Gastrointestinal disease Pancreatitis Genitourinary symptoms Patient education on side effects Anticipated side effects How to manage/prevent When to report Hypoglycemia is one of the most common effects patients on insulin, sulfonylureas or meglitinides will experience. Pharmacists should ask at every encounter: How often do you experience low blood sugar? What are your symptoms of low blood sugar? What do you do when you think your blood sugar is low? Hypoglycemia is defined as a blood glucose value less than 70 mg/dl. It may be caused by: too much insulin, sulfonylurea, or glinide; Skipped meals, Increased activity, medication timing. Patients should be educated to recognize the symptoms of low blood sugar (shaky, confusion, sweaty, heart palpitations, etc) and to test the blood sugar when these symptoms occur. If the BG is less than 70, the “Rule of 15” can be applied: Administer 15 grams Carbohydrate, Wait 15 minutes, re-check blood sugar and Continue this every 15 minutes until blood sugar is above 70. The patient can then eat their meal. Many drug related problems can be avoided through the appropriate, individualized selection of agents. Conditions such as CHF, Impaired renal function, Gastrointestinal disease etc will guide therapy away from agents that may contribute to disease or exacerbate symptoms. A common example here is the avoidance of use of pioglitazone in patients with class 3/4 heart failure. Several of the DPP-4 inhibitors have similar warnings as well. Finally, pharmacists can provide patient education on side effects. Specifically for each agent the anticipated side effects, how to prevent or manage should they occur and what symptoms must be reported immediately.

References (Slide 1 of 3) American Diabetes Association. “FAST FACTS: Data and Statistics about Diabetes” ast_facts_ a.pdf. Updated Triplitt CL, Repas T, Alvarez C. Chapter 57. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; id= Accessed November 05, 2016. Herrier RN, Apgar DA, Boyce RW, Foster SL. Diabetes Mellitus. In: Herrier RN, Apgar DA, Boyce RW, Foster SL. eds. Patient Assessment in Pharmacy. New York, NY: McGraw-Hill; nid= Accessed November 05, 2016.

References (Slide 2 of 3) Diabetes Care 2016;39(Suppl. 1):S1–S108
James PA, Oparil S, Carter BL, et al Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA doi: /jama Stone NJ, et al ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;00:000–000

References (Slide 3 of 3) U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function Accessed November 12, 2016.

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