Updated 5/28/19 MRE Internal Medicine Clerkship Case

Internal Medicine Clerkship Case Discussions ______

Diabetes Mellitus Faculty Answer Guide

Objectives:

1. Define and discuss diagnostic criteria for impaired fasting glucose and impaired glucose tolerance. 2. Define and discuss diagnostic criteria for type I and type II diabetes mellitus, based on a history, physical examination, and laboratory testing. 3. Identify major causes of morbidity and mortality in diabetes mellitus (coronary artery disease, peripheral vascular disease, hypoglycemia, DKA, NKH coma, retinopathy, neuropathy— peripheral and autonomic, nephropathy, foot disorders, infections). 4. Identify laboratory tests needed to screen, diagnose, and follow diabetic patients including: glucose, electrolytes, blood urea nitrogen/creatinine, fasting lipid profile, HgA1c, urine microalbumin/creatinine ratio, urine dipstick for protein. 5. Compare and contrast non-pharmacologic and pharmacologic drugs and side effects noting advantages and disadvantages of treatment of diabetes mellitus to maintain acceptable levels of glycemic control, prevent target organ disease, and other associated complications. 6. Identify the specific components of the American Diabetes Association (ADA) dietary recommendations for type I and type II diabetes mellitus. 7. Outline the fundamental aspects of the American Diabetes Association (ADA) clinical practice recommendations and how they encourage high quality diabetes care. 8. Discuss basic management of hypertension and hyperlipidemia in the diabetic patient.

Clinical Case:

A 58-year-old male had type 2 diabetes mellitus diagnosed about three and a half years ago. In the first year after diagnosis he was maintained on diet alone with good blood sugar control but then increasing levels of blood sugar led to the use of metformin, which was gradually increased to 1000 mg with breakfast and dinner. With this regime, he obtained better blood sugar control with a hemoglobin A1C of 6.8% (normal to 6%). Subsequent to that he was lost to follow up and had not been checking his blood sugars at home. He now reappeared because he felt he should see his physician for a check-up and, more especially, has been troubled with the onset of other problems. He has not seen an ophthalmologist in over two years and his vision is now blurred even with glasses. He also is experiencing pain in his legs on walking two blocks. This pain resolves once he sits down and rests. He has noted pain in his toes which is worse at night and impairs his ability to sleep. When he finally got to sleep, he frequently awakes with drenching night sweats. His family history is strongly positive for diabetes and remarkable for hypertension and coronary artery disease.

His past medical history is positive for hypertension diagnosed about five years ago; his surgical history is negative. Aside from metformin, his only other medication is hydrochlorothiazide 50 mg each morning. There are no known allergies. He is married, works as a construction worker, and has two adult children, both in good health. He does not smoke or drink. Review of systems is positive for episodic constipation and impotence.

Updated 5/28/19 MRE

Physical Examination: Height: 5'10", weight 210 pounds (12 pounds more than at his last visit), BMI = 29 kg/m2, pulse 84 and regular, blood pressure 155/94. Head: Normocephalic. Eyes: Visual fields grossly intact. Extraocular muscle movements full. Funduscopic revealed bilateral microaneurysms. Ears, nose, mouth, throat, and neck were normal. Carotids: Left carotid bruit Thyroid: Normal. Lungs: Clear. Heart: Regular rate and rhythm, S1 and S2 normal, no S3 or S4. Grade I/VI systolic ejection murmur heard at the base. Abdominal exam: Normal. Extremities: Normal. Rectal: Normal. Stool negative for occult blood. Prostate: Smooth enlargement. Genitalia: Normal male. Extremities: No clubbing, cyanosis or edema. Skin: Normal. Lymph nodes: Negative. Peripheral vascular exam: Remarkable for bilateral femoral bruits and lack of pulses in the feet, as well as the left carotid bruit indicated above. Neurologic: Cranial nerves- normal. Motor - normal. Sensory - decreased vibration and pinprick sensation in the feet. Deep tendon reflexes - areflexic. Romberg: Negative. Cerebellar: Normal. Gait: Normal.

Laboratory data: Hemoglobin A1C 10.1%. BUN 17 Creatinine 1.3 Sodium 140 Potassium 4.9 Chloride 90 CO2 24

Urinalysis: Normal except for 1+ glucose. Albumin to creatinine ratio (ACR) = 16 mg/gm.

Total cholesterol 210 mg%. HDL 32 mg% LDL 150 mg% Triglycerides 290 mg%

TSH 1.2 mU/ml.

Questions:

1. What his hemoglobin A1c? What is an appropriate glycemic (HbA1C) goal for this patient?

ADA recommendations <7%, but individualize based on a patient’s health condition.

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2. Is there a role for diet and exercise in this patient who has failed on maximum dose of metformin?

Diet and exercise are the cornerstone of diabetes. Only ~10% attain acceptable control with Total Lifestyle Change.

3. How does metformin work?

By reducing hepatic glucose output via decreasing glycogenolysis & gluconeogenesis.

4. After 2 months of diet and exercise limited by his intermittent claudication, his HBGM results averaged 225 mg/dL and HbA1c was 9.5% Besides metformin, what are the other classes of oral anti-diabetic agents and what are their mechanisms of action?

Harrison's Principles of Internal Medicine, 20e > Diabetes Mellitus: Management and Therapies

Hba1c Mechanism of Agent-specific Agent-specific Examples reduction Contraindications action advantages disadvantages (1%) Oral Weight neutral, Renal insufficiency do not cause (see text for GFR ↓ Hepatic hypoglycemia, Diarrhea, nausea, lactic <45 mL/min), CHF, c* Biguanides glucose Metformin 1–2 inexpensive, acidosis, vitamin B12 radiographic production extensive deficiency contrast studies, experience, ↓ hospitalized CV events patients, acidosis Acarbose, Reduce α-Glucosidase ↓ GI glucose GI flatulence, liver miglitol, 0.5–0.8 postprandial Renal/liver disease c** absorption function tests inhibitors voglibose glycemia Prolong Alogliptin, endogenous linagliptin, Well tolerated, Angioedema/urticarial Dipeptidyl peptidase Reduced dose with GLP-1 action; saxagliptin, 0.5–0.8 do not cause and immune-mediated c*** renal disease IV inhibitors ↑ Insulin, ↓ sitagliptin, hypoglycemia dermatologic effects glucagon vildagliptin Glibornuride, gliclazide, Short onset of glimepiride, action, lower Insulin secretagogues: ↑ Insulin Hypoglycemia, weight glipizide, 1–2 postprandial Renal/liver disease c* secretion gain Sulfonylureas gliquidone, glucose, glyburide, inexpensive glyclopyramide Short onset of Mitiglinide Insulin secretagogues: ↑ Insulin action, lower nateglinide, 0.5–1.0 Hypoglycemia Renal/liver disease c*** secretion postprandial Nonsulfonylureas repaglinide glucose do not cause Canagliflozin, Urinary and genital Moderate renal Sodium-glucose ↑ renal hypoglycemia, ↓ dapagliflozin, infections, polyuria, insufficiency, cotransporter 2 glucose 0.5–1.0 weight and BP; empagliflozin, dehydration, insulin- deficient *** excretion see text for inhibitors ertugliflozin exacerbate tendency to DM CVD effect

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hyperkalemia and DKA; see text ↓ Insulin Peripheral edema, resistance, ↑ Pioglitazone, Lower insulin CHF, weight gain, c*** 0.5–1.4 CHF, liver disease Thiazolidinediones glucose rosiglitazone requirements fractures, macular utilization edema Parenteral Reduce Slow gastric Injection, nausea, ↑ risk postprandial Agents that also c,d*** emptying, ↓ Pramlintide 0.25–0.5 of hypoglycemia with Amylin agonists glycemia, slow GI motility glucagon insulin weight loss Renal disease, Albiglutide, ↑ Insulin, ↓ Weight loss, do agents that also dulaglutide, glucagon, not cause Injection, nausea, ↑ risk slow GI motility; GLP-1 receptor exenatide, slow gastric 0.5–1.0 hypoglycemia; of hypoglycemia with medullary c*** liraglutide, agonists emptying, see text for insulin secretagogues carcinoma of lixisenatide, satiety CVD effect thyroid, pancreatic semaglutide disease ↑ Glucose utilization, ↓ hepatic c,d**** glucose See text and Not Known safety Injection, weight gain, Insulin production, Table 397-4 limited profile hypoglycemia and other anabolic actions a Examples are approved for use in the United States; others are available in other countries. Examples b c may not include all agents in the class. HbA1c reduction (absolute) depends partly on starting HbA . 1c d Used for treatment of type 2 diabetes. Used in conjunction with insulin for treatment of type 1 diabetes. * ** *** **** Cost of agent in the United States: low, moderate, high, variable. Note: Some agents used to treat type 2 DM are not included in table (see text). Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; CV, cardiovascular; GI, gastrointestinal; HbA , hemoglobin A . 1c 1c

5. Besides reemphasizing the importance of diet, exercise, education and glycemic management, what else might you do for this patient at this time?

Blood pressure control, lipid control, evaluation for microvascular complications (eyes, kidney, foot care-nerves), evaluation for macrovascular complications (lipids, cardiovascular), carotid doppler, ABI

6. Is this patient’s blood pressure adequately controlled?

Per current ADA recommendations:

Updated 5/28/19 MRE

a. For individuals with diabetes and hypertension at higher cardiovascular risk (existing atherosclerotic cardiovascular disease or 10-year atherosclerotic cardiovascular disease risk >15%), a blood pressure target of <130/80 mmHg may be appropriate, if it can be safely attained. Grade C recommendation b. For individuals with diabetes and hypertension at lower risk for cardiovascular disease (10-year atherosclerotic cardiovascular disease risk <15%), treat to a blood pressure target of <140/90 mmHg. Grade A recommendation c. Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers). Grade A recommendation d. Multiple-drug therapy is generally required to achieve blood pressure targets. However, combinations of ACE inhibitors and angiotensin receptor blockers and combinations of ACE inhibitors or angiotensin receptor blockers with direct renin inhibitors should not be used. Grade A recommendation e. An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio ≥300 mg/g creatinine A or 30–299 mg/g creatinine. B If one class is not tolerated, the other should be substituted. Grade B recommendation

7. Has kidney function been satisfactorily evaluated?

Yes, need to evaluate annually. normal albumin to creatinine ratio <30 mg/g. 30-300 = microalbuminuria, >300 macroalbuminuria, >3000 nephrotic syndrome

8. Is his lipid control adequate?

a. For patients of all ages with diabetes and atherosclerotic cardiovascular disease or 10-year atherosclerotic cardiovascular disease risk >20%, high-intensity statin therapy should be added to lifestyle therapy. Grade A recommendation b. For patients with diabetes aged <40 years with additional atherosclerotic cardiovascular disease risk factors, the patient and provider should consider using moderate-intensity statin in addition to lifestyle therapy. Grade C recommendation c. For patients with diabetes aged 40–75 years A and >75 years B without atherosclerotic cardiovascular disease, use moderate-intensity statin in addition to lifestyle therapy. d. In patients with diabetes who have multiple atherosclerotic cardiovascular disease risk factors, it is reasonable to consider high-intensity statin therapy. Grade C recommendation e. For patients who do not tolerate the intended intensity, the maximally tolerated statin dose should be used. Grade E recommendation f. For patients with diabetes and atherosclerotic cardiovascular disease, if LDL cholesterol is ≥70 mg/dL on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor). A Ezetimibe may be preferred due to lower cost. g. Statin therapy is contraindicated in pregnancy. Grade B recommendation

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9. What is the standard of eye care for this patient?

Annual, by ophthalmologist or fundus photos

10. The patient’s neurologic symptoms have not resolved. What can be done?

a. Refer to podiatrist if-smoker, h/o lower-extremity complications, loss of protective sensation, structural abnormalities, peripheral arterial disease. b. Good glycemic control c. Analgesics, d. FDA approved: Anticonvulsants-Pregabalin (lyrica), duloxetine (cymbalta); tapentadol (an opioid); e. Non FDA approved: Gabapentin, carbamazepine, tramadol, tricyclic antidepressants, venlafaxine, Capsaicin

11. What is the cause of his nocturnal night sweats?

Autonomic neuropathy. Rule out hypothyroidism, hypogonadism. Hypoglycemia unlikely

12. What is the cause of the patient’s impotence?

Microvascular disease, autonomic neuropathy. Rule out hypogonadism.

13. Pharmacologically, what else can be done for this patient?

a. For secondary prevention of established CV disease, benefit of ASA is well known. b. For primary prevention (ASCEND trial 2018): i. Adults with DM 1 or DM 2 who are at high CV risk (10-year risk >10%) e.g. most men and women with DM aged ≥50 years who have at least one additional major risk factor (F/H of premature atherosclerotic CV disease, hypertension, smoking, dyslipidemia, or albuminuria) and are not at increased risk of bleeding. Can consider aspirin (75–162 mg/day. ii. Risk of major bleeding may be > benefit after 60 yr age. iii. Adults with DM aged <50 years with moderate CV risk (10-year risk 5-10%) e.g. multiple other risk factors. clinical judgment is required. iv. Adults with DM at low risk (10-year risk <5%) e.g. men and women with DM aged <50 years with no major additional atherosclerotic CV disease risk factors, CV benefit < risk of major bleeding (e.g. intracranial hemorrhage, sight-threatening bleeding in the eye, GI bleeding, any other serious bleeding that resulted in hospitalization or transfusion or was fatal). Aspirin should not be recommended.

Updated 5/28/19 MRE

References:

Diabetes Standards of Care Guidelines, 2019. http://care.diabetesjournals.org/content/42/Supplement_1

Harrison’s Principles of Internal Medicine, 20e. Chapter 396: Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology https://accessmedicine-mhmedical- com.archer.luhs.org/content.aspx?sectionid=192288322&bookid=2129&Resultclick=2

Harrison’s Principles of Internal Medicine, 20e. Chapter 397: Diabetes Mellitus: Management and Therapies https://accessmedicine-mhmedical- com.archer.luhs.org/content.aspx?sectionid=192288412&bookid=2129&Resultclick=2

Harrison’s Principles of Internal Medicine, 20e. Chapter 398: Diabetes Mellitus: Complications https://accessmedicine-mhmedical- com.archer.luhs.org/content.aspx?sectionid=192288577&bookid=2129&Resultclick=2

Harrison’s Manual of Medicine, 19e. Chapter 173: Diabetes Mellitus https://accessmedicine-mhmedical- com.archer.luhs.org/content.aspx?sectionid=127559730&bookid=1820&Resultclick=2

Symptom to Diagnosis: An Evidence-Based Guide, 3e. 12: Diabetes https://accessmedicine-mhmedical- com.archer.luhs.org/content.aspx?sectionid=61697929&bookid=1088&Resultclick=2

Updated 5/28/19 MRE