Endocrinology Cases and Clinical Pearls QUANG NGUYEN, DO, FACE, FTOS LAS VEGAS ENDOCRINOLOGY 5/5/18

Q1 A 59-year-old man with an 18-year history of diabetes mellits is being treated with inslin glargine and metformin. He has had longstanding hypertension, hyperlipidemia, and renal insfficiency, bt no previos heart attack or stroke. His review of systems is negative. He stopped smoking cigarettes 2 years ago. He asks for recommendations to help him redce his risk of a cardiovasclar event. Both his father and paternal ncle have diabetes and developed coronary artery disease reqiring stenting.

Q1 His medication regimen is as follows: inslin glargine, 36 nits at bedtime metformin, 500 mg twice daily atorvastatin lisinopril hydrochlorothiazide amlodipine

Q1 Blood pressre is 138/82 mm Hg and plse rate is 88 beats/min. His height is 73.5 in (186.7 cm), and weight is 247 lb (112 kg) (BMI = 32.1 kg/m2). Eye examination reveals bilateral retinal microanerysms. On cardiac examination, he has a reglar rate and rhythm, a lod S4, no S3, and no mrmrs. There are no carotid brits. His abdomen is obese with no striae or renal brits. On nerologic examination, there is symmetric decreased light toch and vibration sense in both feet.

Q1 Laboratory test reslts: Hemoglobin A1c = 8.3% (4.0%-5.6%) Fasting glcose = 142 mg/dl (70-99 mg/dl) Serm rea nitrogen = 31 mg/dl (8-23 mg/dl) Creatinine = 1.8 mg/dl (0.7-1.3 mg/dl) Estimated glomerlar filtration rate = 40 ml/min per 1.73 m2 (>60 ml/min per 1.73 m2) Liver fnction, normal

Q1 Yo decided to add therapy. Which of the following is the best agent for this patient? A. Premeal aspart inslin B. Glipizide C. Acarbose D. Sitagliptin E. Liragltide

14 Classes of Drgs Available for the Treatment of Type 2 DM in the USA ### Class A1c Redction Hypoglycemia Weight Change Dosing (times/day) 01 Metformin 1.5-2.0 No Netral-Loss 2-3 02 GLP-1 agonists 0.5-1.5 No Loss 1-2, QW Injected 03 DPP-IV inhibitors 0.6-0.8 No Netral 1, QW 04 SGLT2 inhibitors 0.8-1.2 No Loss 1 05 Slfonylreas 1.5-2.0 Yes Gain 1-2 06 Repaglinide 1.0-1.5 Yes Gain 3 07 Nateglinide 0.5-0.8 Rare Gain 3 08 Bromocriptine 0.5-0.7 No Netral 1 09 Bile acid seqestrant 0.5 No Netral 1-2 10 α-glcosidase inhibitor 0.5-0.8 No Netral 3 11 Thiazolidinediones 0.5-1.4 No Gain 1 12 Amylin mimetics 0.5-1.0 No Loss 3, Injected 13 Inslin, rapid-acting 1.5-2.5 Yes Gain 1-4, Injected 14 Inslin, long-acting 1.5-2. 5 Yes Gain 1-2, Injected

The Ominos Octet Islet b-cell Impaired Inslin Secretion Islet a-cell Decreased Incretin Effect Increased Lipolysis Increased Glcagon Secretion Increased Glcose Resorption Increased Hepatic Glcose Prodction Nerotransmitter Dysfnction Decreased Glcose Uptake

Complementary Mechanisms of Action of Crrent Diabetes Medications Inslin SlfonylreasIslet b-cell Megltinides TZDs GLP-1 RA GLP-1 RA DPP-4 inhibitors Decreased Incretin Effect Impaired Inslin Secretion GLP-1 RA Islet a-cell DPP-4 inhibitors Pramlintide Bromocriptine GLP-1 RA Increased Hepatic Glcose Prodction Nerotransmitter Dysfnction Diabetes 2009;58:774-795 Increased Lipolysis SGLT-2 inhibitors Increased Glcose Resorption Increased Glcagon Secretion Metformin Inslin TZD GLP-1RA Inslin TZDs Inslin TZDs Decreased Glcose Uptake

Diabetes Cardiovasclar Otcome Trials Drg MACE CV Non-Fatal Non-Fatal Death MI Stroke Empagliflozin SGLT2i Canagliflozin SGLT2i Liragltide GLP-1A Semagltide GLP-1A Exenatide GLP-1A Lixisenatide GLP-1A ITCA 650 GLP-1A Saxagliptin DPP-IVi Sitagliptin DPP-IVi Alogliptin DPP-IVi Acarbose a-glcosidase = speriority = non-inferiority

QUESTIONS? Endocr Pract 2016;22 (No. 1)

GLP-1 Receptor Agonists Exenatide (Byetta) Lixisenatide (Lyxmia) Liragltide (Victoza) Dlagltide (Trlicity) Exenatide ER (Bydreon) Albigltide (Tanzem) Semagltide (Ozempic)

GLP-1 Agonists

Incretin Effect in Healthy Sbjects

Beta-Cell Workload and Response Are Balanced in Healthy Sbjects Carbohydrate Meal Healthy Sbjects Inslin (µu/ml) Glcagon (pg/ml) Glcose (mg/dl) 120 60 0 140 120 100 360 300 240 140 80 Meal -60 0 60 120 180 240 Time (min) n = 14; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:109-115

Beta-Cell Workload Otpaces Response in Type 2 Diabetes Inslin (µu/ml) Glcagon (pg/ml) 120 60 0 140 120 100 Carbohydrate Meal Healthy Sbjects Type 2 Diabetes Glcose (mg/dl) 360 300 240 140 80 Meal -60 0 60 120 180 240 Time (min) N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:109-115

GLP-1 Actions Increase inslin secretion in a glcose-dependent manner Decrease glcagon secretion from pancreas Increases B-cell mass, increase inslin secretion Decrease food intake by increasing satiety Promote inslin sensitivity A1c: 1-1.5%

Exenatide Restores First-Phase Inslin Response Type 2 Diabetes Healthy Controls Placebo Inslin (pm/kg/min) Inslin (pm/kg/min) 20 10 0 Exenatide 30 30 20 Exenatide 10 Placebo 0-180 -90 0 30 60 90 Glcose Time (min) 120-180 -90 0 30 60 90 120 Glcose Time (min) Evalable; N = 25; Mean (SE) Data from Fehse F, et al. Diabetologia. 2004;47 (sppl 1): A279

* * * * * * Postprandial GLP-1 Concentrations Are Lower in Patients With IGT and Type 2 Diabetes Meal Healthy (n = 33) IGT (n = 15) Type 2 Diabetes (n = 54) 20 GLP-1 (pmol/l) 15 10 5 * * 0 0 60 120 180 240 Time (min) Mean ± SE; *P<0.05 between patients with type 2 diabetes and healthy sbjects; IGT indicates impaired glcose tolerance Data from Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723

The GLP-1 Receptor Agonist Class: Pharmacokinetic Properties GLP-1 Receptor Agonist Short-acting (<24 hors) Long-acting ( 24 hors) Exenatide BID Lixisenatide QDay Liragltide QDay Dlagltide QWeek Albigltide QWeek Semagltide QWeek Exenatide QWeek Byetta. Smmary of Prodct Characteristics 1 ; Lyxmia. Smmary of Prodct Characteristics 2 ; Victoza. Smmary of Prodct Characteristics 3 ; Diabetes Obes Metab 2011;13:434-438 4 ; Diabetes Obes Metab 2009;11:498-505 5 ; J Clin Endo Metab 2008;93:4810-4817 6 ; Novo Nordisk. Data on file; 8. Clin Pharmacokinet 2011;50:65-74 7

Short- and Long-acting GLP-1 Receptor Agonists Have Different Effects on Glcose GLP-1 Receptor Agonist Short-acting (<24 hors) Long-acting ( 24 hors) FPG PPG FPG PPG Bols > Basal Basal > Bols Diabetes Obes Metab 2012;14:675

Q1 Yo decided to add therapy. Which of the following is the best agent for this patient? A. Premeal aspart inslin B. Glipizide C. Acarbose D. Sitagliptin E. Liragltide

Q2 A previosly healthy 20-year-old African American man comes to clinic for a follow-p visit. He was hospitalized for treatment of diabetic ketoacidosis 4 months ago. Laboratory test reslts at hospital admission: Plasma glcose = 748 mg/dl (70-99 mg/dl) Bicarbonate = 10 meq/l (21-28 meq/l) Anion gap = 22 meq/l (3-11 meq/l) Creatinine = 2.2 mg/dl (0.7-1.3 mg/dl) Estimated glomerlar filtration rate = 34 ml/min per 1.73 m2 (>60 ml/min per 1.73 m2) Moderate ketones present in the serm

Q2 Admitted to Valley Hospital Medical Center. He was treated with intravenos flids and a continos inslin infsion. The acidosis resolved and he was discharged on basalbols inslin. The total inslin dose at the time of discharge was 1.0 nits/kg per day. He received diabetes edcation and has modified his diet. He has lost 22 lb (10 kg) since hospital discharge. The inslin doses have been gradally redced over time. He is now administering 12 nits of inslin glargine at bedtime and 3 nits of inslin aspart before breakfast and dinner (he only eats 2 meals per day). The 2-week average glcose vale is 107 mg/dl. The fasting glcose vales range from 79 to 106 mg/dl.

Q2 On physical examination, his height is 73 in (185 cm) and weight is 142 lb (BMI = 18.7 kg/m2). His blood pressre is 122/83 mm Hg, and plse rate is 82 beats/min. There is no evidence of acanthosis nigricans. The cardiac, lng, abdominal, and nerologic findings on examination are all normal.

Q2 Crrent laboratory test reslts (fasting): Hemoglobin A1c = 5.8% (4.0%-5.6%) Creatinine = 1.3 mg/dl (0.7-1.3 mg/dl) Estimated glomerlar filtration rate = >60 ml/min per 1.73 m2 (>60 ml/min per 1.73 m2) Electrolytes, normal TSH, normal C-peptide = 3.2 ng/ml (0.9-4.3 ng/ml) Glcose = 124 mg/dl (70-99 mg/dl) Gltamic acid decarboxylase antibodies: POSITIVE

Q2 Which of the following is the best next step in treating this patient s diabetes? A. Stop inslin and start empagliflozin B. Stop inslin aspart and start glimepiride C. Stop all inslin and start metformin D. Stop inslin aspart and contine diet treatment E. Contine the crrent inslin regimen

Honeymoon Phase

Honeymoon Phase Period of time shortly following diabetes diagnosis when the pancreas is still able to prodce enogh amont of inslin to aid blood glcose control. Seqence: DKA When a patient starts on inslin injections, the pancreas is nder less pressre to prodce inslin. This period of rest, afforded by the injections, stimlate the pancreas to prodce inslin from the remaining beta cells. However, after a period of months, the vast majority of these remaining beta cells will also be destroyed, and the honeymoon period ends when the pancreas stops prodcing sfficient inslin to aid blood glcose control any more.

Q2 (Honeymoon Phase) Which of the following is the best next step in treating this patient s diabetes? A. Stop inslin and start empagliflozin B. Stop inslin aspart and start glimepiride C. Stop all inslin and start metformin D. Stop inslin aspart and contine diet treatment E. Contine the crrent inslin regimen

Q3 A 54-year-old man is referred to yo after a low serm testosterone concentration (120 ng/dl [4.2 nmol/l]) was identified dring the workp of new-onset erectile dysfnction. He has noted no change in weight and no new headache pattern. He has no history of hypertension or diabetes mellits.

Q3 On physical examination, his blood pressre is 128/75 mm Hg. His height is 69 in (175.3 cm), and weight is 177 lb (80.5 kg) (BMI = 26.1 kg/m2). Examination findings are normal. Testes are 10 ml bilaterally. Formal visal field testing shows a mild bitemporal defect.

Q3 Laboratory test reslts: LH = 2.0 miu/ml (1.0-9.0 miu/ml) (SI: 2.0 IU/L [1.0-9.0 IU/L]) FSH = 4.2 miu/ml (1.0-13.0 miu/ml) (SI: 4.2 IU/L [1.0-13.0 IU/L]) Prolactin = 81 ng/ml (4-23 ng/ml) (SI: 3.5 nmol/l [0.17-1.00 nmol/l]) Cortisol (8 AM) = 21 µg/dl (5-25 µg/dl) (SI: 579.3 nmol/l [137.9-689.7 nmol/l]) Free T4, normal TSH, normal IGF-1, normal

Q3 2.3 x 2.2 cm pititary macroademona with sprasellar extension

Q3 (bitemporal hemianopsia)

Q3 Which of the following is the most appropriate next management step? A. Measre macroprolactin B. Start therapy with bromocriptine or cabergoline C. Refer to nerosrgery D. Start testosterone therapy E. Measre ACTH

Q3 (Pititary Adenoma) Common: 10% incidental findings 2 Qestions: 1) Fnctionality Check hormones: (FSH, LH, IGF-1, Prolactin, TSH, ACTH, alpha sbnits) Other tests: CBC, CMP, testosterone, estradiol, am cortisol 2) Physical compression Visal field testing

Q3 Testosterone = 120 ng/dl (350-1100 ng/dl) LH = 2.0 miu/ml (1.0-9.0 miu/ml) FSH = 4.2 miu/ml (1.0-13.0 miu/ml) Prolactin = 81 ng/ml (4-23 ng/ml) 1 cm = 200 ng/ml Pearls: Don t act only on a low testosterone Normal vales don t mean they are normal. Evalate in relation to the hormonal abnormalities

Q3 Pititary Stalk Compression

Q3 Which of the following is the most appropriate next management step? A. Measre macro-prolactin B. Start therapy with bromocriptine or cabergoline C. Refer to nerosrgery D. Start testosterone therapy E. Measre ACTH

Q4 29 yo male presented with 3 yr hx of headache, decreased peripheral vision and low libido No meds Exam: BMI: 40.3 kg/m2 BP: 120/82, HR 92 Bitemporal visal loss on confrontation Breast and GU exam: normal

Q4 Laboratory data: Prolactin= 36 ng/dl (N: 4-23) Total testosterone= 88 ng/dl (N: 240-800) FSH= 4.2 (N: 1-13) LH= 2.8 (N: 1-9) IGF-1= 188 (N: 182-780) TSH= 2.9 (N: 0.45-4.5) 8 am cortisol= 24 (N: 7-26) Free T4: 1.1 (N:0.8-1.77)

Q4 Radiologist read very big tmor present in the pititary gland extending otside the sella trcica and protrde into the cavernos sinses Measred: 5.0 x 5.2 x 5.6 cm

Q4 Qestion: Which one of the following is the next best step? A. Initiate medical therapy with bromocriptine B. Measre 24 hr rinary cortisol C. Re-measre prolactin with serial diltions D. Perform transphenoidal srgery to remove the tmor E. Measre sodim level

Q4 HOOK EFFECT

Figre 2 Schematic illstrating the principle of a two-site immnometric assay for prolactin Smith TP et al. (2007) Technology Insight: measring prolactin in clinical samples Nat Clin Pract Endocrinol Metab 3: 279 289 doi:10.1038/ncpendmet0447

Hook Effect

Q4 Prolactin was remeasred at 1:10 and 1:100 diltions and the actal vale was 6400 ng/dl (N: 4-23) Final diagnosis: PROLACTINOMA

Q4 (Smmary) Hook effect is present in 6% of clinically nonfnctioning adenomas and 14% of pititary macroadenoma Correct diagnosis is important as prolactinoma can be treated medically whereas nonfnctioning macroadenoma will reqire srgery

Clinical Pearls 1. Serial diltions of serm PRL are mandatory in the diagnostic evalation of patients with large pititary tmors 2. Prolactin level correlates with the size of the prolactinoma

Hang in there

Q5 65 yo woman with cc: hypercalcemia Underwent menopase 14 years ago Denies h/o kidney stones or broken bones bt is constipated and always tired

Q5 DXA scan 5 years ago revealed osteoporosis at the wrist Hip T: -1.7 Spine T: -1.5 Wrist: T: -2.9

Q5 Meds: Calcim carbonate 500 mg tidac Vitamin D3: 2000IU/day Eats 3 cps of yogrt and drinks 2-3 glasses of milk daily Fosamax 70 mg weekly Fmhx: negative Physical Exam: Unremarkable

Q5 Labs: CMP NL except: Calcim: 10.4 (8.2-10.2) Albmin: 4.0 Phosphors: 2.8 Vitamin D: 32 PTH: 46 (10-65) Urinary calcim: 300 mg/24 hr (100-250 mg/24 hr) Urinary Creatinine: 1gm/24 hr

Q5 Which one of the following is the most likely case of the patient s hypercalcemia? A. Hypercalcemia of malignancy B. Milk-alkali syndrome C. Primary hyperparathyroidism D. Familial hypocalciric hypercalcemia (FHH) E. Sarcoidosis

Q5 Labs: CMP NL except: Calcim: 10.4 (8.2-10.2) Albmin: 4.0 Phosphors: 2.8 Vitamin D: 32 PTH: 46 (10-65) Urinary calcim: 300 mg/24 hr (100-250 mg/24 hr) Urinary Creatinine: 1gm/24 hr

Q5 PTH is INAPPROPRIATELY NORMAL in the setting of hypercalcemia Calcim 10.4 (<10.2), PTH 46 (10-65) Occr in 15-20% of all primary hyperparathyroidism cases Main cle: Worst DXA vales at WRIST

Densitometric Signatre of Primary Hyperparathyroidism Silverberg et al. JBMR, 1989

Q5 Workp: History: bones, stones, abdominal moans, and psychological overtones DXA 24 hr rinary calcim with Cr. Sestamibi scan +/- parathyroid Ultrasond CT angiogram of parathyroid 4-D CT with SPECT imaging MRI

Withot Parathyroid Srgery 15- Year Natral History

Withot Parathyroid Srgery 15- Year Corse of BMD

Indications for Srgery in Asymptomatic Primary Hyperparathyroidism Serm Ca > 1.0 mg/dl pper normal BMD < -2.5 at any sites or fractres Urinary calcim excretion (24 hr) > 400 mg/d Age < 50

Clinical Pearls Strong correlation between PTH level and calcim concentration, jst becase there is no H or L next to the lab doesn t mean it s normal. Always think abot primary hyperparathyroidism when wrist DXA vale is ot of proportion to the rest of the DXA scan

Thank God He Stopped Talking!!!