Diabetes Family Medicine Board Review Sarah Kim, MD Assistant - PowerPoint PPT Presentation

Diabetes Family Medicine Board Review Sarah Kim, MD Assistant Clinical Professor of Clinical Medicine, UCSF Division of Endocrinology, SFGH March 9, 2017

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Diabetes Test Topics • Majority Type 2 Diabetes (vs. Type 1) • Medications – mechanism of action, contraindications • Standards of care (CVD risk reduction, etc) • Treatment of complications • Newest medications & recommendations unlikely to be on the test 3

Case #1 64 yom with HTN, CAD, CHF and hyper-TG with a prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. An A1C was obtained and was 6.4%. The patient has no symptoms such as polyuria, polydipsia or polyphagia. Does he meet the criteria for the diagnosis of diabetes? 4

Diagnosis of Diabetes & Pre-diabetes Pre-Diabetes Criteria Diabetes Criteria* Fasting Glucose 100-125 mg/dL ≥ 126 mg/ dL 2 hour post 75g 140-199 mg/dL ≥ 200 mg/ dL OGTT Random glucose N/A ≥ 200 with symptoms of hyperglycemia HbA1c 5.7- 6.4%** ≥ 6.5%** *unless unequivocally hyperglycemic, results should be confirmed with another or repeat test ** in absence of anemia or hemoglobinopathy Diabetes Care, Vol 35, Supp 1, 2012

Case #1 continued You obtain a fasting BG which is 154 mg/dl confirming the diagnosis of diabetes mellitus for which he has a strong family history. You obtain further labs and plan to start treatment. MEDS : EXAM : 100 kg; BMI 32; BP 145/95 • furosemide 40 mg BID sitting, 120/84 standing • KCl 20 meq • Lungs: CTA • ASA 81 mg • CV: S3 gallop • lisinopril 40 mg • Ext: 1+ edema, feet with no • metoprolol 100 mg BID ulcerations, normal monofilament exam LABS : A1C = 6.4%, 140 111 28 Lipids: TC 350;LDL NC;HDL 22;TG 505 4.5 28 2.5 eGFR 44 6

Case #1 Which of the following medications would be the most appropriate initial therapy for this patient ’ s DM2? A. metformin B. bromocriptine C. colesevalem D. pioglitazone E. glipizide F. exenatide 7

Case #1 Which of the following medications would be the most appropriate initial therapy for this patient ’ s DM2? A. metformin B. bromocriptine C. colesevalem D. pioglitazone E. glipizide F. exenatide 8

Beta Cell Loss in Diabetes T1DM Non Diabetic T2DM

Sulfonylureas • Mechanism: binds ATP-dependent K+ channels on surface of beta cells  opening voltage gated Ca++ channels  release of insulin. • Lower A1C 1-2% • Advantages – Long history of use & cheap • Disadvantages – Weight gain ( ≈ 2 kg) – Hypoglycemia – Must be dose reduced in renal and liver – Ongoing, unsettled debate on whether SU’s increase CV mortality 10

Sulfonylureas 2 nd generation Duration Daily Dose Glipizide 6-12hr 2.5-20mg once daily (XL version= 24 hr) or 2 divided doses Glyburide 20-24hr 2.5-10mg once daily Glimepiride 24hr 2-4 mg once daily 1 st generation Duration Daily Dose Chlorpropamide 24-72hr 250-500mg once daily Tolbutamide 6-12hr 500-2000 mg in 2-3 divided doses Tolazamide 10-24hr 100-500mg daily U. Masharani and M. German, Ch 18 Pancreatic Hormones and Diabetes Mellitus. In: D Shoback and D Gardner (editors): Greenspan’s Basic and Clinical Endocrinology, 8 th edi. McGraw Hill 2007.

Meglitinides • Enhances insulin release like sulfonylureas • Repaglinide lowers A1C 1-1.5%; Nateglinide 0.2-0.6% • Advantages: – Short acting (take 15 minutes prior to meals) – Repaglinide undergoes little renal clearance • Disadvantages – qAC dosing – Hypoglycemia (less than sulfonylureas) – More expensive than SU 12

Meglitinides Drug Duration of Action Daily Dose Nateglinide 1.5 hr 60-120mg qAC Repaglinide 3 hr 0.5-2mg qAC U. Masharani and M. German, Ch 18 Pancreatic Hormones and Diabetes Mellitus. In: D Shoback and D Gardner (editors): Greenspan’s Basic and Clinical Endocrinology, 8 th edi. McGraw Hill 2007.

Sulfonylureas Meglitinides Biguanides

Biguanides (Metformin) • Inhibits hepatic gluconeogenesis & increases peripheral insulin sensitivity • Lowers A1C 1.5-2% • Advantages: – Weight loss (0-2 kg) – Lowers TG, LDLc; Increases HDLc – No hypoglycemia when used alone – Long history of use and cheap – CVD and cancer benefit? • Disadvantages – Majority of patients with GI side effects (titrate slowly) – Impaired B12 absorption (5% or more of patients) – Reputation for risk of lactic acidosis (risk=small/non-existent?) 15

Metformin Biguanide Duration Daily Dosing Metformin 7-12 hr • 1000-2250mg in 2-3 divided doses XR version 24 hrs • 500-2000mg nightly 16 U. Masharani and M. German, Ch 18 Pancreatic Hormones and Diabetes Mellitus. In: D Shoback and D Gardner (editors): Greenspan’s Basic and Clinical Endocrinology, 8 th edi. McGraw Hill 2007.

Metformin Contraindications: • Renal insufficiency – PA still says creatinine ≥1.5 men, ≥ 1.4 in women or abnormal Cr Cl – Will hopefully be updated • End stage liver disease (ok in mild-mod cirrhosis) • Excessive alcohol use- theoretical • Iodinated contrast – Discontinue within 48 hrs of exposure • Elderly (≥80 yo unless normal renal function)-theoretical • Severe or acute CVD- particularly unstable CHF or AMI- theoretical

TZDs Sulfonylureas Meglitinides Biguanides

Thiazolidinediones (TZD) • Activate PPAR- γ , improve insulin sensitivity by altering gene transcription (takes 8-12 weeks for max effect) • Lower A1C 0.5-1.4% • CVD risk possibly increased with rosiglitazone & decreased with pioglitazone • Advantages: – Improves decreases TG, increases in HDL (pioglitazone) – No hypoglycemia when used alone 19

TZDs Drug Duration Dosing Pioglitazone 24 hr 15-45 mg qDay Rosiglitazone 24 hr 4-8 mg qDay or BID U. Masharani and M. German, Ch 18 Pancreatic Hormones and Diabetes Mellitus. In: D Shoback and D Gardner (editors): Greenspan’s Basic and Clinical Endocrinology, 8 th edi. McGraw Hill 2007.

TZDs Adverse Event Frequency Increased Risk vs Placebo Edema 5% 2 fold Congestive Heart Failure 5% 2-7 fold Weight Gain 60% +0.5-4 kg Fractures 2-5% 2 fold Bladder Cancer 0.3% 20%

TZDs Sulfonylureas Meglitinides Biguanides SGLT2 inhibitors

Sodium Glucose Co-Transporter 2 Inhibitors • Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption in proximal tubule • Renal glucose reabsorption is increased in type 2 diabetes • Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose J Intern Med . 2007;261:32-43.

Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% 10% No Glucose J Intern Med . 2007;261:32-43. Endocr Pract . 2008;14:782-790

Dapagliflozin: Glucosuric and Metabolic Effects ↑ 52-85 g/day Glucosuria ↓ 16-30 mg/dL FPG ↓ 23-29 mg/dL PPG ↓ 2.2- 3.2 kg (↓ 2.5% -3.4%) Body weight ↑ 107-470 mL/day Urine volume List JF, et al. Diabetes Care . 2009;32:650-657.

SGLT2 Inhibitors Lowers A1C about 0.6-1% at max dose • • No hypoglycemia when used alone or with MF • Advantages – Weight loss 2.5-4 kg – Decrease in SBP 5 mmHg – CV mortality benefit – Reduces albuminuria • Disadvantages – Increased mycotic genital infections in men (4%) and women (10%) – UTIs (5%) – Bladder cancer concern – Polyuria, presyncope/sycope, fractures – Increases Cr, decreases eGFR (contraindicated in lower GFR), hyperkalemia – $$$

SGLT2 Inhibitors Duration Dose Canagliflozin* 24 hrs 100-300mg daily Dapagliflozin* 24 hrs 5-10mg daily Empagliflozin* 24 hrs 10-25 mg daily * Renal dosing/contraindicated in renal failure

Case #1 continued 64 yom with HTN, CAD, CHF and hyperTG with a prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. The patient has no symptoms such as polyuria, polydipsia or polyphagia. MEDS : EXAM : 100 kg; BMI 32; BP145/94 • furosemide 40 mg BID • Lungs: CTA • KCl 20 meq • CV: S3 gallop • ASA 81 mg • Ext: 1+ edema , feet with no • lisinopril 40 mg ulcerations, normal monofilament • metoprolol 100 mg BID exam LABS : A1C = 8.8%, 140 111 28 Lipids: TC 350;LDL NC;HDL 22; TG 505 4.5 28 2.5 eGFR 44 28

Case #1 Which choice below would be the most appropriate initial therapy for this patient ’ s DM2? A. metformin B. glyburide C. canagliflozin D. pioglitazone E. glipizide F. exenatide 29

Case #2 54 yow with DM2 diagnosed 7 years ago presents to you for f/u complaining of increasing hypoglycemia and several URIs. At your last visit you added sitigliptin (Januvia) to her medications for an A1C of 7.6% and persistent SMBG values in the 200s. DM MEDS: LABS : A1C = 7.0%, 140 111 28 metformin 1 gm BID 4.5 28 1.5 glyburide 10 mg daily eGFR is 45 ml/min sitagliptin 100 mg daily Which of the following statements is true? The addition of sitigliptin: A. Did not contribute to hypoglycemia B. Should have been dose adjusted for renal insufficiency C. Was not related to the increased number of URIs D. Typically results in a 1-2 kg weight loss 30