7/8/15 I have no financial disclosures ENDOCRINE Hilary Thomas, MD Assistant Clinical Professor of Medicine, UCSF Division of Endocrinology, SFGH July 8, 2015 2 1
7/8/15 Case 1 Case 1 64 yo M with HTN, CAD, and prior episode of 64 yo M with HTN, CAD, and prior episode of pancreatitis is found to have a random plasma pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for glucose of 205 mg/dl on labs obtained for another reason. An A1C was obtained and another reason. An A1C was obtained and was 6.4%. The patient has no symptoms such was 6.4%. The patient has no symptoms such as polyuria, polydipsia or polyphagia. as polyuria, polydipsia or polyphagia. Does he meet the criteria for the diagnosis of diabetes? Does he meet the criteria for the diagnosis of diabetes? 1. Yes 1. Yes 2. No 2. No 3 4 2
7/8/15 Diagnosis of Diabetes Case 2 64 yo M with HTN, CAD, and a prior episode of pancreatitis is 1. Fasting plasma glucose (FPG) ≥ 126 mg/dl* found to have a random plasma glucose of 205 without polyuria or OR polydipsia. 2. Plasma glucose ≥ 200 mg/dl 2h post 75 g oral You obtain a fasting BG which is 154 mg/dl confirming the glucose load (OGTT)* OR diagnosis of diabetes mellitus. 3. A1C ≥ 6.5%* OR MEDS : EXAM : 100 kg BMI 32 145/94 82 ASA 81 mg; lisinopril 40 mg; acanthosis nigricans 4. Random plasma glucose ≥ 200 mg/dl with metoprolol 100 mg BID otherwise unremarkable symptoms of hyperglycemia LABS : A1C = 8.5%, 140 111 28 4.5 28 1.3 *should be confirmed with same test unless has symptoms of hyperglycemia 5 6 3
7/8/15 What’s the best initial therapy? What’s the best initial therapy? 1. metformin 1. metformin 2. exenatide 2. exenatide 3. pioglitazone 3. pioglitazone 4. glipizide 4. glipizide 5. diet and exercise alone 5. diet and exercise alone 7 8 4
7/8/15 DM2 Therapy Pearls § Lots of different practice styles § Focus on CONTRAINDICATIONS § Some delay in test question writing so newest medications unlikely to be on the test § For T2D, always treat with metformin first unless contraindicated Figure 7.1 — Antihyperglycemic therapy in type 2 diabetes: general recommendations (15). The order in the chart was determined by historical Diabetes Care, 2015; 38(Suppl 1) 9 10 5
7/8/15 Metformin Metformin Mechanism of Inhibits liver gluconeogenesis Mechanism of Inhibits liver gluconeogenesis action (targets fasting BG) action (targets fasting BG) ê HbA1c 1.5 – 2% ê HbA1c 1.5 – 2% Benefits Weight loss Benefits Weight loss FIRST LINE AGENT No hypoglycemia No hypoglycemia CVD benefit CVD benefit Side Effects Nausea/diarrhea Side Effects Nausea/diarrhea Impaired B12 absorption (>5% of patients) Impaired B12 absorption (>5% of patients) Contraindications eGFR < 30 OR do not initiate if unstable Contraindications eGFR < 30 (do not initiate if unstable kidney kidney function function) Severely impaired liver function (AST/ALT > Severely impaired liver function (AST/ALT > 3X ULN) 3X ULN) Decompensated heart failure Decompensated heart failure Contrast studies Contrast studies 11 12 6
7/8/15 Sulfonylureas Medication by HbA1c Lowering Glyburide, Glipizide, Glimepiride Medication Change in HbA1c Mechanism of Action Stimulate insulin release Biguanides (Metformin) 1.5 - 2% ê HbA1c 1 - 2% Sulfonylureas 1 - 2% Benefits Targets post prandial BG Glinides 1 - 1.5% Side Effects Hypoglycemia Weight gain GLP-1 agonists 0.5 – 1.5% Contraindications Caution in renal failure PPARg agonists/TZDs 0.5 – 1.4% SGLT2 Inhibitors 0.5 – 1% DPP-IV Inhibitors 0.5 – 0.8% 13 14 7
7/8/15 Glinides Sulfonylureas – Dosing/Cautions Repaglinide, Nateglinide Mechanism of Action Stimulate insulin release § Glyburide ê HbA1c 1 – 1.5% o Non-linear dose response (more effect of 1.25 to 2.5 than 10 to 20) Benefits Targets post prandial BG Short acting – can skip if not eating o Caution in renal failure and in elderly § Glipizide Side Effects Hypoglycemia Weight gain o Better in renal impairment TID dosing o ? Increased CV risk Contraindications Can use in renal failure (repaglinide) § Glimepiride Caution with meds that affect CYP2C8 and o Caution in renal failure, liver failure, elderly CYP3A4 activity Typically discontinued when patient on prandial insulin 15 16 8
7/8/15 Case 3 Case 3 § You see an active 72yo F with a history of § You see an active 72yo F with a history of osteoporosis, T2D, and HTN for follow up. osteoporosis, T2D, and HTN for follow up. Her diabetes was controlled with metformin Her diabetes was controlled with metformin 1g bid, but her labs now show a HbA1c of 1g bid, but her labs now show a HbA1c of 7.8%. Her Cr is 1.3 with eGFR of 50. She 7.8%. Her Cr is 1.3 with eGFR of 50. She does not want to take injections. does not want to take injections. What should you do? What should you do? 1. Do nothing - a HbA1c of 7.8% is at goal 1. Do nothing - a HbA1c of 7.8% is at goal 2. Add glyburide 2. Add glyburide 3. Add pioglitazone 3. Add pioglitazone 4. Add renally dosed sitaglipitin 4. Add renally dosed sitaglipitin 17 18 9
7/8/15 PPAR- γ Agonists The GLP-1 Effect Pioglitazone, rosiglitazone Mechanism of Action Improve insulin sensitivity ê HbA1c 0.5 – 1.4% Benefits Minimal hypoglycemia GLP-1 (exenatide) Improves lipid panel* Side Effects Weight gain/edema Increased risk of CHF (rosi) DPP-IV Increased fracture risk* Increased risk of bladder cancer* (Sitagliptin) Contraindications CHF (NYHA Class III/IV) Inactive GLP-1 *pioglitazone only 19 20 10
7/8/15 GLP-1 agonists DPP-IV Inhibitors exenatide, liraglutide, dulaglutide, albiglutide sitagliptin, saxagliptin, linagliptin, alogliptin Mechanism of Action Delays gastric emptying Mechanism of Action Increases GLP-1 and GIP levels Increases glucose dependent ê HbA1c 0.5 – 0.8% insulin release Benefits Weight neutral Inhibits post-prandial glucagon Minimal hypoglycemia* release Can dose reduce in renal failure ê HbA1c 0.5 – 1.5% Side Effects Nausea/vomiting Benefits Weight loss (2-3kg) Can increase URIs Minimal hypoglycemia ? Increase heart failure Side Effects Injectable hospitalizations Nausea/vomiting Contraindications Prior pancreatitis Contraindications Prior pancreatitis History of hypersensitivity Medullary thyroid cancer reactions (personal or family history) *unless given with insulin, sulfonylurea or glinide eGFR < 30 Caution in gastroparesis 21 22 11
7/8/15 SGLT2 Inhibitors Case 4 dapagliflozin, canagliflozin, empagloflozin Mechanism of Action Impairs renal absorption of You are asked to see a 72 year old man with CHF with glucose previously well controlled DM2, but now a HbA1c of ê HbA1c 0.5 - 1% 9.1% complicated by gastroparesis. He is on glyburide Benefits Weight loss and metformin at max doses. Decrease BP Minimal hypoglycemia How should you change his regimen? Can dose reduce in renal failure Side Effects GU infections/UTI 1. Add pioglitazone Dehydration/dizziness 2. Add basal insulin (NPH or glargine) Hyperkalemia/elevated Cr 3. Add exenatide Contraindications eGFR <45 4. Add saxagliptin Severe liver failure Active bladder cancer 23 12
7/8/15 Medication by HbA1c Lowering Case 4 You are asked to see a 72 year old man with CHF with Medication Change in HbA1c previously well controlled DM2, but now a HbA1c of Biguanides (Metformin) 1.5 - 2% 9.1%. He is on glyburide and metformin at max doses. Sulfonylureas 1 - 2% How should you change his regimen? Glinides 1 - 1.5% GLP-1 agonists 0.5 – 1.5% 1. Add pioglitazone – CHF PPARg agonists 0.5 – 1.4% 2. Add basal insulin (NPH or glargine) 3. Add exenatide – gastroparesis SGLT2 Inhibitors 0.5 – 1% 4. Add saxagliptin - minimal HbA1c change DPP-IV Inhibitors 0.5 – 0.8% 26 13
7/8/15 Case 5 Case 5 66yo M with DM2 for 5 years started on insulin 2 years ago but still 66yo M with DM2 for 5 years started on insulin 2 years ago but still can ’ t get A1C below 8.5%. Patient reports no symptomatic lows. can ’ t get A1C below 8.5%. Patient reports no symptomatic lows. BS records: BS records: DM Meds: DM Meds: fasting 115-150 fasting 115-150 Metformin 1 gm BID Metformin 1 gm BID pre-lunch 85 -155 pre-lunch 85 -155 NPH 20 units am, 10 units at bedtime NPH 20 units am, 10 units at bedtime pre-dinner 92 - 145 pre-dinner 92 - 145 Regular 5 units before each meal Regular 5 units before each meal bedtime 170-290 bedtime 170-290 What would be the best first next step for improving A1C? What would be the best first next step for improving A1C? a) Change NPH to glargine 30 units a) Change NPH to glargine 30 units b) Increase morning NPH dose to 25 units b) Increase morning NPH dose to 25 units c) Increase bedtime NPH dose 15 units c) Increase bedtime NPH dose 15 units d) Increase meal time R insulin dose to 8 units before each meal d) Increase meal time R insulin dose to 8 units before each meal e) Increase dinner time R insulin to 8 units e) Increase dinner time R insulin to 8 units 27 28 14
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