No disclosures. Diabetes Test Topics. Case #1. Diabetes Family Medicine Board Review: Improving Clinical Care Across the Lifespan

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1 Diabetes Family Medicine Board Review: Improving Clinical Care Across the Lifespan No disclosures Sarah Kim, MD Assistant Clinical Professor of Clinical Medicine, UCSF Division of Endocrinology, SFGH March 25-28, 2013 Diabetes Test Topics Majority Type 2 Diabetes (vs. Type 1) Medications mechanism of action, contraindications Standards of care (LDL and BP goals, aspirin) Treatment of complications Some delay in test question writing so newest algorithms and medications unlikely to be on the test 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? 3 4 1

2 Diagnosis of Diabetes & Pre-diabetes Pre-Diabetes Criteria Diabetes Criteria* Fasting Glucose mg/dl 126 mg/dl 2 hour post 75g OGTT mg/dl 200 mg/dl Random glucose N/A 200 with symptoms of hyperglycemia HbA1c %** 6.5%** *unless unequivocally hyperglycemic, results should be confirmed with another or repeat test **in absence of anemia or hemoglobinopathy 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: furosemide 40 mg BID KCl 20 meq ASA 81 mg lisinopril 40 mg metoprolol 100 mg BID LABS: A1C = 6.4%, EXAM: 100 kg; BMI 32; BP145/94 Lungs: CTA CV: S3 gallop Ext: 1+ edema, feet with no ulcerations, normal monofilament exam Lipids: TC 350;LDL NC;HDL 22;TG 505 Diabetes Care, Vol 35, Supp 1, Case #1 Which of the following medications would be the most appropriate initial therapy for this patient s DM2? A. metformin B. glyburide C. colesevelam D. pioglitazone E. glipizide F. exenatide Case #1 Which of the following medications would be the most appropriate initial therapy for this patient s DM2? A. metformin B. glyburide C. colesevelam D. pioglitazone E. glipizide F. exenatide 7 8 2

3 Beta Cell Loss in Diabetes Sulfonylureas Non Diabetic T2DM T1DM 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 renal-dosed and avoided in liver failure Blunts ischemic preconditioning? 10 Sulfonylureas Meglitinides 2 nd generation Duration Daily Dose Glipizide 6-12hr (XL version= 24 hr) mg once daily or 2 divided doses Glyburide 20-24hr mg once daily Glimepiride 24hr 2-4 mg once daily 1 st generation Duration Daily Dose Chlorpropamide hr mg once daily Tolbutamide 6-12hr mg in 2-3 divided doses Enhances insulin release like sulfonylureas Repaglinide lowers A1C 1-1.5%; Nateglinide % Advantages: Short acting (take 15 minutes prior to meals) Repaglinide undergoes little renal clearance Disadvantages qac dosing Hypoglycemia (less than sulfonylureas) Expensive 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

4 Meglitinides Drug Duration of Action Daily Dose Nateglinide 1.5 hr mg qac Repaglinide 3 hr 0.5-2mg qac Sulfonylureas Meglitinides Biguanides 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 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) Risk of lactic acidosis (very small) Metformin Biguanide Duration Daily Dosing Metformin 7-12 hr mg in 2-3 divided doses XR version 24 hrs mg nightly 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

5 Metformin Contraindications: Renal insufficiency Creatinine 1.5 men, 1.4 in women or abnormal Cr Cl Liver failure Excessive alcohol use Iodinated contrast Discontinue within 48 hrs of exposure Elderly ( 80 yo unless normal renal function) Severe or acute CVD- particularly unstable CHF or AMI Sulfonylureas Meglitinides Biguanides TZDs Thiazolidinediones (TZD) Activate PPAR-γ, improve insulin sensitivity by altering gene transcription (takes 8-12 weeks for max effect) Lower A1C % CVD risk possibly increased with rosiglitazone & decreased pioglitazone Advantages: Improves decreases TG, increases in HDL (pioglitazone) No hypoglycemia when used alone TZDs Drug Duration Dosing Pioglitazone 24 hr mg qday (Rosiglitazone 24 hr 4-8 mg qday or BID) 19 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

6 TZDs Adverse Event Frequency Increased Risk vs Placebo Edema 5% 2 fold Congestive Heart Failure 5% 2-7 fold Weight Gain 60% kg Fractures 2-5% 2 fold Bladder Cancer 0.3% 20% 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: furosemide 40 mg BID KCl 20 meq ASA 81 mg lisinopril 40 mg metoprolol 100 mg BID EXAM: 100 kg; BMI 32; BP145/94 Lungs: CTA CV: S3 gallop Ext: 1+ edema, feet with no ulcerations, normal monofilament exam LABS: A1C = 8.8%, Lipids: TC 350;LDL NC;HDL 22;TG Case #1 Which choice below would be the most appropriate initial therapy for this patient s DM2? A. metformin B. glyburide C. colesevelam D. pioglitazone E. glipizide F. exenatide 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: metformin 1 gm BID glyburide 10 mg daily sitagliptin 100 mg daily LABS: A1C = 7.0%, egfr is 45 ml/min 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

7 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: metformin 1 gm BID glyburide 10 mg daily sitagliptin 100 mg daily LABS: A1C = 7.0%, egfr is 45 ml/min 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 2-3 kg weight loss Sulfonylureas Meglitinides Biguanides GLP-1 Agonists DPP-4 Inhibitors α-glucosidase Inhibitors Bile Acid Sequestrants TZDs 25 The Incretin Effect What Incretins Do Incretins: -Enhance insulin secretion -Suppress glucagon secetion -Slow gastric emptying -Promote satiety 27 J Fam Med. October 2009 Vol. 58, No. 10 7

8 GLP-1 Analogs Resistant to degradation by DPP4 and have a long halflife Lower HbA1C % Advantages: Weight loss (2-3 kg); less hypoglycemia Disadvantages: Injectable GI Side Effects (nausea, vomiting) Pancreatitis, medullary thyroid cancer? DPP-4 Inhibitors Increases GLP-1 and GIP levels Lowers A1C % (mean diff from baseline) Use in conjunction with other oral hypoglycemic agents in DM2 or as monotherapy Advantages: Oral, weight neutral Disadvantages: Costly Increased incidence of URI, nasophyrngitis (mechanism?) Incretin-based therapies GLP-1 Agonists Duration Daily Dose Exenatide* 6hr (ER version 1 wk) 5-10mcg BID subcut. before meals (ER version 2 mg weekly) Liraglutide hr mg subcut. daily DPP-4 Inhibitors Duration Daily Dose Sitagliptin* 24 hr mg Daily Saxagliptin* 24 hr mg Daily Linagliptin 24 hr 5 mg Daily *renal dosing required α-glucosidase Inhibitors Reversible competitive inhibition of a-glucosidase difficulty breaking down disaccharides and complex carbs Lowers A1C % by improving postprandial glucose Advantages: No hypoglycemia when used alone; weight neutral Disadvantages: GI SE, flatulance; TID dosing Caution with hypoglycemia, sucrose is ineffective 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

9 α-glucosidase Inhibitors Bile Acid Sequestrant Duration Daily Dose Acarbose 4 hr mg in 3 divided doses with meals Miglitol 4 hr mg in 3 divided doses with meals Colasevelam Approved for years for cholesterol lowering Lowers HbA1C 0.4% (mechanism largely unknown) Advantages: Lowers LDLc Disadvantages: GI side effects (bloating, cramping, constipation) Increases triglycerides (avoid if TG >500) Impairs absorption of fat soluble vitamins, digoxin, warfarin, thiazides, beta blockers, thyroxine, phenobarbital 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 HbA1c Lowering by Non-Insulin Medications Drug AIC lowering when used as monotherapy Metformin 1.5-2% Sulfonylureas 1-2% Thiazolidinediones % GLP-1 Agonists % Meglitinides % Lifestyle % DPP4 inhibitors % α-glucosidase inhibitors % Bile acid sequestrant 0.4% Bromocriptine < 0.2% Case #3 You are asked to see a 72 year old man with CHF (NYHA class III) with previously well controlled DM2, but now a HbA1c of 9.1%. He is on glyburide and metformin at max doses. What is the most appropriate change to his regimen? A. Add pioglitazone B. Add basal insulin (NPH or glargine) C. Add acarbose D. Add saxagliptin 9

10 Case #3 You are asked to see a 72 year old man with CHF (NYHA class III) with previously well controlled DM2, but now a HbA1c of 9.1%. He is on glyburide and metformin at max doses. What is the most appropriate change to his regimen? A. Add pioglitazone B. Add basal insulin (NPH or glargine) C. Add acarbose D. Add saxagliptin Well-Validated Core Therapy for DM2 At Diagnosis: Lifestyle and Metformin Add Basal Insulin Add Sulfonylurea Nathan DM et al. Diab Care 2009;32: Basal Insulin Hypoglycemia with basal insulin NPH Glargine Detemir Pros 1. Variable dosing possible at different times of day 2. Can be mixed with other insulin types Cons 1. 2 injections/day 2. Peaks 6-8 hrs after injection 1. Usually only one injection needed 2. Generally peakless 1. Cannot be mixed with other insulin types 1. Variable dosing possible at different times of day 2. Mild peak 1. 2 injections/day 2. Cannot be mixed with other insulin types Hypoglycemia Nocturnal Hypoglycemia Glargine or Detemir vs. NPH ~17% less with glargine or detemir ~35% less with glargine or detemir HbA1C 7% Total Dose Cost ( No difference between NPH, Glargine, and Detemir No difference between NPH, Glargine, and Detemir $ $$ $$ * Driven by studies with aggressive titration strategies Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD

11 Well-Validated Core Therapy for DM2 Less Well-Validated Buffet for DM2 At Diagnosis: Lifestyle and Metformin Add Basal Insulin Add Sulfonylurea Nathan DM et al. Diab Care 2009;32: ADA/EASD. Diabetologia 2012; 55: Case #4 66 yom with DM2 for 5 years started on insulin 2 years ago but still can t get A1C below 8.0%. Patient reports no symptomatic lows. Case #4 66 yom 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. DM Meds: Metformin 1 gm BID NPH 20 units am, 10 units at bedtime Regular 5 units before each meal Time Glucose Range Fasting Pre-Lunch Pre-Dinner Bedtime DM Meds: Metformin 1 gm BID NPH 20 units am, 10 units at bedtime Regular 5 units before each meal Time Glucose Range Fasting Pre-Lunch Pre-Dinner Bedtime What would be the best next step for improving A1C? A. Change NPH to glargine 30 units B. Increase morning NPH dose to 25 units C. Increase mealtime R insulin dose to 8 units before each meal D. Increase dinnertime R insulin to 8 units E. Change R to aspart insulin What would be the best next step for improving A1C? A. Change NPH to glargine 30 units B. Increase morning NPH dose to 25 units C. Increase mealtime R insulin dose to 8 units before each meal D. Increase dinnertime R insulin to 8 units E. Change R to aspart insulin

12 Glycemic Goals in Diabetes For Most Adults: Fasting Glucose mg/dl Peak Post-Prandial Glucose <180 mg/dl HbA1c 7.0% Time Glycemic goals differ in: pregnancy (lower goals) children, limited life expectancy, hypoglycemia unawareness, significant cardiovascular disease (higher goals) Glucose Range Fasting Pre-Lunch Pre-Dinner Bedtime Insulin µu/ml Normal Plasma Insulin Profile Basal insulin o o o Near-constant levels Important during night/between meals 50% or more of daily needs B L D Mealtime insulin o o o Limits hyperglycemia after meals Rise and peak post meal 10% to 20% of daily needs at each meal B=breakfast; L=lunch; D=dinner Time of day Diabetes Care (2011) 34: s11-s61 Polonsky KS et al. N Engl J Med. 1988;318: Types of Insulin Basal-Bolus Insulin Treatment Basal Insulin Peak Duration NPH 4-8 hrs 10-20hr Glargine None 24 hr Detemir Small 17 hr Bolus Insulin Peak Duration Regular 2 hr 6 hr Aspart 1 hr 3-4 hr Lispro 1 hr 3-4 hr Glulisine 1 hr 3-4 hr µu/ml NPH B L D NPH at bedtime Combination Insulin Composition 70%/30% 70% NPH 30% Regular or Aspart 75%/25% 75% NPH 25% Lispro Time of day Normal pattern 47 12

13 Basal-Bolus Insulin Treatment Basal-Bolus Insulin Treatment µu/ml µu/ml Meal time insulin B L D Glargine B L D Glargine Normal pattern 40 Normal pattern Time of day Time of day Case #5 A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn t check BS at other times of the day. Medicines include metformin 1 g BID and glipizide 20 mg BID. A1C 9.1%. Of the options listed below, which is the most appropriate therapy for this patient? A. Start morning NPH or glargine and discontinue all oral agents B. Start morning NPH or glargine, maintain sulfonylurea and discontinue metformin C. Start bedtime NPH or insulin glargine, discontinue metformin and continue sulfonylurea. D. Start bedtime NPH or glargine, maintain oral agents Case #5 A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn t check BS at other times of the day. Medicines include metformin 1 g BID and glipizide 20 mg BID. A1C 9.1%. Of the options listed below, which is the most appropriate therapy for this patient? A. Start morning NPH or glargine and discontinue all oral agents B. Start morning NPH or glargine, maintain sulfonylurea and discontinue metformin C. Start bedtime NPH or insulin glargine, discontinue metformin and continue sulfonylurea. D. Start bedtime NPH or glargine, maintain oral agents 13

14 Case #6 67 yom has had DM2 for 2 yrs treated with metformin and glipizide. He also has schizophrenia and started olanzapine 3 months ago. Since then, he gained 20 lbs and his HbA1c increased from %. What should you do to help improve his diabetic control? a. Have a home health nurse assist him with medication compliance b. Add pioglitazone 30mg daily to increase insulin sensitivity c. Contact the treating psychiatrist about possibly changing his antipsychotic d. Add exenatide 10 mcg BID to assist with weight loss e. Switch from glipizide to glyburide Case #6 67 yom has had DM2 for 2 yrs treated with metformin and glipizide. He also has schizophrenia and started olanzapine 3 months ago. Since then, he gained 20 lbs and his HbA1c increased from %. What should you do to help improve his diabetic control? a. Have a home health nurse assist him with medication compliance b. Add pioglitazone 30mg daily to increase insulin sensitivity c. Contact the treating psychiatrist about possibly changing his antipsychotic medication d. Add exenatide 10 mcg BID to assist with weight loss e. Switch from glipizide to glyburide Metabolic side effects of second generation antipsychotics Most weight gain Less weight gain No weight gain Olanzapine Quetiapine Aripiprazole Clozapine Risperidone Ziprasidone Iloperidone Paliperidone Case #7 49 yow with DM2 is seeing you for follow up. Her A1c is 7.3% on metformin, glyburide and significant lifestyle modifications that she has made over the years. She has HTN and albuminuria for which she takes lisinopril. Her recent lipid panel reveals a Tchol of 200, LDL of 90, HDL of 39, TG 190. How do you respond to her lipid panel? A. Begin colasevelam 1875 mg BID B. Begin pioglitazone 30mg daily C. Begin pravastatin 40 mg daily D. Assure her that she has reached the LDL goal for diabetes without medications E. Ask her about a family history of early MI 14

15 Case #7 49 yow with DM2 is seeing you for follow up. Her A1c is 7.3% on metformin, glyburide and significant lifestyle modifications that she has made over the years. She has HTN and albuminuria for which she takes lisinopril. Her recent lipid panel reveals a Tchol of 200, LDL of 90, HDL of 39, TG 190 How do you respond to her lipid panel? A. Begin colasevelam 1875 mg BID B. Begin pioglitazone 30mg daily C. Begin pravastatin 40 mg daily D. Assure her that she has reached the LDL goal for diabetes without medications E. Ask her about a family history of early MI Statin recommendations for DM LDL goal <100mg/dL Statin therapy regardless of LDL in: Overt CVD No overt CVD but >40yo with 1+ risk factor for CVD (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) Case #8 50 yom with DM2 x 2 yrs, HTN, and dyslipidemia has an A1c of 7.5%. He has a family history of early MI. Lowering HbA1c to 7% will NOT reduce his risk of developing: A. Retinopathy B. Nephropahty C. Myocardial infarction D. Neuropathy Case #8 50 yom with DM2 x 2 yrs, HTN, and dyslipidemia has an A1c of 7.5%. He has a family history of early MI. Lowering HbA1c to 7% will NOT reduce his risk of developing: A. Retinopathy B. Nephropahty C. Myocardial infarction D. Neuropathy 15

16 Tight control trials 1977 UKPDS (DM2) * 1983 DCCT (DM1) * 2000 VADT (DM2) 2001 ADVANCE (DM2) * 2001 ACCORD (DM2) *showed that tight control lowers microvascular complications My go-to diabetes resource American Diabetes Association Clinical Practice Recommendations Standards of Medical Care in Diabetes