Diabetes Family Medicine Board Review

Transcription

1 Diabetes Family Medicine Board Review Sarah Kim, MD Assistant Clinical Professor of Clinical Medicine, UCSF Division of Endocrinology, SFGH March 10, 2016

2 No disclosures

3 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

4 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

5 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 Diabetes Care, Vol 35, Supp 1, 2012

6 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; BP 145/95 sitting, 120/84 standing Lungs: CTA CV: S3 gallop Ext: 1+ edema, feet with no ulcerations, normal monofilament exam Lipids: TC 350;LDL NC;HDL 22;TG 505 egfr 44 6

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 7

8 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

9 Beta Cell Loss in Diabetes Non Diabetic T1DM T2DM

10 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

11 Sulfonylureas 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 24-72hr mg once daily Tolbutamide 6-12hr mg in 2-3 divided doses Tolazamide 10-24hr mg 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.

12 Meglitinides 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) More expensive than SU 12

13 Meglitinides Drug Duration of Action Daily Dose Nateglinide 1.5 hr mg 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.

14 Sulfonylureas Meglitinides Biguanides

15 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

16 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

17 Contraindications: Renal insufficiency Metformin 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) Iodinated contrast Discontinue within 48 hrs of exposure Excessive alcohol use- Elderly ( 80 yo unless normal renal function) Severe or acute CVD- particularly unstable CHF or AMI

18 TZDs Sulfonylureas Meglitinides Biguanides

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

20 TZDs Drug Duration Dosing Pioglitazone 24 hr 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.

21 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%

22 TZDs Sulfonylureas Meglitinides Biguanides SGLT2 inhibitors

23 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.

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

25 Dapagliflozin: Glucosuric and Metabolic Effects Glucosuria FPG PPG g/day mg/dl mg/dl Body weight kg ( 2.5%-3.4%) Urine volume ml/day List JF, et al. Diabetes Care. 2009;32:

26 SGLT2 Inhibitors Lowers A1C about 0.6-1% at max dose No hypoglycemia when used alone or with MF Advantages Weight loss 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 $$$

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

28 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 LABS: A1C = 8.8%, 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 egfr 44 28

29 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

30 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 30

31 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 31

32 GLP-1 Agonists DPP-4 Inhibitors α-glucosidase Inhibitors Bile Acid Sequestrants Sulfonylureas Meglitinides TZDs Biguanides SGLT2 inhibitors

33 The Incretin Effect 33

34 What Incretins Do Incretins: -Enhance insulin secretion -Suppress glucagon secetion -Slow gastric emptying -Promote satiety J Fam Med. October 2009 Vol. 58, No. 10

35 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? 35

36 DPP-4 Inhibitors Increases GLP-1 and GIP levels Lowers A1C % Use in conjunction with other oral hypoglycemic agents in DM2 or as monotherapy Advantages: Oral, weight neutral Disadvantages: $$ Increased incidence of URI, nasophyrngitis (mechanism?) 36

37 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 Albiglutide 1 wk mg subcut. weekly Dulaglutide 1 wk mg weekly DPP-4 Inhibitors Duration Daily Dose Sitagliptin* 24 hr mg Daily Saxagliptin* 24 hr mg Daily Linagliptin 24 hr 5 mg Daily Alogliptin* 24 hr 25 mg Daily *renal dosing required 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.

38 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 38

39 α-glucosidase Inhibitors Duration Daily Dose Acarbose 4 hr mg in 3 divided doses with meals Miglitol 4 hr mg in 3 divided doses with meals 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.

40 Bile Acid Sequestrant 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 40

41 HbA1c Lowering by Non-Insulin Drug Medications AIC lowering when used as monotherapy Metformin 1.5-2% Sulfonylureas 1-2% Thiazolidinediones % GLP-1 Agonists % Meglitinides % SGLT2 inhibitors 0.6-1% Lifestyle % DPP4 inhibitors % α-glucosidase inhibitors % Bile acid sequestrant 0.4% Bromocriptine < 0.2%

42 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

43 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

44 Well-Validated Core Therapy for DM2 At Diagnosis: Lifestyle and Metformin Add Basal Insulin Add Sulfonylurea Nathan DM et al. Diab Care 2009;32:

45 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 HbA1C 7% Total Dose Cost ( No difference between NPH, Glargine, and Detemir No difference between NPH, Glargine, and Detemir $ $$ $$ Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD006613

46 Hypoglycemia with basal insulin Hypoglycemia Nocturnal Hypoglycemia Glargine or Detemir vs. NPH ~17% less with glargine or detemir ~35% less with glargine or detemir * Driven by studies with aggressive titration strategies Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD006613

47 Well-Validated Core Therapy for DM2 At Diagnosis: Lifestyle and Metformin Add Basal Insulin Add Sulfonylurea Nathan DM et al. Diab Care 2009;32:

48 Less Well-Validated Buffet for DM2 ADA Standards of Medical Care in Diabetes 2015

49 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. DM Meds: Metformin 1 gm BID NPH 20 units am, 10 units at bedtime Regular 5 units before each meal Time 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 Glucose Range Fasting Pre-Lunch Pre-Dinner Bedtime

50 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 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 Glucose Range Fasting Pre-Lunch Pre-Dinner Bedtime

51 Glycemic Goals in Diabetes For Most Adults: Fasting Glucose mg/dl Peak Post-Prandial Glucose <180 mg/dl HbA1c 7.0% Time Glucose Range Fasting Pre-Lunch Pre-Dinner Glycemic goals differ in: pregnancy (lower goals) Bedtime children, limited life expectancy, hypoglycemia unawareness, significant cardiovascular disease (higher goals) Diabetes Care (2011) 34: s11-s61

52 Normal Plasma Insulin Profile Insulin U/mL 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 Polonsky KS et al. N Engl J Med. 1988;318:

53 Types of Insulin Basal Insulin Peak Duration NPH 4-8 hrs 10-20hr Glargine (U100, U300) None 24 hr Detemir Small hr Degludac U100, U200 None 42 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 Combination Insulin Composition 70%/30% 70% NPH 30% Regular or Aspart 75%/25% 75% NPH 25% Lispro 50%/50% 50%NPH 50% Lispro 53

54 Basal-Bolus Insulin Treatment U/mL NPH B L D NPH at bedtime Normal pattern Time of day

55 Basal-Bolus Insulin Treatment U/mL B L D Glargine Normal pattern Time of day

56 Basal-Bolus Insulin Treatment U/mL Meal time insulin B L D Glargine Normal pattern Time of day

57 Case #5 A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesnt check BS at other times of the day. Medicines include metformin 1 g BID and glipizide 10 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

58 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 10 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

59 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

60 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

61 Metabolic side effects of second generation antipsychotics Most weight gain Less weight gain No weight gain Olanzapine Quetiapine Aripiprazole Clozapine Risperidone Ziprasidone Iloperidone Lurasidone Paliperidone

62 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 atorvastatin 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

63 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 atorvastatin 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

64 Statin recommendations for DM

65 Case #8 50 yom with DM2 x 8 yrs, HTN, and dyslipidemia has an A1c of 8.5%. 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

66 Case #8 50 yom with DM2 x 8 yrs, HTN, and dyslipidemia has an A1c of 8.5%. 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

67 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

68 My go-to diabetes resource American Diabetes Association Clinical Practice Recommendations Standards of Medical Care in Diabetes Care.pdf 68