1. DIABETES Required Medicine Clerkship Lecture Jenny Wright, MD

2. Learning objectives  Know how to screening for and diagnose type 2 diabetes  Know how to prevent diabetes  Be familiar with the “pro and cons” of common pharmacologic treatment of diabetes  Know the common complications of diabetes and how to screening of them

3. Case A 52 year old female with hypertension presents for a preventative medicine visit. She has a family history of hypertension, hyperlipidemia and type 2 diabetes. On exam her BMI is 31 and her BP is 137/86. Do you screen her for diabetes?

4. Screening USPSTF:  Overweight + adults between 40-70  Consider earlier in patients with other risk factors ADA:  All pt at age 45  Earlier in overweight pts with additional risk factors  Screen q 3 yrs

5. Type 2 Diabetes  Non-modifiable risk factors: H/o gestational diabetes, race (Native Americans, Hispanics, African and Asian Americans, Pacific Islanders), family history  Modifiable risk factors: obesity, inactivity  Disease associations: PCOS, dyslipidemia, hypertension  Medication related side-effects: antipsychotics, protease inhibitors, corticosteroids

6. Latent Autoimmune Diabetes in Adults: LADA  Adult onset autoimmune diabetes  Suspect in patients without classic risk factors for type 2 diabetes  Diagnosis supported by presence of auto- antibodies, most commonly glutamic acid decarboxylase [anti-GAD]  More likely to require insulin, respond poorly to oral medications, prone towards DKA

7. Case Fasting lab results: - total cholesterol 204, triglycerides 355 (normal is <150), HDL 40, LDL 108 - sodium 138, potassium 4.9, creatinine 0.8, blood sugar 106. What diagnoses does this patient have?

8. Diagnosis Test“Impaired”Diagnostic for DM Fasting blood sugar*100-125 mg/dL≥126 mg/dL Random blood sugar + symptoms ≥ 200 mg/dL Hemoglobin A1c*5.7% - 6.4%≥ 6.5% 2 hr 75 g OGTT*/**140-199 mg/dL≥ 200 mg/dL *: Confirm by repeat testing **: Rarely used in practice

9. Metabolic ‘syndrome’ 3 of the 5 Waist circumferenceM > 40 in, F > 35 in Triglycerides≥ 150 mg/dL HDL cholesterolM < 40, F < 50 BP≥ 130/85 Fasting blood sugar≥ 100 2001 National Cholesterol Education Program/ATP III Definition

10. Case  What therapy do you recommend?  Simvastatin 20 mg po q day  Fenofibrate 145 mg po q day  Metformin 500 mg po q day  Fish oil supplements  None of the above

11. InterventionWeight loss at 2 yrs Cumulative incidence of DM @ 4 yrs RRR Placebo0.8 kg23% Lifestyle counseling 3.5 kg11%58%  Diabetes Prevention Program  Finnish Diabetes Prevention Study N Engl J Med 2002;346:393-403 InterventionIncidence of DM/100 person-yrs RRRNNT Placebo11 Metformin7.831%14 Lifestyle intervention 4.858%7 N Engl J Med 2001;344:1343-1350 Type 2 DM Prevention = Lifestyle modifications +/- metformin

12. Clue to test… Symptoms: - Polyuria, polydipsia - Unexplained weight loss - erectile dysfunction Physical exam findings: - Acanthosis nigracans - Recurrent vaginal yeast infections - Peripheral neuropathy

13. General Treatment Options  Dietary counseling  Physical activity  Oral hypoglycemic agents  Insulin  Other injectables  Anti-obesity measures

14. Yet again - Diet and exercise are good for you! Remission prevalence JAMA 2012;308(23):2489-2496

15. Case 59 yo male presents for management of type 2 diabetes, hypertension and coronary artery disease. He has a history of subarachnoid hemorrhage with residual cognitive deficits. Initial labs reveal a HgbA1c of 9.9%.  What is your goal HgbA1c for this pt? A. <6.5% B. <7% C. <8% D. <8.5%

16. Recent Studies of Macrovascular Outcomes  Long-standing, poorly controlled T2DM, aggressive A1c lowering:  ACCORD:  all cause death, no benefit/harm re:CV outcomes  ADVANCE: no benefit/harm re:CV outcomes  VADT: no benefit/harm re:CV outcomes, observational f/u with reduction in CV eents, not in CVD or all-cuase death  Newly dx’ed T2DM  UKPDS 10 yr f/u: “legacy” effect CV benefits of metformin tx > insulin or sulfonylurea ACCORD (NEJM 2008;358:2545-59) ADVANCE (NEJM 2008;358:2560-72) VADT (NEJM 2009;360:129-39) UKPDS 10-yr F/U (NEJM 2008; 359:1577-89)

17. Ismail-Beigi F et al. Ann Intern Med 2011;154:554-559 Putting it all together…

18. What does hemoglobin Ac1 mean? Hb A1c (%)Blood glc mg/dL 6126 7154 8183 9212 10240 11269 12298

19. Case You are caring for a 59 year old female in the hospital, admitted with an UGIB. You are now planning for discharge, she has no diagnosis of diabetes but has had persistent blood sugar elevations (fasting blood sugars 155-185, pre- meal blood sugars 175-215) and has been getting small amounts of insulin since she began eating again. You tested her hemoglobin A1c, it was 5.5%. Do you think this patient has diabetes? A. Yes, she likely has diabetes B. No C. Kind of, she is likely ‘pre-diabetic’

20. Accuracy of A1c  Falsely elevated values:  Low RBC turnover: untreated iron def. anemia  Falsely depressed values:  Increased RBC turnover: hemolysis, recently treated iron, B12, folate def. anemias, erythropoietin  Hemodialysis  RBC transfusion

21. Pharmacotherapy

22. Intestine: acarbose Blood stream musclesmuscles Liver: metformin Pancreas: sulfonylureas, glinides Metformin, TZDs Mechanisms of action

23. Dipeptidyl peptidase IV inhibitors GLP-1 inactive Intestinal GLP-1 release Food eaten GLP-1 active DPP-4 Provided by Dr Irl Hirsch, adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. DPP-4 inhibitor

24. Oral diabetes medication  Generalities:  Monotx lowers HgbA1c by an absolute 1% (exception: DDP IV inhibitors)  Addition of a second agent lowered A1c by an additional 1%  Take home: Medication choice is more dependent on secondary benefits/side-effects/cost than effectiveness Not likely to achieve tight control without insulin for patients with HgbA1c>9% Bennett WL, Maruthur NM, et al. Comparative Effectiveness and Safety of Medications for Type 2 Diabetes. Ann Intern Med 2011;154(6).

25. Case 62 year old male presents to establish care after his cardiologist noted that he had a fasting blood sugar of 147, follow up HbA1c of 7.2%. He has hyperlipidemia, ischemic cardiomyopathy (EF40%) and mild CKD, baseline Cr 1.3.  What medication would you start him on? A. Exenatide/Byetta B. Basal insulin (e.g. insulin glargine/Lantus) C. Metformin D. No medication at this time, recommend TLC

26. Metformin  First line therapy  Benefits include:  CVD risk reduction (decreased rates of MI and all- cause mortality)  Weight loss  No risk of hypoglycemia

27. Metformin  Cons:  Lactic acidosis Standard contraindications: Creatinine ≥ 1.5 in men, ≥ 1.4 in women Liver dysfunction Unstable CHF Chronic hypoxia Hold in the hospitalized patient Hold for 48 hrs after IV contrast studies

28. Metformin in Renal Disease Inzucchi SE, Lipska KJ, et al. JAMA. 2014;312(24):2668-2675

29. Metformin  Common side-effects: Loose stool, bloating, gas  Dosing:  start low to minimize side-effects, e.g. 500 mg po q day  titrate up to 1000 mg po BID

30. Case  Back to our patient (newly diagnosed type 2 diabetic, starting metformin monotherapy), does he need a home glucose monitor?  A. Yes  B. No  C. If he wants one.

31. Home glucose monitoring  Role in care of patients not on insulin is unclear  Medicare will cover:  100 test strips and lancets every month if on multiple daily insulin injections  100 test strips and lancets every 3 months if not on insulin Farmer AJ et al. Meta-analysis of individual data in randomized trials of self monitoring of blood glucose in people with non-insulin treated type 2 DM. BMJ 2012 Feb 27:e486.

32. If one medication isn’t enough: ADA Position Statement, 2016

33. Case 82 yo female with type 2 DM and CHF presents with daughter, concerns re: episodic confusion. Meds include glyburide, furosemide, lisinopril. PE: nl VS, Neuro exam, including MS exam, nl. Labs: Cr 1.3, A1c 6.2%. What do you recommend? A. MRI brain B. Discontinue glyburide C. Switch from glyburide to sitagliptan/Januvia D. Decrease furosemide dose Borrowed from MKSAP

34. Glycemic Targets in the Elderly  A1c of 7.5 – 8.0% is a reasonable target in most older adults  American Geriatrics Society, 2013 guidelines  A1c of 8.0 - 8.5% appropriate for individuals with life expectancy <10 years, frail, functional comorbidities  Even higher if needed to maintain quality of life

35. Sulfonylureas  Sulfonylureas  Pros: Cheap, convenient dosing  Cons: Weight gain (≈2 kg) Hypoglycemia Caution in the elderly and CKD Long half-lives: Avoid Glyburide (Diabeta) Drug interactions: Sulfonamides, gemfibrazole increase ½ life

36. Thiazolidinediones  Options: Pioglitizone (Actos) and rosiglitizone (Avandia)  Black box warning on rosiglitizone: increased cardiovascular risks - MI, CHF and death  Bottom line: don’t start anyone on rosiglitizone  Pros:  Preservation of beta-cell function  Possible benefits: treatment of NASH and impaired glucose tolerance  Cons:  Both increase risk of CHF, fractures, and cause weight gain Comparative cardiovascular effects of thiazolidinediones:systematic review and meta-analysis of observational studies. BMJ 2011;342:d1309

37. Case 73 yo female with poorly controlled T2DM, HgbA1c 8.7%, h/o CVA, and osteoporosis. H/o orthostatic hypotension and falls. On metformin, no longer on SU d/t recurrent severe hypoglycemia. Is hesitant to change her medications d/t fear of low blood sugars. What oral medication would you recommend adding to her regimen? A. Sitagliptin/Januvia B. Pioglitazone/Actos C. Repaglinide/Prandin D. Canagliflozin/Invokana

38. Dipeptidyl peptidase IV inhibitors  Agents: Sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina)  Pros:  Weight neutral, no hypoglycemia  Cons:  Expensive,  relatively less effective as monotherapy  long-term safety data lacking  Dose reduce in patient’s with renal insufficiency

39. New on the market…  Sodium-glucose co- transporter 2 (SGLT2) inhibitors  Canagliflozin (Invokana) and Dapagliflozin/Farxiga  A1c lowering 0.5-0.7%  No hypoglycemia, weight loss (2-3 kg), daily dosing  Contraindicated in CKD  Increased rates of hyperkalemia and genital candida infections http://www.endocrinetoday.com/pda.aspx?rid=91618

40. Injectable Therapies  Insulins  Incretin based therapies

41. Insulin OnsetPeakDuration Rapid (lispro/Humalog, aspart/Novolog, glulisine/Apidra) 5-15 min0.5-1.5 hrs< 5 hrs Short (regular/Humulin R) 30 min – 1 hr1-5 hrs5-7 hrs Intermediate (NPH/Humulin N) 3-4 hr4-10 hrs10-18 hrs Long (glargine/Lantus, detemir/Levemir) 1-2 hrsNone24 hrs

42. Insulin in Type 1 DM  Require intensive insulin therapy:  Prandial blood glucose: short/rapid-acting insulin  Basal blood glucose: intermediate/long-acting insulin  Total insulin requirement typically 0.5-1 U/kg/d, divided 50:50 long:short acting  Insulin pump: basal and bolus rates of a continuous infusion of rapid-acting insulin  Without insulin will go into DKA (even if NPO)

43. Case 55 yr old overweight female with uncontrolled type 2 DM, recent Ac1 9.2% on metformin 1000 BID and glipizide 10 mg with dinner, presents for follow up. You decide she needs insulin therapy. How do you start her on insulin? A. Prescribe insulin glargine 5 units q HS and insulin lispro 2 units with meals, d/c oral medications B. Prescribe insulin 70/30 5 units BID, d/c oral medications C. Prescribe insulin glargine, 10 units q HS, continue metformin, decrease glipizide dose D. Start insulin lispro 2 units q AC, continue metformin, d/c glipizide

44. Adding insulin in Type 2 DM: ADA treatment algorithm Basal Insulin: ex. Insulin glargine 10 units SQ q HS Check fasting BS, increasing insulin until fasting level controlled If A1c >7%, check BS before lunch, dinner and bedtime Add short acting insulin with preceding meal: ex. Insulin lispro 4 units before lunch If hypoglycemia develops decrease insulin dose Nathan DM et al. Med Mgmt of Hypergly in Type 2 DM. ADA Consensus Statement. Diabetes Care 32:193-203.

45. Sliding scale vs correction dose What to call itWhat we’re talking about BasalLong acting insulin, given to manage baseline blood sugar PrandialShort acting insulin, given to manage the anticipated increase in blood sugar due to food intake CorrectionVariable amount of insulin given to correct an elevation in blood sugar (typically given with prandial insulin) Sliding scaleSimilar in theory to correction dose, but used at times to imply a situation in which the only insulin given is ‘correction’

46. Case She calls into clinic a few days later, she hasn’t started her insulin because she read that it’ll lead to weight gain. “I want to try Byetta.” What do you think? A. Reassure patient that insulin will not lead to weight gain B. Advise patient that exenatide/Byetta will not adequate control her blood sugar C. Sounds reasonable, d/c oral medications (metformin and glipizide) and start exenatide D. Advise patient that she needs insulin therapy and that you cannot use basal insulin in addition to exenatide

47. Incretin based injxn therapies  Glucagon like peptide-1 agonists (ex. exenatide/Byetta, liraglutide/Victoza):  Mechanism: augments glucose mediated insulin secretion (no hypoglycemia), slows gastric emptying (n/v, weight loss)  SE: GI, increased risk of pancreatitis (?), $$$  Indications: Type 2 DM, use with oral agents or basal insulin, modest A1c lower (0.5-1%)

48. Question  What are the major causes of morbidity and mortality in diabetes?

49. Longterm complications  A 54 year old male patient with type 2 diabetes being seen in clinic for diabetes management. He is on metformin 1000 mg po BID, last A1c 6.8%.

50. Diabetic Neuropathy  He tells you that he occasionally has his foot “go to sleep” but otherwise hasn’t noted any concerning pain or numbness in his feet.  How do you screen for distal symmetric polyneuropathy?  Options include pinprick sensation, vibration perception (using a 128-Hz tuning fork), monofilament testing, and assessment of ankle reflexes, ideally do two of these tests.  At this time also complete a good foot exam, checking pedal pulses and visually inspecting the foot.

51. Monofilament testing  Monofilament testing: with eyes closed pt indicates if they feel the monofilament, pressure applied until it buckles; typically tested at 5 sites (1 st, 4 th toe, 1 st, 3 rd, 5 th metatarsal heads)

52. Now what?  If the test(s) is/are normal, what now?  Re-screen annually  If the test(s) is/are abnormal, what now?  Consider other etiologies: e.g. vitamin B12 deficiency  In high-risk patients (e.g. h/o foot ulcer or amputation) refer to podiatry  In low-risk patients (e.g. unable to appreciate monofilament at 1/5 sites, otherwise normal exam) I recommend patient education re:foot care and examination of feet at every visit

53. Question  Which of the following are manifestations of diabetes neuropathy?  Painful burning of the feet  Gastroparesis  Erectile dysfunction  Resting sinus tachycardia

54. Nephropathy  Recent labs reveal a Cr of 0.9 and a spot albumin to creatinine ratio of 40 μ g/mg (uln 30 μ g/mg ).  Now what?  Spot albumin secretion is convenient but susceptible to false-positive results (causes can include recent exercise, infection, fever, significant hyperglycemia or hypertension) therefore it should be repeated prior to making mgmt changes based on this abnormality

55. Now what?  So, let’s say that he has another spot urine with albuminuria, say 45 μ g/mg creatinine. Now what?  Start an ACE I or ARB, work on good blood pressure and blood sugar control  What if his repeat test is very normal, now what?  Consider going to the typical screening interval, once a year

56. Retinopathy  Your patient tells you he saw a ophthalmologist when he was initially diagnosed 5 years ago and was told he was fine.  Does he need to go back?  Yes  Follow up timeline will be recommended by the ophthalmologist based on their exam findings

57. Macrovascular complications  His blood pressure today is 135/80, you repeat it and get 136/78.  What is the goal blood pressure in the diabetic patient?  JNC 8 <140/90  If his blood pressure was above goal what class of antihypertensive would you prescribe?

58. Macrovascular complications  On review of the labs he brings in you see that his lipids are: total cholesterol 198/triglycerides 246/HDL 40/LDL 102.  What do you do now? a. Nothing, recheck in 1 year b. Start atorvastatin c. Prescribe fenofibrate d. Recommend fish oil supplements

59. Statins  AHA/ACC Guideline, 2013: Statin therapy recommended for diabetic patients, ages 40-75, with LDL >70.  Recommended intensity of therapy determined by calculated 10 year risk of ASCVD  < 7.5% Moderate intensity statin (atorvastatin 10 mg q day, simvastatin 20-40 mg daily)  >7.5% High-intensity therapy (atorvastatin 80 mg daily, rosuvastatin 20 mg daily)

60. Macrovascular complications  Should he take a baby aspirin daily?  Yes  ASA for 1º prevention: Framingham 10 yr risk >10%, generally >50 yo with DM and an additional risk factor (e.g. HTN)

61. Immunizations  What immunizations would you recommend for this 54 year old diabetic patient?  Annual influenza vaccination  Hepatitis B vaccination  Pneumococcal vaccination  Tdap (not specific to this patient)

62. Learning objectives  Know how to screening for and diagnose type 2 diabetes  Know how to prevent diabetes  Be familiar with the “pro and cons” of common pharmacologic treatment of diabetes  Know the common complications of diabetes and how to screening of them