Insulin use in Type 2 Diabetes

Transcription

1 Insulin use in Type 2 Diabetes Kenneth Izuora, MD, MBA University of Nevada School of Medicine May 16, 2015

2 Conflict of Interest I have received research support from Sanofi in the past. 2

3 Learning Objectives Understand the physiology of insulin and its analogs. Understand the indications for insulin in patients with Type 2 diabetes. Understand strategies for initiating and titrating insulin during therapy for type 2 diabetes. Understand strategies for managing insulin resistance in type 2 diabetes. 3

4 Learning Objectives Understand the physiology of insulin and its analogs. Understand the indications for insulin in patients with Type 2 diabetes. Understand strategies for initiating and titrating insulin during therapy for type 2 diabetes. Understand strategies for managing insulin resistance in type 2 diabetes. 4

5 Insulin The currency of diabetes. 5

6 Physiology Insulin is produced in the beta cells of the pancreas. Constant basal secretion + bolus secretion in response to glucose load. It is amino acid based, water soluble hormone. Travels free in plasma (does not require protein binding). Easily cleared in the kidneys Has a short half life Modifications to the molecule results in analogues with different profiles. Besides lowering glucose, it has other metabolic effects. 6

7 Proinsulin 7

8 Plasma Insulin Insulin secretory pattern Breakfast Lunch Dinner 8:00 12:00 20:00 24:00 Time 8

9 Insulin Action 9

10 Insulin Action Carbohydrate metabolism glucose entry into muscle, adipose & other tissues Stimulates glycogen synthesis in the liver. Prevents gluconeogenesis/glycogenolysis. Lipid Metabolism Promotes synthesis of fatty acids in the liver Inhibits breakdown of fat in adipose tissue Other Stimulates the uptake of amino acids into cells permeability of cells to K, Mg and PO4 ions 10

11 Insulin Action Profiles Cash, credit card, check or 401k 11

12 Action Irrespective of the type, once at the receptor, action is the same. At point of sale, $1 = $1, same applies to insulin, 1 unit = 1 unit (at receptor). Produced and stored as hexamers but need to be in monomeric form to act. 12

13 Prandial Basal- Prandial Basal Pharmacokinetics of Insulin Agent Onset (h) Peak (h) Duration (h) Considerations NPH Greater risk of nocturnal hypoglycemia compared to insulin analogs Glargine Detemir ~1-4 No pronounced peak* Up to 24 Less nocturnal hypoglycemia compared to NPH Regular U ~ Inject 30 min before a meal Indicated for highly insulin resistant individuals Use caution when measuring dosage to avoid inadvertent overdose Regular ~0.5-1 ~2-3 Up to 8 Must be injected min before a meal Injection with or after a meal could increase risk for hypoglycemia Aspart Glulisine Lispro Inhaled insulin <0.5 ~ ~3-5 Can be administered 0-15 min before a meal Less risk of postprandial hypoglycemia compared to regular insulin * Exhibits a peak at higher dosages. Dose-dependent. NPH, Neutral Protamine Hagedorn. Moghissi E et al. Endocr Pract. 2013;19: Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC. 13

14 Insulin Analogs Lispro: Reversal of lysine and proline on C- terminal of B-chain Aspart: Substitution of proline for aspart on position B28. Glulisine: Asparagine at B3 replaced by lysine, lysine in B29 replaced by glutamic acid. Detemir: Fatty acid is bound to lysine at B29 Glargine: 2 arginine added to B-chain and replaced asparagine with glycine at A21 14

15 Mixed Insulins NPH/Regular insulin Novolin 70/30 Humulin 70/30 Humulin 50/50 Lispro protamine/lispro Humalog Mix 75/25 Humalog mix 50/50 Aspart protamine/aspart Novolog 70/30 15

16 Insulin Concentrations Typically U-100 (100 units/ml). U-500 regular insulin available for severe insulin resistance. Newly approved U-300 glargine. 16

17 Insulin Forms Vials/syringes Cheap Less convenient Pens Convenient Encourages compliance Easy to dose More expensive Pumps Improves outcomes Limited use in T2DM More complex Most expensive 17

18 Inhaled Insulin (regular) Formulation: Single use cartridges Comes as 4 or 8 units doses (oral inhalation). Rapid acting pre-meal boluses. Contraindicated in asthma or COPD. Concerns about acute and chronic pulmonary safety. Requires PFT monitoring (baseline, 6 months, annually). Stop if FEV1 decline by >20% from baseline 18

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20 Learning Objectives Understand the physiology of insulin and its analogs. Understand the indications for insulin in patients with Type 2 diabetes. Understand strategies for initiating and titrating insulin during therapy for type 2 diabetes. Understand strategies for managing insulin resistance in type 2 diabetes. 20

21 Case 48 y/o man with T2DM diagnosed 8 years ago. BMI = 36 kg/m 2 Presents for f/u with A1c 9.4% On Metformin and glipizide. You add Januvia (patient is compliant). Returns in 2 month with A1c 10.2% What would be the next step? 21

22 Case 48 y/o man with T2DM diagnosed 8 years ago. BMI = 36 kg/m 2 Presents for f/u with A1c 9.4% On Metformin and glipizide. You add Januvia (patient is compliant). Returns in 2 month with A1c 10.2% What would be the next step? 22

23 T2DM and Beta Cell Decline 23

24 Steps Towards Goal Basal/Bolus Basal plus Basal Insulin Oral/injectable non-insulin agents Lifestyle 24

25 Treatment Goals* AACE ADA A1c (%) 6.5 <7 Fasting/Pre-prandial glucose (mg/dl) Post-prandial glucose (mg/dl) <180 *Needs to be individualized 25

26 Patient and disease factors used to determine optimal A1C targets American Diabetes Association Dia Care 2015;38:S33-S by American Diabetes Association 26

27 Where does insulin fit in? When everything else fails. there is the government bail out American Diabetes Association Dia Care 2015;38:S41-S by American Diabetes Association 27

28 Indications for insulin in T2DM At diagnosis with very high A1c/glucose. Failure to achieve control with oral agents. Glycotoxicity: Inadequate Beta cell decline over time insulin (duration production of DM). caused by decreased insulin gene A1c 9 12%: Consider add on basal insulin* transcription due to A1c> 12%: Mixed, Basal/plus hyperglycemia-induced or Basal/bolus. changes in the activity of beta-cell transcription factors. During most hospitalizations. *Can try dual or triple non-insulin therapy if asymptomatic. 28

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30 Learning Objectives Understand the physiology of insulin and its analogs. Understand the indications for insulin in patients with Type 2 diabetes. Understand strategies for initiating and titrating insulin during therapy for type 2 diabetes. Understand strategies for managing insulin resistance in type 2 diabetes. 30

31 Basal Insulin Usually easy to start and adjust. One shot daily while patient remain on orals. Acceptable (easier to negotiate) with patients. Easy to titrate with FBG Low risk for hypoglycemia* *Except for NPH. 31

32 Basal Insulin Start with; 10 units once daily units/kg/day. Adjust every 3 7 days; 10 15% 2 4 units Aim for individual patient FBG goal averaged over 3-7 days. If hypoglycemia, determine cause and reduce dose; 4 units % Determine upper limit of titration. 32

33 Common causes of elevated FBG Inadequate basal insulin Heavy dinner (or inadequate pre-meal bolus) Excessive bedtime snack (the 4 th meal) Dawn phenomenon Somogyi effect 33

34 Case Continued eag = 28.7 x A1c Patient returns with A1c 8.4% (eag = 194) Tests only once daily and reports lows on some morning. FBG average 96 mg/dl What would you do? You reduce basal and ask him to test more often. He returns 3 weeks later with logs: 34

35 What does he need? 35

36 Bolus insulin Start with once daily bolus (largest meal). Can use single daily dose of mixed insulin (less complex but not flexible). Add on multiple premeal insulin. Use most appropriate bolus insulin; Rapid acting for most (0 15 minutes) Regular if gastroparesis (30 45 minutes) Remember to instruct on when to inject. 36

37 Bolus Insulin Start with (each meal); 4 units 0.1 units/kg 10% basal dose* If not at goal, increase every 3 7days; 1 2 units 10 15% If hypoglycemia reduce by; 2 4 units 10 20% All premeal boluses do not have to be same. Consider reducing basal dose by 10% if A1c <8% 37

38 How to Start and Adjust Insulin American Diabetes Association Dia Care 2015;38:S41-S by American Diabetes Association 38

39 Starting Basal/Bolus Estimate TDD = units/kg Basal = ½ TDD Bolus = ½ TDD Each meal = ⅓ bolus dose Monitoring BGs important. If titrating start with basal then bolus adjustment. 39

40 Plasma Insulin Basal Bolus Insulin Therapy Bolus Bolus Bolus Basal 8:00 12:00 Time 20:00 24:00 40

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42 Advanced Bolus Dosing Corrections: How much 1 unit of insulin lowers BG. Most T2DM patients have low sensitivities (2 20) Corrections are driven by goals. Formula (Insulin dose = BG Target/Sensitivity) Carbohydrate ratio: How many grams of carbs corrected by 1 unit of insulin. Requires carb counting by patient. Insulin dose depends on accuracy of carb counting Lower ratios for T2DM Start off with estimate and adjust based on response. 42

43 Self-monitoring of Blood Glucose (SMBG) Noninsulin Users Introduce at diagnosis Personalize frequency of testing Use SMBG results to inform decisions about whether to target FPG or PPG for any individual patient Testing positively affects glycemia in T2D when the results are used to: Modify behavior Modify pharmacologic treatment Insulin Users All patients using insulin should test glucose 2 times daily Before any injection of insulin More frequent SMBG (after meals or in the middle of the night) may be required Frequent hypoglycemia Not at A1C target Monitor before meals 43

44 Mean A1C SMBG Frequency vs A1C Most insurance will cover for 3 strips/ day if on insulin. If <3 strips/day, stagger testing to get average over time. Write reason for testing >3 times/day on Rx SMBG per day 50+ years years years 1-13 years Miller KM, et al. Diabetes Care. 2013;36:

45 Adverse effects of insulin

46 Hypoglycemia Whipple s Triad; Symptoms suggesting hypoglycemia Low plasma glucose at time of symptoms Relief of symptoms with glucose Some patients do not have symptoms until plasma glucose very low. Some patients have symptoms and relief with glucose but plasma glucose not low. 46

47 Symptoms of Hypoglycemia Classification Blood Glucose Level (mg/dl) Mild hypoglycemia ~50-70 Moderate hypoglycemia ~50-70 Severe hypoglycemia <50* Typical Signs and Symptoms Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesia Neuroglycopenic: behavioral changes, emotional lability, difficulty thinking, confusion Severe confusion, unconsciousness, seizure, coma, death Requires help from another individual *Severe hypoglycemia symptoms should be treated regardless of blood glucose level. 47

48 Consequences of Hypoglycemia Cognitive, psychological changes (eg, confusion, irritability) Accidents Falls Recurrent hypoglycemia and hypoglycemia unawareness Refractory diabetes Dementia (elderly) CV events Cardiac autonomic neuropathy Cardiac ischemia Angina Fatal arrhythmia 48

49 Treatment of Hypoglycemia Hypoglycemia symptoms (BG <70 mg/dl) Patient conscious and alert Patient severely confused or unconscious (requires help) Consume glucose-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat Repeat glucose intake if SMBG result remains low after 15 minutes Consume meal or snack after SMBG has returned to normal to avoid recurrence Glucagon injection, delivered by another person Patient should be taken to hospital for evaluation and treatment after any severe episode BG = blood glucose; SMBG = self-monitoring of blood glucose. 49

50 Weight gain Results from lowering of BG and need to eat to avoid hypoglycemia. Weight gain worsens insulin resistance and increases need for insulin. Weight gain is a psychological barrier to initiating or optimization of insulin. Limit weight gain by; Increase sensitivity (lifestyle, metformin) Use insulin sparing agents (incretins) Basal/Bolus regimen (mimics physiologic doses) Detemir associated with less weight gain* *Hermansen K, Davies M. Does insulin detemir have a role in reducing risk of insulinassociated weight gain? Diabetes Obes Metab May;9(3):

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52 Learning Objectives Understand the physiology of insulin and its analogs. Understand the indications for insulin in patients with Type 2 diabetes. Understand strategies for initiating and titrating insulin during therapy for type 2 diabetes. Understand strategies for managing insulin resistance in type 2 diabetes. 52

53 Insulin Resistance When greater than normal amounts of insulin is required to produce a normal biologic response. Applies to all of the biologic actions of insulin. Olefsky JM. In: Ellenberg and Rifkin s Diabetes Mellitus. 5th ed. 1997:

54 The Problem with Inflation I heard the dollar is very weak these days. Let the feds print more dollars and we will be just fine! 54

55 Etiology Inherited Rare Mutations Insulin receptor Glucose transporter Signaling proteins Acquired Inactivity Obesity Aging Medications Hyperglycemia Elevated FFAs Insulin Resistance 55

56 Measurement of IR Homeostatic Model Assessment (HOMA) Relies on fasting glucose and insulin levels. HOMA-IR = FBG x Insulin/405 Higher levels of glucose and insulin indicate more IR. 56

57 ACANTHOSIS NIGRICANS SKIN TAGS 57

58 Mechanisms Hepatic FFA flux (portal hypothesis) suppression of lipolysis by insulin Secretion of metabolically active substances (adipokines) Intra-abdominal adiposity PAI-1 FFA Adiponectin IL-6 Insulin resistance Dyslipidemia Pro-atherogenic TNFa Net result: Insulin resistance Inflammation Heilbronn et al 2004; Coppack 2001; Skurk & Hauner

59 Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults Obesity (BMI 30 kg/m 2 ) No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% Diabetes No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at

60 Insulin (pmol/l) Effect of Weight Reduction on Insulin Sensitivity * * 50 0 Before >13.6 *P<.01; P<.001. Wing RR et al. Arch Intern Med.1987;147: Weight loss at 1 year (kg) 60

61 Managing IR Lifestyle (weight reduction) Need to make better investment decisions. Energy expenditure > energy intake. Moderate intensity exercise (walk) for minutes, 3-5 days a week. Increase activity as tolerated. Reduce caloric intake (portion size and frequency) Macronutrient content may not be as important as the total calories. Refer to dietician/cde 61

62 First Line Therapy This is for your fridge 62

63 Medications Limited effectiveness without change in behavior. Insulin sensitizers Biguanides (metformin) Increases insulin sensitivity Suppress hepatic gluconeogenesis Enhances peripheral glucose uptake Decreases GI glucose absorption TZDs (pioglitazone) Modulates insulin sensitive gene transcription (PPAR) in muscle, adipose tissue and liver Reduces TG and increases HDL 63

64 Medications Weight loss agents Phentermine Orlistat Locaserin Phentermine/topiramate ER Naltrexone/buporpion Liraglutide Avoid precipitating medications (Steroids, Antipsychotics) 64

65 Thank you. Questions?

66 References Handelsman Y et al. American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan Endocr Pract Apr 1;21(0):1-87. American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. January 2015; 38 (Supplement 1) The National Diabetes Information Clearinghouse. NIDDK. 66