Lecture title. Name Family name Country

Transcription

1 Lecture title Name Family name Country

2 Patricia B. Gatbonton, MD, FPCP, FPSEM Endocrinology, Diabetes & Metabolism When insulin is NOT an option

3 Learning Objectives Define factors leading to uncontrolled diabetes Describe the main factors leading patients to avoid insulin therapy Discuss about the strategies to manage patients that do not accept insulin therapy: relevance of optimizing metformin and use of new agents in addon to metformin (not as alternative to metformin) Illustrate conditions preventing from getting the best from anti-diabetic drugs such as use of low doses, wrong timing.

4 Outline Case Mr. RC Currently available oral hypoglycemic agents Can treatment algorithms: ADA/EASD, AACE, help? Barriers to insulin initiation Patient and Physician psychologic insulin resistance Fear of hypoglycemia Treatment resistant DM Innovative Triple & Quadruple OAD Therapies Summary

5 Mr. RC 54 years-old male, (78 kg, BMI 28 kg/m2) DM x 2 years, took Metformin 850 mg BID under medical supervision 6 months ago, GP added Gliclazide 60 mg 2 tabs OD 2 months ago, GP added Pioglitazone 30 mg HS Sx: dry mouth, associated with tingling and cramps in the legs at night Bakery owner, with a sedentary lifestyle and irregular eating habits; additionally he denies drinking alcohol or smoking CBGs: mg/dl, reduced to around 220 mg/dl after OAD Rx for HPN using Losartan/Hydrochlorothiazide 100 mg/25 mg daily Physical exam VS BP 145/95 Pulse rate: 94 Ht 68 Wt: 78 kg BMI Cardiopulmonary: Normal Abdomen: Globularly enlarged, palpable liver Extremities: Normal pulses Notes occasionally pitting edema particularly in mid-late afternoon

6 Gliclazide 120 mg Metformin 850 mg 78 kg/28kg.m2 91 cm Pioglitzone 30 mg

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9 What do I do Now & Next?

10 Options ADA algorithm A1c of 14% Patient on combination therapy of SU, Gliclazide 120 mg Metformin 850 mg BID Pioglitazone 30 mg OD AACE algorithm

11 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables - Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - SGLT-2 inhibitors - Meglitinides - a-glucosidase inhibitors - Colesevelam - Dopamine-2 agonists - Amylin mimetics - GLP-1 receptor agonists Diabetes Care 2012;35: ; Diabetologia 2012;55: Diabetes Care 2015;38: ; Diabetologia 2015;58:

12 Oral Class Mechanism Advantages Disadvantages Cost Biguanides Sulfonylureas Meglitinides Activates AMPkinase (?other) Hepatic glucose production Closes K ATP channels Insulin secretion Closes K ATP channels Insulin secretion Extensive experience No hypoglycemia Weight neutral? CVD Extensive experience Microvascular risk Postprandial glucose Dosing flexibility Gastrointestinal Lactic acidosis (rare) B-12 deficiency Contraindications Hypoglycemia Weight Low durability? Blunts ischemic preconditioning Hypoglycemia Weight? Blunts ischemic preconditioning Dosing frequency Low Low Mod. TZDs PPAR-g activator Insulin sensitivity No hypoglycemia Durability TGs (pio) HDL-C? CVD events (pio) Weight Edema/heart failure Bone fractures LDL-C (rosi)? MI (rosi) Low Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015;58:

13 Oral Class Mechanism Advantages Disadvantages Cost a-glucosidase inhibitors DPP-4 inhibitors Bile acid sequestrants Dopamine-2 agonists SGLT2 inhibitors Inhibits a-glucosidase Slows carbohydrate digestion / absorption Inhibits DPP-4 Increases incretin (GLP-1, GIP) levels Bind bile acids? Hepatic glucose production Activates DA receptor Alters hypothalamic control of metabolism insulin sensitivity Inhibits SGLT2 in proximal nephron Increases glucosuria No hypoglycemia Nonsystemic Postprandial glucose? CVD events No hypoglycemia Well tolerated No hypoglycemia LDL-C No hypoglyemia? CVD events Weight No hypoglycemia BP Effective at all stages Gastrointestinal Dosing frequency Modest A1c Angioedema / urticaria? Pancreatitis? Heart failure Gastrointestinal Modest A1c Dosing frequency Modest A1c Dizziness, fatigue Nausea Rhinitis GU infections Polyuria Volume depletion LDL-C Cr (transient) Mod. High High High High Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015;58:

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16 SGLT2 inhibitors

17 Antihyperglycemic Therapy in T2DM Individualized A1c goal No A1c stratification All drugs equally weighted 3 month interval adjustments Metformin + 2 nd drug at HBA1C of 9% Metformin + 2 nd + 3 rd agent if still not controlled after 3 mos No option for quadruple drug therapy After triple therapy, go to Metformin + basal insulin or GLP-RA On GLP-RA add basal insulin On optimal basal insulin, add GLP-1 RA or mealtime insulin Insulin if CBG 300mg or A1C 10% ADA Standards of Medical Care in Diabetes. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

18 What are your options? ADA algorithm Patient on combination therapy of Gliclazide 120 mg Metformin 850 mg BID Pioglitazone 30 mg OD A1c of 14% Increase dose of gliclazide? AACE algorithm

19 B-Glucose (mmol/l) Average Home-Monitored Blood Glucose With Increasing Glipizide Dose 14 P< ,4 9,6 n.s. 9,2 8, mg 10 mg 20 mg 40 mg Dose Adapted from Stenman S. Ann Intern Med. 1993;118:

20 Graph of theoretical dose-effect relationships for many drugs, showing that half-maximal dosages yield far more than 50% of the therapeutic effects and that side effects sharply increase as the dosage nears maximal levels* *American Journal of Medicine Vol 108 (6A) pp 20s

21 What are your options? ADA algorithm Patient on combination therapy of Gliclazide 120 mg Metformin 850 mg BID Pioglitazone 30 mg OD A1c of 14% Increase dose of gliclazide? Increase dose of metformin? AACE algorithm

22 Change in HbA 1c from placebo (%) Up-titrating monotherapy to the maximum recommended dose may not provide benefit Patients stopping treatment (%) HbA 1c Gastrointestinal side effects Metformin dosage (mg) Metformin dosage (mg) Garber AJ, et al. Am J Med 1997; 103:

23 Metformin & renal function egfr level (ml/min per 1.73 m 2 ) Action > 60 No renal contraindication to metformin < 60 and > 45 < 45 and > 30 Continue use Increase monitoring of renal function (every 3-6 months) Prescribe metformin with caution Use lower dose (eg, 50%, or half-maximal dose) Closely monitor renal function (every 3 months) < 30 Stop metformin Lipska KJ et al. Diabetes Care 2011;34:

24 The European Medicines Agency (EMA) has announced that metformin-containing medicines can now be used in patients with moderately reduced kidney function defined as a glomerular filtration rate (GFR) of 30 to 59 ml/min for the treatment of type 2 diabetes.

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27 Anticipated efficacy of initial & add on OHDs Metformin Gliclazide TZD, DDPiv, SGLT2, GLP1-RA, basal insulin Med Clin N Am 99 (2015)

28 Recognizing Oral Therapy Inadequacy When A1C is not at goal of 7% & 2 OADs being used maximally Increased hyperglycemic symptoms, weight loss SMBG shows significant hyperglycemia >200 mg/dl and/or day long >300 mg/dl Duration of diabetes >5 years Low C-peptide Physiologic stress Therapeutic decision Add a 3 rd oral agent (anticipate A1C reduction of %) Start insulin

29 Triple Oral Therapy In T2DM 38 Greek on maximum Met + Glimepiride with mean duration of diabetes of 10.5 years and mean BMI of 31 was randomized to either 4mg (n=19) or 8 mg (n=19) per day of rosiglitazone * B: baseline; A: 20 weeks treatment * p<0.001; p< vs. baseline B A B A B A B A HbA1c (%) FPG (mmol/l) Kiaylas JA et., Diabetes Care 25: , 2002

30 Sherwyn Schwartz et al. Dia Care 2003;26: A and C: A1C values by American Diabetes Association

31 Options ADA algorithm Already on combination therapy with Metformin 850 mg + Gliclazide 180 mg + Pioglitazone 30 mg AACE algorithm No recommendation to 1. Add 4 th agent DDP4vi or SGLT2 2. Replace one agent with another agent DDPIV-1 or SGLT2 Start basal insulin or GLP1-RA

32 A1c goal < 6.5% A1c stratification at entry Drugs: green vs yellow 3 month interval adjustments Combination therapy at 7.5% Triple therapy at 9% if patient Asx Insulin if Sx, A1c>9

33 Options ADA algorithm Already on combination therapy with Metformin 850 mg + Gliclazide 180 mg + Pioglitazone 30 mg No recommendation to 1. Add 4 th agent DDP4vi or SGLT2 2. Replace one agent with another agent DDPIV-1 or SGLT2 Start basal insulin or GLP1-RA AACE algorithm Not favorable triple combination, two yellow classes, use with caution No recommendation to 1. Add 4 th agent DDP4vi or SGLT2 2. Replace one agent with another agent DDPIV-1 or SGLT2 If on triple with no improvement, proceed to insulin Entry level A1c >9% with symptoms: Insulin +/- other agents Start basal insulin

34 Indications for Insulin Therapy in Patients With Type 2 Diabetes Hyperglycemia despite optimal oral therapy (A1C >8%) Decompensation Injury, stress, illness Severe hyperglycemia with ketonemia/ketonuria Uncontrolled weight loss Surgery Gestational diabetes Hypersensitivity to oral agents Diabetes associated with certain conditions/syndromes (eg, pancreatic diabetes, drug- or chemical-induced diabetes, endocrinopathies, insulin-receptor disorders, some genetic syndromes) American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125. DeWitt DE, Hirsch IB. JAMA. 2003;289:

35 Insulin initiation The decision to start insulin therapy should be made individually, based on several factors: Whether the patient is willing to try it The degree of hyperglycemia How relevant the potential side effects of insulin are to the patient compared with those of other hypoglycemic agents Whether oral hypoglycemic agents with or without GLP1 analogues are expected to provide the desired benefit The patient s work schedule & lifestyle Cost The availability of nurses, diabetes educators, & others to implement & follow the insulin treatment. c l e v e l a n d c l i n i c j o u r n a l o f m e d i c i n e v o l u m e 7 8 n u m b e r 5 may

36 You are symptomatic with poor A1C level and 3 maximal medications. You really need to go on insulin. 78 kg/28kg.m2 91 cm Gliclazide 120 mg Metformin 850 mg Pioglitazone 30 mg

37 Noooooo! I don t want insulin, Doctor. I m scared of needles, & its going to hurt & it will be too complicated.

38 Plus it ll make me fatter and I ll get low sugar shakes & die, just like my neighbor!

39 Barriers to Using Insulin & GLP1-RAs Patient resistance Perceived significance of needing insulin Fear of injections Complexity of regimens Pain, lipohypertrophy Physician resistance Perceived cardiovascular risks Lack of time & resources to supervise treatment Medical limitations of insulin treatment Hypoglycemia Weight gain

40 Causes of psychological insulin resistance The Review of Diabetic Studies Phillips Vol. 2 No

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42 diabetes care, volume 28, number 12, december 2005

43 Hypoglycemia rates ACCORD, ADVANCE & VADT VADT

44 Physician & patient responsibilities at the initiation of treatment

45 2015 by British Medical Journal Publishing Group Wen Ting Tong et al. BMJ Open 2015;5:e006407

46 Should not be confounded with the classical insulin resistance that is a key feature of T2D Different from the patient reluctance to accept antidiabetes therapy, especially when insulin therapy should be considered (so called psychological insulin resistance) Resistant T2D may refer to patients with persistent poorly controlled diabetes mellitus (PPDM) despite standard care (triple oral therapy; Met+SU+3 rd agent)

47 expert opinion on pharmacotherapy, 2017

48 expert opinion on pharmacotherapy, 2017

49 The problem with algorithms There are 7 therapeutic classes of hypoglycaemic agents currently available metformin, sulphonylureas (including glinides), α-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists & insulin If therapy is initiated with 1 of the 5 classes of oral agents & adequate glycaemic control is not achieved, the next therapeutic option involves a choice between 6 classes. If a 3 rd agent is required, there are 5 classes of agents from which to choose, & if a 4 th agent is contemplated there are another 4 classes of options. There are 150 therapeutic options (5 x 6 x 5) for triple therapy & 600 options (5 x 6 x 5 x 4) for quadruple therapy not including the different options within each class for example, basal vs. premixed insulin Treatment algorithms cannot be truly evidence-based because of a lack of studies comparing all available treatment combination options. It is possible to derive evidence-informed consensus algorithms, although balancing available evidence & consensus is important in order to avoid the potential for bias evident in some algorithms. Diabetes, Obesity and Metabolism 14 (Suppl. 1): 3 8, 2012.

50 7% 14%-7%= 7 Endocrine (2013) 44:

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52 Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects more stringent low Approach to the management of hyperglycemia HbA1c 7% less stringent high Disease duration newly diagnosed long-standing Life expectancy long short Usually not modifiable Important comorbidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities less motivated, non-adherent, poor self-care capacities Potentially modifiable Resources and support system Readily available limited Diabetes Care 2015;38: ; Diabetologia 2015;58:

53 Treatment Considerations Macrovascular complications not clear Long standing HYP, no ECG, Stress Test, 2DE Microvascular complications not clear Nephropathy, Micral? Consider A1c target of 7% without hypoglycemia or SE Considerations for selecting therapy Effect of additional meds on patient s weight remove or replace SU? Remove or replace Pioglitazone? Role of CV or renal function in selection or adjustment of therapy With A1c of 14%, it s unlikely that one additional agent will lower A1c to target Reinforce lifestyle modification & encourage exercise Individualize treatment choices SGLT-2: for weight loss and cardiovascular protection GLP1-RA: for weight loss?? Insulin???

54 Wt gain risk for edema best potential reduction Neutral weight Potential option Weight loss CV protection? expert opinion on pharmacotherapy, 2017

55 expert opinion on pharmacotherapy, 2017

56 expert opinion on pharmacotherapy, 2017

57 EXPERT OPINION ON PHARMACOTHERAPY, 2017

58 Metformin 2000 mg/d Linagliptin 5 mg/od Empagliflozin 25 mg/d 78 kg/28kg.m2 91 cm Rosuvastatin 10 m Allopurinol 300 mg

59 HbA 1c (%) Conservative management of glycemia: traditional stepwise approach Diet and exercise OAD* monotherapy OAD monotherapy up-titration OAD combination OAD + basal insulin OAD + multiple daily insulin injections Duration of diabetes HbA 1c = 7% HbA 1c = 6.5% *OAD = oral antidiabetic Campbell IW. Br J Cardiol 2000; 7:

60 HbA 1c (%) Proactive management of glycemia: early combination approach Diet and exercise 10 OAD* monotherapy OAD combinations OAD up-titration OAD + basal insulin 9 OAD + multiple daily insulin injections 8 ACTION POINT: kg/28kg.m2 Duration of diabetes HbA 1c = 7% HbA 1c = 6.5% *OAD = oral antidiabetic

61 When insulin is not an option: 1. Make every effort to ensure compliance with diet, appropriate timing & dosing of medication is followed 2. Try to relieve patient anxiety by reassurance, education, supervise & teach patient injection technique & observe 3. If all efforts fail, review patient s diabetes duration, do a cardiometabolic & complications assessment & combine drugs together in a efficacious & safe manner to lower blood sugar without causing hypoglycemia 4. Newer, innovative drugs provide us a variety of potential combinations to help delay insulin initiation in patients who are reluctant to use injectable therapy

62 Treat as individually as possible Gatbonton, PB. April 2012