Hypoglycemic Therapy :What to start & stop

Transcription

1 The Cork Diabetes & Endocrinology Clinic CDEC.IE Bon Secours Hospital, Cork Hypoglycemic Therapy :What to start & stop Maeve C. Durkan MBBS.FACP, Mmed.Ed Consultant in Diabetes, Endocrinology & Metabolism

2 Importance & Limitations of Hypoglycemia Safety Independence Morbidity Mortality Advancing therapy Fear & QOL

3 ADA criteria Hypoglycemia < 3.9 mmol < 3.9 mmol < 3.9 Probable : Presumption of < 3.9 mmol in setting symptoms Severe Hypoglycemia : Requiring assistance

4 NICE criteria Hypoglycemia < 3.0 mmol Patholological < 2.5 mmol

5 Unresponsive Treatment Glucagon. Repeat at 15 mins * Responsive 15-20gms CHO or glucose Repeat after 15 mins * If still low sandwich

6 Pseudo-Hypoglycemia Symptomatic Symptoms Blood sugar > 3.9 mmol*

7 Hypoglycemia Aware Mild Moderate Severe Unaware No gradation Critical Need to reset! Frequency Requiring Intervention Timing

8 Questions to be asked 1. Do you get low sugars? 2. How low do you go? 3. Do you feel them? 4. How often do they happen? 5. Is there a pattern? 6. Why do you get them? 7. How do you treat them? 8. What are you taking?

9 Medications / Insulin Diabetes Duration New / repetitive Timing & frequency The Hypo History early morning, pre/post meal, night, exercise Severity / Awareness Management Identifiable precipitants exercise, shopping Co-morbidities

10 Annualised rate of severe hypoglycaemia (%) Higher rate of severe hypoglycaemia with intensive glycaemic control* UKPDS 1 ADVANCE 2 ACCORD 3 VADT 4 p<0.001 vs.. conventional HR 1.86 ( ) p<0.001 p< p= HbA 1C = Conv Gly Ins Std Int Std Int Std Int 7.9% 7.1% 7.2% 7.3% 6.5% 7.5% 6.4% 8.4% 6.9% *Intensive glycaemic control was defined differently in these trials. Hypoglycaemia requiring any assistance in glucoselowering trials. Conv, conventional therapy; Gly, glibenclamide; HbA 1c, glycated haemoglobin; HR, hazard ratio; Ins, insulin; Int, intensive therapy; Std, standard therapy 1 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837 53; 2 Patel et al; ADVANCE Collaborative Group [ADVANCE]. N Engl J Med 2008;358: ; 3 Gerstein et al; Action to Control Cardiovascular Risk in Diabetes Study Group [ACCORD]. N Engl J Med 2008;358: ; 4 Date of preparation: August Duckworth et al. N Engl J Med 2009;360: UK/DB/0811/

11 After Metformin Sulphonylureas Incretin drugs GLP analogues DPPIV inhibitors SGLT2s TZDs Insulin

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13 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS Glyburide Glimepiride SU Glyburide GLY SU Gliclazide Glyburide Gliclazide Glyburide Alvarsson (n=39) Alvarsson (n=48) RECORD (n=272) Hanefeld (n=250) Charbonnel (n=313) UKPDS (n=1,573) Chicago (n=230) ADOPT (n=1,441) PERISCOPE (n=181) Tan (n=297) TIME (years)

14 Meal Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia Gut GIP GLP-1 Increased insulin (beta cells) Glucose Dependent Glucose Dependent Pancreas Muscle Adipose tissue Peripheral glucose uptake Physiologic Glucose Control Decreased glucagon (alpha cells) Liver Glucose production GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Endocrinology 2004;145: ; Zander M et al. Lancet 2002;359: ; Ahren B. Curr Diab Rep 2003;3: ; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003: ; Drucker DJ. Diabetes Care 2003;26:

15 SGLT2 inhibitors reduce renal glucose reabsorption Glomerulus Proximal tubule Distal tubule Collecting duct Glucose filtration S1 SGLT2 SGLT1 S3 Reduced glucose reabsorption Dapagliflozin SGLT2 inhibitor Loop of Henle Increased glucose excretion

16 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH TZDs 1 0 Hanefeld (n=250) Charbonnel (n=317) PERISCOPE (n=178) RECORD (n=301) PIO Chicago (n=232) ADOPT (n=1,456) Rosenstock (n=115) Tan (n=249) Rosiglitazone -1 PIO ROSI PIO PIO PIO TIME (years)

17 Which causes Hypoglycemia? 1. Glucophage 2. Pioglitazone 3. DPP IV inhibitors 4. GLP analogues 5. Suphonylureas 6. SGLT2 6. Insulin Analogues vs. NPH/ Insulatard Analogues : Lantus / Levemir vs. Degludec / Toujeo Mixed Insulins Prandial insulin vs.. Actrapid

18 Causes Medication * : Su. / Combination Su/DPPIV* Too much Insulin Malabsorption* Co-existent endocrinppathy Addisons ( reduced counter-regulatory effect) Long duration diabetes Tight control* Alcohol* CKD

19 DM 2 & HYPOGLYCEMIA YES : It happens! Its not a Myth! Advancing therapy after metformin Risks & Pitfalls

20 Proportion reporting at least one hypoglycaemic episode Epidemiology of hypoglycaemia in UK Severe hypoglycaemia 1 Mild hypoglycaemia SU <2 yr >5 yr <5 yr >15 yr T2D T1D SU <2 yr >5 yr <5 yr >15 yr T2D T1D SU, sulphonylurea 1 UK Hypoglycaemia Study Group Diabetologia 2007;50:1140 7; 2 DCCT. Am J Med 1991;90:450 9

21 Co-morbidities CAD CKD Obesity & Insulin Resistance Autonomic neuropathy Age

22 Date of preparation: August 2011 Cardiovascular effects of QRS complex hypoglycaemia Euglycaemia T Hypoglycaemia T PR segment ST segment PR interval QT QT QT interval Hypoglycaemia is known to prolong both the QT interval and cardiac repolarisation increased risk of cardiac arrhythmia UK/DB/0811/0382 Adapted from Frier et al. Diabetes Care 2011;34(Suppl 2):S132 7

23 CKD & Hypoglycemia Remember 1. CKD 2. Acute on chronic renal failure 3. Progressive CKD Will delay clearance of OHA s & Insulin

24 Phenotype of DM2 Younger Less co-morbidities Drivers and independent Alcohol Non-compliance Older CV disease, CKD and risks Blunted neurogenic response Fear of running low Non-compliance

25 Driving Guidelines New European, UK & Irish Guidelines > 2 hypos / year ( On sulphonylureas ) Glucose records required on SU s Insulin

26 Autonomic Dysfunction & Hypoglycemia Lack of response Exaggerated in elderly More common in Diabetes Blunting of response with prolonged/ recurrent hypoglycemia

27 Rate of severe hypoglycaemia (per 100 patient-years) Rate of progression of retinopathy (per 100 patient-years) The physician s dilemma: prognosis vs. tolerability Glycated haemoglobin (%) Retinopathy risk Hypoglycaemia rate Adapted from DCCT Research Group N Engl J Med 1993;329:977 86

28 Why we want lower HbA1c? DCCT EDIC UKPDS STENO ADVANCE, VADT, ACCORD But the risks of lower A1c

29 What is the target HbA1c? 1. < 6% 2. < 6.5% 3. < 7% 4. < 7.5 % 5. < 8.0%

30 HbA1c Targets Individualized < 7.0% : For all? < 6.5% : For Newly diagnosed? What about the newly diagnosed 75year old?

31 What did we get? What do we want? Past Limited choice Weight gain Hypoglycemia risk approaching target Β cell fatigue Loss durability Complications Options Now More choice Weight loss / neutrality Less hypoglycemia risk approaching targets Β cell preservation! Durability Complications *

32 Meal Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia Gut GIP GLP-1 Increased insulin (beta cells) Glucose Dependent Glucose Dependent Pancreas Muscle Adipose tissue Peripheral glucose uptake Physiologic Glucose Control Decreased glucagon (alpha cells) Liver Glucose production GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Endocrinology 2004;145: ; Zander M et al. Lancet 2002;359: ; Ahren B. Curr Diab Rep 2003;3: ; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003: ; Drucker DJ. Diabetes Care 2003;26:

33 SGLT2 inhibitors reduce renal glucose reabsorption Glomerulus Proximal tubule Distal tubule Collecting duct Glucose filtration S1 SGLT2 SGLT1 S3 Reduced glucose reabsorption Dapagliflozin SGLT2 inhibitor Loop of Henle Increased glucose excretion

34 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH TZDs 1 0 Hanefeld (n=250) Charbonnel (n=317) PERISCOPE (n=178) RECORD (n=301) PIO Chicago (n=232) ADOPT (n=1,456) Rosenstock (n=115) Tan (n=249) Rosiglitazone -1 PIO ROSI PIO PIO PIO TIME (years)

35 78 year old man, BMI 30 DM2 X 10 years Converted to Insulin 1 year prior Novomix 20/12, Sitagliptin 100, Diamicron 60 egfr 51, HbA1c 8.5% Partially blind wife administers injections BD Regular lows Terrified What to do?

36 78 year old man, BMI 30 On Novo mix BD 20 / 12, Sitagliptin 100, Diamicron MR 60 Stopped Novo mix Started basal Insulin Degludec 24, Once day Doubled the diamicron, Continue sitagliptin Added Pioglitazone 15 Target Blood sugars 6-12

37 78 year old man, BMI 30 On Novo mix BD 20 / 12, Sitagliptin 100, Diamicron MR 60 Stopped Novo mix Started basal Insulin Degludec 24, Once day Doubled diamicron 120,Continue sitagliptin Added Pioglitazone 15 All home readings in single digits / FBS 4 s Reduced basal insulin to 18

38 71 year old obese man DM diagnosed in 2003,14 years ago (MI) Managed with medications for 10 years Transitioned to insulin admits retrospectively diet poor, compliance poor On Levemir 14 units BD, Novo rapid On janumet 50/1000 BD HbA1c 73 mmol ( 9%) What to do?

39 71 year old man On Levemir 14 units BD, Novo rapid On janumet 50/1000 BD HbA1c 73 mmol ( 9%) Regular hypos Runs nighttime sugars at 15, or nocturnal hypo Brings sandwiches into garden as regular lows What now?

40 71 year old man On Levemir 14 units BD, Novo rapid 4-6-8, janumet 50/1000 BD HbA1c 73 mmol ( 9%) Regular hypos Night & day Stopped BD Levemir Started Toujeo 20 Stopped novo rapid Started diamicron 30 Target nighttime sugar 8. Overall ( 6-12)

41 71 year old man On Levemir 14 units BD, Novo rapid 4-6-8, janumet 50/1000 BD HbA1c 73 mmol ( 9%) Regular hypos Night & day Stopped BD Levemir Started Toujeo 20 Now on Toujeo 18 Started diamicron,30, Now on 90 Target nighttime sugar 8. Overall ( 6-12)

42 62 year old woman DM2 x 12 years ( aged 50) Failed medications, started insulin after 4 year Challenged with Glucophage only On Novo mix 6 & 8 HbA1c 66 mmol(8.3%), Meter readings 4 &5s What's wrong? Why is there a mismatch?

43 62 year old / New meter Challenged with Glucophage only On Novo mix 6 & 8 HbA1c 66 mmol(8.3%), Meter readings 4 &5s Gets a hypo every week, Blood sugars in 4s Cannot stick to rigidity of fixed meals What next?

44 62 year old / New meter On Novo mix 6 & 8 HbA1c 66 mmol(8.3%), Gets a hypo weekly Novo mix stopped Degludec 8 started Diamicron 60 started

45 62 year old / New meter Novo mix stopped Degludec 8 started Diamicron 60 started Feels great No hypos New meter : FBS in 5s, Post meals 6-7 Next plan :

46 52 year old female DM2 HbA1c 11% You are trying to improve control. She complains of regular hypos. Her corresponding blood sugars are in the 8 s. Is this hypoglycemia?

47 55 Year 67 old year Man. old DM2 man x 5 years Nephropathy : egfr 60, A/c ratio 3.5* BP & Cholesterol Meds. Glucophage 500 bd, Diamicron MR 60 Independent. Drives. Obese : BMI 35. Central fat ++. BP 145>90 HbA1c 8.4% Current investigation for SOBOE

48 What s his priority? Weight & Insulin resistance (IR my priority!) Attenuating beta cell failure & achieving Tighter targets Avoiding hypoglycemia & Safety

49 Options Increase Glucophage Stop diamicron sacrifice control Alternative class for control & avoid Hypos Alternative class facilitating weight loss Alternative class favoring durability efficacy

50 67 y/o man : What did I do? DM2 x 5 years Nephropathy : egfr 50, A/c ratio 3.5* Meds. Glucophage 500 bd, Diamicron MR 60 Independent. Drives. Obese : Central fat ++. BP 145>90. HbA1c 8.4% Increased Glucophage to 850 BD Reduced Diamicron to 30 with view to d/c Added GLP1 analogue

51 1 stone lost F/u 4 /12 HbA1c 7% Off diamicron as sugars low Feels great SOBOE resolved

52 50 Year old Woman DM2 on Insulin ( Glargine 60 ) BMI 39 Glucophage 1000 tds, HbA1c 8.5% egfr 90 Drives her children to school Advancing therapy? What next?

53 What s her priority? Massive & spiraling Insulin resistance Attenuating beta cell failure ( young) Achieving Tighter targets Avoiding hypoglycemia. Driving!

54 Options A.GLP analogue / DPPIV B.SGLT2 Inhibitor C.Pioglitazone D. Insulin

55 What What I did!hat did I do? Recommended SGLT2 combination Alternative TZD Pioglitazone / Add on later? Alternative GLP Inhibitor Recommended GLP1 analogue

56 68 Year old Man DM2 on Insulin BMI 27 Glucophage 1000 tds, Lantus 10, diamicron 30, Linagliptin 5mgs HbA1c 7.5% Spends 4/7 working on farm 200 km away Stable CKD, egfr 30 Significant low one night ( requiring 3 rd party) Driving license due for renewal What next?

57 What s What is his priority? priority in treatment? Safety Independence Free of hypoglycemia Can drive Can tend to his farm Personalized HbA1c targets Comorbidities egfr 30

58 So what What to do? real options? Stop Lantus sacrifice control Stop diamicron sacrifice control Alternative class maintain control & avoid Hypo Safety in setting CKD 3B/4

59 What did I do? Stopped Lantus Stopped diamicron Started Competact ( Glucophage/Competact) Continued Linagliptin

60 Back 3 / 12 later No hypos Driving to farm HbA1c 7.5%

61 80 year old man DM2 x 7 years On Glucophage (max), Diamicron MR (max) CKD ( egfr 38), No DR, DN, Drives Lives alone in mountains HbA1c 10% What next?

62 78 year old, DM2 x 5 years, Independent & lives alone. Glucophage 2500mgs & Diamicron MR 90 FBS 5, PB 13, PL 7,PD 9.HbA1c 7.8% What next? 1. Increase diamicron MR 2.Increase Glucophage to 3gms 3.Add DPP4 inhibitor (Gliptin) 4.Add Insulin

63 55 year old female on Detemir 40 She reports fasting hypoglycemia Do you reduce detemir? If she had fasting hyperglycemia Would you increase levemir?

64 Morning Hypoglycemia Morning hyperglycemia You check her night-time sugars and they are < 5, You check her night-time values which at 12. With post supper values 6. She takes a snack to bolster sugars What now? What now?

65 DM 1 & HYPOGLYCEMIA The Spectrum

66 The Hypoglycemic Patient! 28 year old patient with DM1 at clinic Wife noticed a bit off Blood Glucose 1.8 What to do? Treat and how? Treat successfully and send home?

67 36 year old Male DM 1 x 20 years,no complications HbA1c % Hypoglycemic events not an issue 4 episodes in last 12 months No hospital admission Those low blood sugars creep up on you

68 DM1 x 20 years 38 year old female No complications Is a blood sugar of 2mmol to worry about? Had driven 50 miles in car. BS 1.8 on arrival. No symptoms

69 DM1 x 10 years Likes good control HbA1c 5.8% 28 year old female FBS 4, 2-hour 5-6 No hypoglycemic episodes of concern What do you think?

70 Same 28 year old female Handbag falls open : Bottle of coke! That s for when I go low

71 26 year old male DM1 x 8 years. No complications Always well controlled. hba1c 7% No history hypoglycemia Now : Recurrent hypoglycemia x 3 weeks No intervention required What do you think?

72 26 year old : New Hypo Thinks Addison's : Measure cortisol Think Celiac : Measure TgA

73 Observational Cohort Study 917,440 patients SUPREME-DM Annual rates events/ 100 person years Higher rates of severe hypoglycemia Older age Use of insulin, secretagogues, beta blockers Higher HbA1c, longer duration DM In identifiable patient subgroups CKD, CHF & CVD Depression