Insulin or GLP1 How to make this choice in Practice Tara Kadis Lead Nurse - Diabetes & Endocrinology Mid Yorkshire Hospitals NHS Trust
Workshop Over View Considerations/barriers to treatments in type 2 diabetes NICE recommendations Clinical application of these therapies in managing type 2 diabetes Group discussions on How & what to choose Feed back
Key Challenges of Type 2 Diabetes Diabetes is a progressive multi-system disease characterized by: Declining beta-cell function Deterioration of glycaemic control Increased risk of cardiovascular disease (including hypertension and coronary heart disease) Increase in body weight
The trade off! As diabetes treatments are added to improve glucose control, clinicians & patients face trade-offs such as: Hypoglycaemia Weight gain Complex treatment regimens
NICE guidelines Usual approach Alternatives NHS National Institute for Clinical Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes May 2009;87
GLP-1 Effects in Humans GLP-1 secreted upon the ingestion of food 5.Brain: promotes satiety and reduces appetite 4,5 2.α-cell: suppresses postprandial glucagon secretion 1 1.β-cell: enhances glucose-dependent insulin secretion in the pancreas 1 3.Liver: reduces hepatic glucose output 2 4.Stomach: slows the rate of gastric emptying 3 Adapted from 1 Nauck MA, et al. Diabetologia 1993;36:741 744; 2 Larsson H, et al. Acta Physiol Scand 1997;160:413 422; 3 Nauck MA, et al. Diabetologia 1996;39:1546 1553; 4 Flint A, et al. J Clin Invest 1998;101:515 520; 5 Zander et al. Lancet 2002;359:824 830.
Exenatide (Byetta) Commence on 5mcgs twice a day up to one hour before the 2 main meals of the day. Needs to be given at least 6 hours apart Increase to 10mcgs BD after one month 1 pen = one months treatment. Exenatide Summary of Product Characteristics 2006
Liraglutide(Victosa) Prefilled, disposable pen for s.c. injection Contains 18 mg liraglutide in 3 ml 0.6 m g selected 1.2 m g selected Once-daily s.c. injection Select dose (0.6, 1.2 or 1.8 mg) Inject at any time, independent of mealtimes (preferably same time each day) Start with 0.6mgs for 1 week increasing to 1.2 mgs there after 1.8 m g selected Victoza Summary of Product Characteristics
Exenatide 3 year extension study Open label extension study To evaluate the effects of 3 years exenatide therapy on glycaemic control, body weight, cardiometabolic markers and safety. Open-ended, open label extension of 3 placebo-controlled trials and their open label extensions. 217 adult type 2 diabetes patients: HbA 1c 11.0%, FPG <240 mg/dl, BMI 27-45kg/m 2, pre-study MET dose 1500 mg/d for 3 months, or at least the maximally tolerated effective dose of SU, or a combination. Klonoff DC et al. Curr Med Res Opin 2008; 24(1): 275-286
At 3 years Exenatide 10µg BD provided sustained reductions in HbA 1c in the completer population 46% of patients achieved HbA 1c 7% Klonoff DC et al. Curr Med Res Opin 2008; 24(1): 275-286
and progressive weight loss 84% of exenatide patients lost weight over 3 years of treatment 50% of patients lost at least 5% of baseline body weight Klonoff DC et al. Curr Med Res Opin 2008; 24(1): 275-286
Exenatide versus insulin glargine in patients with sub-optimally controlled type 2 diabetes Overview To compare effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes that is sub-optimally controlled with metformin (MET) and sulphonylurea (SU) 26-week treatment, BD fixed dose exenatide versus OD insulin glargine (titrate to fasting blood glucose level < 5.6 mmol/l) Primary endpoint: change in HbA 1c from baseline ITT sample: N = 549 randomised patients with 1 post-baseline measurement Heine R, et al. Ann Intern Med 2005;143:559 569.
Study design Randomised, open-label, controlled, multi-centre study in patients with type 2 diabetes failing to achieve adequate glycaemic control with metformin (MET) and sulphonylurea (SU) Screening (HbA 1c > 7.0% to <10.0%) Randomisation Current MET and SU therapy Exenatide 5 µg BD + MET and SU Exenatide 10 µg BD + MET and SU Insulin glargine + MET and SU (insulin titrated to target FPG < 5.6 mmol/l by daily monitoring) -4-2 0 2 4 8 12 18 26 Time (weeks) Heine R, et al. Ann Intern Med 2005;143:559 569.
Change in HbA 1c over time, ITT population 8.5 8.0 HbA 1c (%) 7.5 7.0 6.5 0 0 12 26 Time (weeks) Exenatide, 10 μg (N = 275) Insulin glargine, mean dose at endpoint = 25.0 U/day (N = 260) ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shown Heine R, et al. Ann Intern Med 2005;143:559 569.
Change in body weight over time, ITT population 2 +1.8 kg Change in body weight (kg) 1 0-1 -2-3 * * * * * * -2.3 kg 4.1 kg 0 2 4 8 12 18 26 Time (weeks) Exenatide (N = 275) Insulin glargine (N = 260) ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shown; * P < 0.0001, exenatide versus insulin glargine at same time point Heine R, et al. Ann Intern Med 2005;143:559 569.
Summary Exenatide was as effective as titrated insulin Glargine in improving glycaemic control (based on HbA 1c measurement) in type 2 diabetes patients Exenatide was associated with progressive reductions in body weight Insulin Glargine was associated with progressive weight gain The most common adverse effects of Exenatide were GI-related, decreased in incidence throughout the study. Exenatide may be an effective alternative to starter basal insulin for type 2 diabetes sub-optimally controlled with MET + SU Heine R, et al. Ann Intern Med 2005;143:559 569.
Contraindications / precautions of GLP-1 Not recommended in moderate/severe renal impairment Pregnancy/breast feeding Type 1 Diabetes Pancreatitis Risk of Hypoglycaemia in combination with Sulphonylurea
Duration of diabetes Should we consider...? GLP-1 may be beneficial when used early in the treatment algorithm Ability and willingness to self-measure blood glucose if put on SU s or insulin GLP-1 require no additional blood glucose monitoring (unless on Sulphonylureas) Dosing flexibility Weight GLP-1 induce significant and sustained weight loss Cardiovascular risk Weight loss induced by GLP-1 may improve CV risk profile in overweight and obese type 2 diabetes patients
NICE- type 2 guidelines positioning for GLP-1 (Exenatide) Consider adding a GLP-1 mimetic (exenatide) as third-line therapy to first-line metformin and a second-line sulfonylurea when control of blood glucose remains or becomes inadequate A body mass index (BMI) 35.0 kg/m 2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, or A BMI < 35.0 kg/m 2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related co morbidities. National Institute for Health and Clinical Excellence. Type 2 diabetes: Newer agents for blood glucose control in type 2 diabetes. Short Clinical Guideline 87. London: NICE; 2009 (www.nice.org.uk)
NICE Recommendation Only continue GLP-1 mimetic (Exenatide) therapy if the person has had a beneficial metabolic response a reduction of at least 1.0% in HbA1c & weight loss of at least 3.0% of initial body weight at 6 months.
Nice -Type 2 positioning for Insulin therapy Third line treatment option after Metformin / SU Should be initiated with a structured education programme If other measures do not keep HbA1c to <7.5% particularly if person is markedly hyperglycaemic Begin with human NPH insulin taken at bed time Twice daily should be considered if HbA1c >9.0% Consider a one daily long acting analogue (Detemir/Insulin Glargine) if the person needs support with injecting, does not reach target HbA1c due to hypoglycaemia or cannot use the delivery device for NPH National Institute for Health and Clinical Excellence. Type 2 diabetes: Newer agents for blood glucose control in type 2 diabetes. Short Clinical Guideline 87. London: NICE; 2009 (www.nice.org.uk) 21
Insulin V s GLP-1 Insulin Appropriate treatment for Type 2 symptomatic patients with Hba1c >9% Considerations/Barriers Weight increase Titration of dose Driving/employment considerations Side effects GLP 1 Appropriate treatment for overweight Type 2 patients Considerations/Barriers Weight loss Minimal titration Less considerations re driving/employment Side effects Contra Indications
Female 54 yrs old Case Study 1 Shirley Admin support worker Type 2 Diabetes 4 yrs duration Referred from GP with deterioration in diabetes control HbA1c 8.7% (72mmol/mol) WT 148.6kgs BMI 52.9 Non Symptomatic Complications. Background retinopathy Medication Gliclazide 160mgs BD Metformin SR 2G daily Orlistat 120mgs TDS
Shirley Commenced on Exenatide Wt reduction 13.3Kgs HbA1c reduction 1.6% Weight Kg BMI HbA1c Start 148.6 52.9 8.7 3 mts 139.7 49.7 7.1 6 mts 137 48.8 7 1 year 135.3 48.2 7.4
Case study 2 Richard Male 54 yrs old Lorry Driver Type 2 Diabetes 14yrs duration Referred to Diabetes Team with poor diabetes control HbA1c: 8%(64mmol/mol) Wt: 154.4 BMI: 46.6 Complications: Background Retinopathy, Hyperlipidaemia, Hypertension Medication: Metformin 1G TDS Gliclazide 160mg BD. Rosiglitazone 8mg
Richard Commenced Exenatide Pioglitazone stopped Gliclazide reduced to 80mgs BD Wt reduction 9.9Kg HbA1c reduction 0.1% ( at 1 year) Weight Kg BMI Waist HbA1c Start 154.5 46.6 127 8 3 mts 153.2 46.3 128 7.8 6 mts 152.8 46.1 125 8.1 1 year 144.6 43.7 7.9
Case Study 3 Frank 63 yrs Type 2 DM 5yrs Retired HbA1c 12.1%(109mmol/mol) Wt 87.8kgs BMI 29.7 Non symptomatic Complications: Background Retinopathy Diabetes Medication: Gliclazide 160mgs BD Pioglitazone/Metformin 15/850 1 BD
Frank Commenced Insulin Humulin Isophane 10units at bedtime Continued on Pioglitazone/Metformin and Gliclazide 3.9% drop in HbA1c 5.6kgs increase in weight Weight BMI HbA1c Kg Start 87.8 29.7 12.1 3 mts 89.9 30.4 9.1 6 mts 91.2 30.8 8.7 12mts 93.4 31.6 8.2
Case Study 4 Peter 68 yrs Type 2 DM 2 yrs Retired HbA1c 9.8%(84mmol/mol) Wt 72kgs BMI 24.9 Symptomatic: thirst, weight loss Complications : NAD Diabetes Medication: Gliclazide 160mgs BD Pioglitazone 45mgs OD Metformin SR 1G daily
Peter Commenced BD Pre Mixed Insulin 10 units BD Gliclazide & Pioglitazone stopped 1.2% drop in HbA1c at 1yr 4.2kg increase in weight Wt Kg BMI HbA1c % Start 72 24.9 9.8 3mts 73.6 25.5 9.2 6mts 76.2 26.4 8.6
Case study 5 Christine 59 yrs Type 2 DM -11 yrs duration HbA1c 8.8%(73mmol/mol) Wt 104.8 BMI 35.8 Symptomatic lethargy Complications: CKD stage 4 (egfr 27, Creatinine 219mmol/l) Diabetes Medications: Gliclazide 160mgs BD Pioglitazone 30mgs OD
Christine Commenced basal insulin 10 units Humulin Isophane Gliclazide stopped 0.9% drop in HbA1c 1.8Kg weight increase Wt Kg BMI HbA1c % Start 104.8 35.8 8.8 3mts 106.8 36.5 8.5 6mts 106.6 36.5 7.9
Summary and conclusions Treatment needs to be patients focussed based on individual targets decided by the patient and clinician. GLP-1 therapies represents a therapeutic option for patients with type 2 diabetes especially where weight is an issue Considerations: Efficacy Significance of weight control for the individual patient Patient preference Practicalities of treatment initiation and administration Tolerability Kendall et al. Eur J Intern Med 2009;20:S329 S339