BEDTIME INSULIN IN TYPE 2 DIABETES J. Robin Conway M.D. Diabetes Clinic, Smiths Falls,ON www.diabetesclinic.ca www.diabetesclinic.ca

Objectives Optimize type 2 diabetes management Assist you in initiating insulin in your office When to start insulin therapy? Insulins, doses, delivery options Patient training The objective of this presentation is to assist you in optimizing the management of type 2 diabetes by initiating insulin treatment in your office. The goal is to help you identify those patients that are candidates for insulin treatment as well as help you get them started. Specifically, when to start insulin, what insulin to prescribe and at what dose, the various insulin delivery options and patient training. Why is this important? Because of the sheer number of patients relative to the number of Endocrinologists. www.diabetesclinic.ca

Challenges in Initiating Insulin? 1. Patient attitudes Fear of needles Insulin viewed as a threat by patient & physician Hypoglycemia 2. Physician Attitudes Discomfort with insulin Lack of knowledge and experience There are a few challenges when initiating insulin. First of all, we have to change the patient mind set. There is the basic fear of needles and the idea that injections are painful. Also, insulin has been used as a threat for years creating dread and fear in the minds of patients. Insulin should not be viewed as a threat. In counselling patients it is better to explain that the pancreas has ceased to be able to do its job properly and therefore insulin needs to be added to assist in achieving glycemic control. The use of guilt and blame only complicate the treatment of diabetes and play no role in positive outcomes. We also need to change the mindset of you as GPs so that you don’t view insulin as difficult. If so, your own fears get in the way of using a great therapy. Insulin is another tool to use for blood glucose control and should not be viewed as a last resort when all else fails. www.diabetesclinic.ca

Insulin in Type 2 Diabetes 87% of Type 2 Diabetes is treated by Primary Care Providers 10% of Type 1 Diabetes is treated by Primary Care Providers 23.5% of visits to GP offices involve Diabetics Diabetics have multiple comorbidities www.diabetesclinic.ca

Diabetes in Canada Affects 5 - 10 % of population Diagnosed: 2.0 million Undiagnosed: ??? www.diabetesclinic.ca

Diabetes: mortality Male Male projected Female Female projected 8000 7000 6000 5000 4000 3000 2000 1000 Number of deaths 1950 1958 1966 1974 1982 1990 1998 2006 2014 Year Male Male projected Female Female projected Diabetes in Canada, National Statistics and Opportunities for Improved Surveillance, Prevention, and Control. Minister of Public Works and Government Services Canada, 1999. www.diabetesclinic.ca

Diabetes: complications Macrovascular Microvascular Stroke Diabetic eye disease (retinopathy and cataracts) Heart disease and hypertension Renal disease Peripheral vascular disease Neuropathy Foot problems Foot problems www.diabetesclinic.ca

Pathophysiology of Type 2 Diabetes Time Insulin resistance Insulin production Glucose level Non- diabetes Pre- diabetes Type 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:1162-1168. www.diabetesclinic.ca

UKPDS: long-term glucose control 9 Conventional 8 HbA1c (%) Intensive 7 ULN = 6.2% 6 3 6 9 12 15 Years of treatment UKPDS Study Group, Lancet, 1998;352:837-853. www.diabetesclinic.ca

Beta cell function in the UKPDS 100 90 80 70 60 50 40 30 20 10 Beta cell function (%) –12 –10 –8 –6 –4 –2 0 2 4 6 Years from diagnosis Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25 www.diabetesclinic.ca

Type 2 Diabetes: Double Impairment Impaired ß cell function:  insulin secretion Impaired insulin action:  insulin resistance Results in unacceptable blood glucose control www.diabetesclinic.ca

Insulin resistance: progressive ß-cell failure Hyperinsulinemia Increasing insulin resistance Impaired glucose tolerance Hyperglycemia / Type 2 DIABETES ß-cell failure Insulin deficiency www.diabetesclinic.ca

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Findings from Clinical Trials Intensive therapy to reduce glycemia reduces the risk of microvascular and neurologic complications. Insulin therapy does not increase the risk of complications. Type 2 diabetes is a progressive disease. Managing postprandial glucose is critical to effective diabetes management. Studies have shown the following: Intensive therapy to reduce glycemia reduces risk of complications. Insulin therapy does not increase the risk of cardiovascular complications, contrary to what many physicians have believed. Type 2 diabetes is a progressive disease with relentless deterioration of beta cell function. As diabetes progresses, increased monitoring and more intense management of glucose, including postprandial glucose levels, become necessary. Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837-853. 14 www.diabetesclinic.ca

Good Glycemic Control Reduces Incidence of Complications DCCT 9  7% 63% 54% 60% 41%* Kumamoto 9  7% 69% 70% – UKPDS 8  7% 17-21% 24-33% – 16%* HbA1c Retinopathy Nephropathy Neuropathy Macrovascular disease Three independent studies: DCCT (type 1), Kumamoto (type 2-lean), UKPDS (type 2-typical) showed significant benefits of similar magnitude. In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely. The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant. * not statistically significant Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837-853. 15 www.diabetesclinic.ca

Type 2 Diabetes: Key Concepts Minimizing the complications of diabetes requires: Early diagnosis and treatment of diabetes Maintaining HbA1C level < 7% Achieving HbA1C < 7% requires control of post-prandial and fasting hyperglycemia They key concepts in type 2 diabetes are (1) minimize diabetes complications with early diagnosis and treatment with maintenance of HbA1C below 7% and (2) achieving this control by reducing both post-prandial and fasting hyperglycemia. New treatment guidelines are expected in December 2003 which stress the need for tighter glycemic control. The recommendations will be for fewer steps and more aggressive treatment earlier on in order to reach glucose target levels. www.diabetesclinic.ca

CDA Guidelines (for glycemic control) Normal Optimal A1C level (0.04-0.06) (< 0.07) Preprandial glycemia 3.5-6.1 4-7 (mmol/L) Postprandial glycemia 4.4-7.8 7-11 ( mmol/L) Haars s et al., CMAJ 2003; 159 (Suppl.): S1-29. Gerstein, H.C. et al. CDA views on the UKPDS and revision of the guidelines affected by the results of this study. www.diabetesclinic.ca

When oral agents are insufficent to achieve target HbA1c 1. Add bedtime insulin to oral agents Why combine insulin and oral agents rather than just switching to insulin? Better glycemic control with smaller insulin dose + fewer injections. Less weight gain. Why just switch, rather than combining? Cost, simplicity www.diabetesclinic.ca

Next steps 2. OPTIMIZE INSULIN THERAPY Increase insulin dose as needed. IF BEDTIME INSULIN THERAPY FAILS TO ACHIEVE SATISFACTORY CONTROL Add daytime insulin according to needs.Consider adding rosiglitazone, metformin or acarbose to insulin regimens to attempt further improvements in glucose control. Once full insulin support is given there is no point in continuing secretagogues www.diabetesclinic.ca

Indications for Starting Insulin 1. Sub-optimal glycemic control despite maximal doses of oral hypoglycemics HbA1C > 7% (NEW CPG SUGGEST 7%) AC glycemia > 10 mmol PC glycemia > 14 mmol 2. Complications New guidelines will be even tighter and suggest a target blood glucose value of 7% for all patients. www.diabetesclinic.ca

Type 2 Diabetes: Double Impairment Impaired ß cell function:  insulin secretion Impaired insulin action:  insulin resistance Results in unacceptable blood glucose control www.diabetesclinic.ca

Insulin: Advantages Controls ANY patient Can be used to overcome glucose toxicity Flexibility of dose and lifestyle Ease of use with new insulin delivery technology www.diabetesclinic.ca

Insulin: Disadvantages Hypoglycemia Weight gain Injections www.diabetesclinic.ca

Plasma Glucose Normally Maintained in Narrow Range 22.0 16.5 11.0 5.5 Diabetic Control Plasma Glucose, mmol/L This slide illustrates that in healthy individuals, changes in glucose after meals are modest and kept within a very narrow range. Therefore, the natural defense against hyperglycemia is very aggressive. In patients with type 2 diabetes who have established fasting hyperglycemia, increases in postprandial glucose levels are further exaggerated. B L D 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM Time of Day Data from Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239. 24 www.diabetesclinic.ca

Targets for Glycemic Control HbA1c < 7% Fasting/preprandial glucose 4-7 mmol/L Postprandial glucose 5-8 mmol/L Bedtime glucose 5-8 mmol/L In healthy individuals, the postprandial glucose level increases less than 20-40 mg/dL above the preprandial glucose value. In patients with diabetes, the postprandial glucose has a recommended target of 100 to 180 mg/dL. American Diabetes Association. Diabetes Care. 1999; 22(supp 1): S32-S41. Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders, 3rd ed. ADA Clinical Education Series, 1998. Alexandria, VA: ADA, Inc. 25 www.diabetesclinic.ca

BEDTIME INSULIN NPH Insulin at Bedtime Signalling to liver to decrease hepatic glu Decreases Gluconeogenesis Dose usually small Risk of Hypoglycemia Small Patient can adjust dose www.diabetesclinic.ca

Novolin®ge NPH Time-Action Profile Intermediate-acting insulin Onset: 1.5 hour Maximum effect: 4-12 hours Duration: 24 hours www.diabetesclinic.ca

Bedtime Insulin Advantages Safe, unlikely to cause Hypoglycemia Small doses of Insulin, no weight gain One injection a day Good starting point Learn Insulin adjustment Easy to Teach, no mixing, use Pen www.diabetesclinic.ca

Advancing Insulin Therapy Through Device Innovation Pens, for example Novolin-Pen® 3, is the most commonly used insulin delivery device. Innovo® is the first ‘ doser ’ on the market. It has a memory feature that tells patients if and when they took their last dose and the number of units of their last dose. It has a number of other helpful features. InDuo® is the newest insulin delivery system that has integrated both the insulin delivery device and the glucose meter. Note to speaker: Speak to your Novo Nordisk representative about the opportunity for the attending physicians to inject themselves, using Novo-Pen® 1.5 and NovoFine® needles. This may be useful in having them overcome their own fears. www.diabetesclinic.ca

Bedtime Insulin-Pt Selection No longer responding to oral agents Relative Insulin deficiency Pt must have ability & be motivated Physically capable of injecting Must be self monitoring Helps with glucose toxicity www.diabetesclinic.ca

Bedtime Insulin Start at low dose, give the patient time to get used to injections Give first injection in the office Review in a Month Then start insulin adjustment www.diabetesclinic.ca

Bedtime Insulin-Adjustment Start with 10u (or .1-.3 u/kg) Target Fasting Glucose <7 mmol/L If FBS >7 for 3 days in a row, increase Give ceiling dose (+/- 30u) Review in a month After 3 mo do A1c (goal <7%) www.diabetesclinic.ca

Bedtime Insulin-Goals FBS <7 mmol/L A1c <7% If Goals not reached look at next highest glucose and treat this If Glu >8 in evening, consider Novomix 30/70 or Humalog Mix 25 at supper, or Novolin 30/70, Humulin 30/70 www.diabetesclinic.ca

SUMMARY If A1c <7% cannot be achieved on OHA, add bedtime insulin Use NPH, start with low dose until patient is comfortable Titrate up until Fasting Glucose <7 If daytime glucose remains elevated go to full insulin support www.diabetesclinic.ca