Insulin use in type 2 diabetes

1. Insulin use in type 2 diabetes A GP’s Perspective

2. T2 diabetes is a progressive disease Not only is the incidence of diabetes progressing toward a global epidemic, the disease itself is progressive in nature, and requires us to constantly monitor and frequently modify treatment regimens. The figure indicates the progressive increase in insulin resistance over time, and a corresponding decline in the body’s ability to secrete insulin [in people with type 2 diabetes]. Here (at time zero) insulin secretion is high and resistance to the insulin produced is low, resulting in normal blood glucose levels (BGL).1 However, over time insulin secretion declines and insulin resistance increases; meaning that the body’s ability to produce insulin and the body’s capacity to respond to insulin, both decrease until the point when resistance exceeds secretion capacity. At that point (of intersection), blood glucose has reached prediabetes levels and will progressively worsen with time (diabetes). In this scenario, insulin sensitisers, like metformin will continue to have a beneficial effect (because they improve the body’s ability to respond to the lower levels of insulin produced); whereas insulin secretagogues, such as sulfonylureas, have a diminishing effect (because the beta-cells cannot secrete what the body does not produce).2 It follows that initial insulin sensitiser and insulin secretagogue therapy may need to be supplemented with alternate treatments as T2D progresses. 1. Phillips PJ. Aust Fam Physician, 2006; 35: 975-978 [p976, Fig 1] 2. Phillips PJ. Medicine Today 2007; 8(3): 23-37 [p24, Fig 1]. Not only is the incidence of diabetes progressing toward a global epidemic, the disease itself is progressive in nature, and requires us to constantly monitor and frequently modify treatment regimens. The figure indicates the progressive increase in insulin resistance over time, and a corresponding decline in the body’s ability to secrete insulin [in people with type 2 diabetes]. Here (at time zero) insulin secretion is high and resistance to the insulin produced is low, resulting in normal blood glucose levels (BGL).1 However, over time insulin secretion declines and insulin resistance increases; meaning that the body’s ability to produce insulin and the body’s capacity to respond to insulin, both decrease until the point when resistance exceeds secretion capacity. At that point (of intersection), blood glucose has reached prediabetes levels and will progressively worsen with time (diabetes). In this scenario, insulin sensitisers, like metformin will continue to have a beneficial effect (because they improve the body’s ability to respond to the lower levels of insulin produced); whereas insulin secretagogues, such as sulfonylureas, have a diminishing effect (because the beta-cells cannot secrete what the body does not produce).2 It follows that initial insulin sensitiser and insulin secretagogue therapy may need to be supplemented with alternate treatments as T2D progresses. 1. Phillips PJ. Aust Fam Physician, 2006; 35: 975-978 [p976, Fig 1] 2. Phillips PJ. Medicine Today 2007; 8(3): 23-37 [p24, Fig 1].

3. Benefits of tight glycaemic control The potential for those complications associated with T2D [just discussed] are all significantly associated with glycaemia, and this graphic provides a timely reminder about why blood glucose control matters. A 1% absolute reduction in A1C can substantially reduce the risk of serious complications, including all-cause mortality. The higher the A1C, the larger the risk reduction that might be expected.1 Information such as this can be used in the continuing education and motivation of patients. 1. Stratton IM et al. BMJ, 2000; 321: 405-412 [p405, Col1, Results.] The potential for those complications associated with T2D [just discussed] are all significantly associated with glycaemia, and this graphic provides a timely reminder about why blood glucose control matters. A 1% absolute reduction in A1C can substantially reduce the risk of serious complications, including all-cause mortality. The higher the A1C, the larger the risk reduction that might be expected.1 Information such as this can be used in the continuing education and motivation of patients.

5. Glitazones - precautions Ineffective in 20% of patients. Average reduction in A1c of 1%. Rosiglitazone contraindicated in all classes of heart failure and in patients with ischaemic heart disease. Rosiglitazone contraindicated in triple therapy with metformin and a sulphonylurea . Pioglitazone contraindicated in moderate or severe heart failure.

6. Glitazones – more precautions Not recommended in combination with insulin as fluid retention increases risk of cardiac failure. Weight gain of 5kg on average after 5 years which continues indefinitely, fat deposition on arms. Peripheral fractures in women, 1% per year. Macular oedema may be caused or exacerbated Potential liver toxicity.

7. Starting insulin Start insulin early: if A1c > 7% on maximum tolerated dose on appropriate oral hypoglycaemic agents. Average BGL = (2 x A1c) -6 Insulin always makes diabetic patients feel better. Review patients frequently. Develop a recall system to facilitate regular follow-up. Refer to a dietician and/or diabetes educator.

8. The body’s physiologic insulin pattern The body’s normal insulin secretory response is biphasic We mentioned that unlike conventional insulin preparations, the contemporary analogue insulins more closely approximate the body’s normal insulin secretory pattern, but what do we actually mean by this? Well, the body’s physiological pattern of insulin secretion is biphasic in nature, and both phases are triggered by circulating levels of plasma glucose. The first phase consists of a basal secretion, which maintains insulin levels continuously between meals and throughout the night, and the second is post-prandial secretion, in response to a meal or snack.1 In both phases, insulin decreases plasma glucose levels by: • Reducing glucose production from the liver • Increasing glucose uptake in peripheral tissues (e.g., muscle and fat) • Decreasing glucagon secretion from the pancreas [glucagon stimulates glucose production from the liver] In the fed state, such as after a meal, blood glucose levels increase (hyperglycemia) and this triggers a prandial insulin response from the [beta cells in the] pancreas that reduces glucagon secretion by [alpha cells in] the pancreas. This tells the liver to stop producing glucose, as it is coming into the body via the gut. In the fasting state (e.g., after an overnight fast or between meals), plasma glucose levels decrease (hypoglycemia) and this triggers [the alpha cells in] the pancreas to secrete glucagon. Simultaneously, the basal insulin response is to decrease the amount of insulin secreted by [beta cells in] the pancreas to a low, “background” level. This action allows the liver to produce the needed glucose.2 So, in order to match the body’s insulin pattern, you either require a “smart insulin” that can increase or decrease its effect based on blood glucose across a 24 hour period, or you will require different insulins that provide different benefits – in other words, one that supplements the basal insulin response and a second that mimics the post-prandial insulin response.1 1. White JR, et al. Post Grad Med 2003; 113: 30-6. [p4/10. para3 &4] 2. Porte D & Kahn S. Clin Invest Med 1995; 18(4): 247-254. [abstract; p248, Figure 1 & col2, para2; p 249 col1, para2, s1-2 & para3, s1&3]We mentioned that unlike conventional insulin preparations, the contemporary analogue insulins more closely approximate the body’s normal insulin secretory pattern, but what do we actually mean by this? Well, the body’s physiological pattern of insulin secretion is biphasic in nature, and both phases are triggered by circulating levels of plasma glucose. The first phase consists of a basal secretion, which maintains insulin levels continuously between meals and throughout the night, and the second is post-prandial secretion, in response to a meal or snack.1 In both phases, insulin decreases plasma glucose levels by: • Reducing glucose production from the liver • Increasing glucose uptake in peripheral tissues (e.g., muscle and fat) • Decreasing glucagon secretion from the pancreas [glucagon stimulates glucose production from the liver] In the fed state, such as after a meal, blood glucose levels increase (hyperglycemia) and this triggers a prandial insulin response from the [beta cells in the] pancreas that reduces glucagon secretion by [alpha cells in] the pancreas. This tells the liver to stop producing glucose, as it is coming into the body via the gut. In the fasting state (e.g., after an overnight fast or between meals), plasma glucose levels decrease (hypoglycemia) and this triggers [the alpha cells in] the pancreas to secrete glucagon. Simultaneously, the basal insulin response is to decrease the amount of insulin secreted by [beta cells in] the pancreas to a low, “background” level. This action allows the liver to produce the needed glucose.2 So, in order to match the body’s insulin pattern, you either require a “smart insulin” that can increase or decrease its effect based on blood glucose across a 24 hour period, or you will require different insulins that provide different benefits – in other words, one that supplements the basal insulin response and a second that mimics the post-prandial insulin response.1 1. White JR, et al. Post Grad Med 2003; 113: 30-6. [p4/10. para3 &4] 2. Porte D & Kahn S. Clin Invest Med 1995; 18(4): 247-254. [abstract; p248, Figure 1 & col2, para2; p 249 col1, para2, s1-2 & para3, s1&3]

11. Three types of insulin Basal Premixed Rapid-acting

12. First fix the fasting BGL Start with 10 units of basal insulin. Isophane insulin must be given nocte Glargine insulin can be given nocte or mane Increase dose by 2 to 4 units every 3 days until fasting BGL under 6.0 If using glargine insulin mane and fasting BGL is above 6.0 consider giving nocte

13. Fixing the fasting BGL faster If fasting BGL > 10.0 increase insulin by 8 units every 3 days. If fasting BGL 8.1-10.0 increase insulin by 6 units every 3 days. If fasting BGL 7.1-8.0 increase insulin by 4 units every 3 days If fasting BGL 6.1-7.0 increase insulin by 2 units every 3 days until fasting BGL <6.1

14. Then fix tea If after 3 months pre-evening meal BGL remains above 7.0 and A1c above 7% consider giving basal insulin bd. An alternative option is to add rapid-acting insulin before lunch.

15. Considering rapid-acting insulin If A1C > 7% after 3 months with basal insulin. If patient is requiring more than 0.7 units of insulin per kg they will usually require rapid-acting insulin. First review meal sizes and composition, and exercise levels.

16. Adding rapid-acting insulin

17. Stopping oral hypoglycaemic agents If patient is on a glitazones cease early. Once glycaemic control is established (A1c<7.1%) consider ceasing the sulphonylurea or reducing the dose. Some patients may prefer to stay on a sulphonylurea and take less insulin. Continue metformin at a dose of 2gm daily if tolerated.

18. Switching to insulin glargine Determine total daily dose of isophane insulin. Decrease total daily dose of isophane insulin by 20%. Administer insulin glargine once daily. Monitor fasting BGL and adjust dose accordingly.

19. Take home messages Start insulin early with 10 units of basal insulin. First fix the fasting BGL. Use a diabetes recall system.