Module 203.1 en_0

Editor's Notes

1. This module will cover the oral medications and injectable blood glucose-lowering medicines excluding insulin used in type 2 diabetes. Glucose-lowering medicines are also known as: Blood glucose-lowering medicines Oral hypoglycaemic agents – although not all are oral, nor do all produce hypoglycaemia Antihyperglycaemic agents Oral anti-diabetic agents
2. Firstly, the treatment with blood glucose-lowering medicines should reduce hyperglycaemia. Treatment should be planned so as to minimise the adverse effects of treatment, such as hypoglycaemia. Quality of life and well-being should be improved where possible, or at least maintained. Secondly, treatment should lead to the best possible blood glucose levels in order to prevent or delay the development of complications such as: Cardiovascular disease (heart) and cerebrovascular disease (stroke) Retinopathy (eye damage) Nephropathy (kidney disease) Neuropathy (nerve damage) Peripheral vascular disease (circulation) For more information on complications see Section 5
3. The progressive nature of diabetes is demonstrated in this slide. It shows levels of glycated haemoglobin (haemoglobin A1c, A1c, A1c) over the study period of the UKPDS. Although A1c increased over the years in both groups, it remained significantly lower in the group receiving intensive therapy. Over 10 years, the mean A1c was 7% in the intensive group and 7.9% in the conventional group – representing an 11% reduction with intensive treatment. Even with intensive therapy, the goal of normal glucose levels (A1c of 6%) was achieved for only a limited period of time and only by the intensively treated group. After the first year of treatment, A1c levels started to rise. By the end of the study, people with diabetes in the intensive treatment group required multiple medications. Results for fasting blood glucose levels followed very similar curves to those depicted for A1c. The message from this study is that, due to the destruction of beta cells, diabetes is a progressive condition, and that even with intensive therapy, blood glucose control will deteriorate. Blood glucose-lowering medicines should be used as soon as necessary. Often blood glucose lowering medicines need to be used in combination to achieve the best possible blood glucose levels. Another important finding was that after 5 years of type 2 diabetes, approximately 50% of people required insulin therapy. UK Prospective Diabetes Study (UKPDS) Group. (1998). Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in person with diabetes with type 2 diabetes (UKPDS 33). Lancet, 352: 837-53.
4. This slide shows the natural history of type 2 diabetes: The pale blue line represents insulin resistance – notice that it continues to increase as time goes on. Note the pale yellow line in this slide showing that approximately 50% of the beta cells are lost by the time a person is diagnosed with type 2 diabetes. The darker yellow line shows decreasing amounts of insulin released as Beta cells decrease. The dark blue line shows the fasting glucose rises as the number of Beta cells decrease, and the green line shows post meal glucose rising over time as well. Note that post meal glucose rises before the fasting glucose does in the presence of decreasing amounts of insulin. It is also important to point out that complications start before the diagnosis is made as represented by the two bars at the bottom of the graph. It is important to understand the process in order to use the appropriate blood glucose-lowering medicines at the appropriate time. For many, medicine will be necessary at the time of diagnosis. Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789
5. The blood glucose-lowering medicines can be divided into five groups by their mode of action: The insulin secretagogues – stimulate the pancreas to release more insulin; this group can be divided into: - sulphonylureas: release more insulin, unrelated to time or glucose level - meglitinides: release more insulin, possibly related to blood glucose level Those that reduce glucose production by the liver – Biguanides are the main group - although the thiazolidinediones (TZD) have some action on the liver Those that reduce peripheral tissue insulin resistance – primarily the thiazolidinediones - but biguanides act similarly to an extent Those that slow the absorption of complex sugars and therefore slow the rise in glucose are called alpha-glucosidase inhibitors GLP-1 (incretins) – increase the response of the beta cells to circulating levels of glucose DPP-4 inhibitors – increase the effects of the incretin hormones by decreasing the rate of breakdown of incretins.
6. The following slides will cover the action, side effects, contraindications and general information on each of the categories of medication. Biguanides decrease glucose production in the liver (gluconeogenesis). They also have some effect at the periphery, thus increasing sensitivity to insulin. Gastrointestinal side effects occur in about 30% of people with diabetes. However, by starting with low doses (no more than 500 mg at bedtime) and gradually increasing, tolerance to the side effects may develop and most people can go on to the maximum dose. A relatively small number of people do not tolerate this family of medication. Lactic acidosis is extremely uncommon. This happens most commonly when biguanides are given despite contraindications. People with renal insufficiency (creatinine clearance less than 60 ml/min) should not take biguanides because clearance will be impaired and there is a risk of developing lactic acidosis. Biguanides are also contraindicated in people with liver disease and those with heart failure (as classed III or IV by the New York Heart Association). Women who previously were not menstruating due to polycystic ovary disease may ovulate. Therefore, birth control should be discussed with these women prior to starting a biguanide. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab, 32(suppl 1). Nathan, D.M., Buse, J.B., Davidson, M.B. et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care, 32(1),193-203. Bailey, C.J., Feher, M.D. (2004). Therapies for diabetes. Edgbaston UK: Sherborne Gibbs
7. CrCl/eGFR is creatinine clearance to estimated glomerular filtration rate The administration of contrast dyes can induce kidney failure in those predisposed to renal dysfunction. Metformin is primarily excreted via the kidneys and can accumulate, causing lactic acidosis. Therefore, metformin should be discontinued before the procedure, and for 48 hours post-procedure. Metformin can cause hypos; it is very rare but is does occur. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association (2008) Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab, 27(supple 2).
8. There are different groups of insulin secretagogues. The most common and the ones that have been around the longest are the sulphonylureas. There are many medicines in this group, some familiar names are chlorpropamide, tolbutamide, glyburide, glibenclamide, gliclazide and glimeperide. The onset of action and duration of action differ for each of these. Sulphonylureas should be used with caution in the elderly due to risk of hypoglycaemia. The most common side effect is hypoglycaemia, which is most likely to occur when either activity levels increase or meals are late or missed. This group of medications should be taken before meals. Weight gain is often seen in this group of medicines, perhaps because people are obliged to treat the resulting hypoglycaemia. Furthermore, insulin is a potent stimulant of appetite; these medications continuously stimulate insulin secretion. As the highest dose is approached there is not usually a substantial response with regard to efficacy, however the adverse effects worsen proportionately. It is better to use combination therapy than to continue to increase the dose of a sulfonylurea. The other side effects are seen rarely – rash in about 2% of people, for example. *One study in the USA showed the safety of using glyburide in pregnancy for women with type 2 diabetes. However, this has not been widely accepted in clinical practice. Meglitinides The short-acting secretagogues have a shorter duration of action than the sulphonylureas and should be taken prior to meals. Duration of action is about 4-5 hours. These medicines are particularly useful when targeting post-meal glucose levels. Because they are taken prior to meals, they are particularly useful for people who often miss meals and would otherwise have a high risk of hypoglycaemia. If the meal is skipped, the medication is also skipped. These medicines may be useful for older adults. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association (2008) Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab, 27(supple 2). Bailey, C.J., Feher, M.D. (2004). Therapies for diabetes. Edgbaston UK: Sherborne Gibbs Nathan, D.M., et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care, 32(1),193-203.
9. Hypoglycaemia is a definite risk when using sulphonylureas, especially in the elderly. Therefore, in order to reduce this risk, it is sometimes useful to use a drug with slower onset and shorter duration of action. Remembering to take medication 2 or 3 times a day is a challenge for some people. At least two of the sulphonylureas allow for once-a-day dosing (gliclazide in long-acting formulation, and glimepiride). Longer-acting sulphonylureas should be avoided in older adults.
10. People taking TZDs should be warned about the possibility of fluid retention which may lead to breathlessness and swelling in the legs. They should be advised to call their health professional should they notice these symptoms. Haemoglobin levels may decrease (usually due to the dilutive effect of fluid retention). When used as monotherapy or with metformin, they do not cause hypoglycaemia. Women who previously were not menstruating due to polycystic ovary disease may ovulate. Therefore, birth control should be discussed with these women prior to starting a TZD. TZDs are contraindicated in people with liver damage (serum ALT >2.5xULN) or known liver disease. TZDs are also contraindicated in people with severe heart failure (New York Heart Association stages III to IV). They may prove to be of specific benefit to those with non-alcoholic steaterohepatosis (NASH). Bailey, C.J., Feher, M.D. (2004). Therapies for diabetes. Edgbaston UK: Sherborne Gibbs
11. These medicines do not decrease the amount of glucose that is absorbed from the intestine; they slow down the digestion and absorption of glucose in the small intestine. Side effects can be very pronounced. Therefore, it is important to warn people starting this medicine to start with small doses, and gradually increase the dose as tolerated. As dosage requirement approach the maximum dose there is not usually a substantial response with regard to efficacy, however the adverse effects worsen proportionately. It is better to use combination therapy than to continue to increase the dose of an alpha-glucosidase inhibitor. Because alpha glucosidase inhibitors slow the absorption of sucrose, if hypoglycaemia occurs – caused by another agent taken concurrently – this must be treated with glucose. This medicine is not absorbed systemically. Therefore, the only contraindication is with previously existing intestinal disease. Important teaching point: alpha glucosidase inhibitors must be taken just prior to eating or with the first bite. They will not be effective if taken after a meal. Bailey, C.J., Feher, M.D. (2004). Therapies for diabetes. Edgbaston UK: Sherborne Gibbs
12. This medication, which needs to be injected twice a day, improves the beta-cell responsiveness to blood glucose levels. It also has an effect on satiety, making people feel full before they have eaten too much. It targets post-prandial blood glucose levels. Side effects are nausea, weight loss – although some would think that was a good thing! Diarrhoea has also been reported. Starting with a small dose and working up will minimise the side effects in most people. This medication is contraindicated in renal disease (creatinine clearance <30mL/min), as well as pregnancy or severe gastrointestinal disease.
13. DPP-4 inhibitors raise GLP-1 levels 2 to 3 fold by inhibiting the effect of DPP-4. Therefore effects of the incretin hormones increase such as improved pancreatic islet glucose sensing, increased glucose-mediated insulin secretion and suppressed glucagon secretion. DPP-4 inhibitors are given orally once a day.
14. Note to the educator: It is impossible to list the names; these are different in different countries. Before giving this talk, find out the names used in your region/country for the medications. In some countries there may be less expensive brands (often called generic brands) of a particular brand name product available.
15. Note to the educator: Ask the participants to make a list of the medications used in their country. Ask them to categorise these by action and include both the generic and brand names.
16. Some medications are better suited for some people than others. We do know that a combination of agents works very well, and in fact some of the newly published guidelines for the management of diabetes are recommending combination therapy right from the start of treatment. Combination therapy is often necessary to achieve target blood glucose levels in people with type 2 diabetes. In combination therapy, medicines are recommended from different categories to affect different mechanisms. It is rarely advised, if ever, to give two medications from the same category. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008) Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab, 32(suppl 1).
17. It is important to keep in mind when deciding to use an oral medicine that if a person with diabetes has an A1c of 10%, and their lifestyle remains constant, a single oral medicine cannot be expected to bring blood glucose levels into target range and combination therapy is required. It is also important to bear in mind the cost when selecting a medication. For example, if a medicine is still under patent protection it will be much more expensive than a medicine that is no longer under patent protection. Nathan, D.M., Buse, J.B., Davidson, M.B. et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care, 32(1),193-203.
18. Several studies have been done looking at whether or not people take their medication as prescribed . As educators it is important that we assess whether people are actually taking the prescribed dose and at the correct times before any changes are made to therapy. The health care professional needs to discuss strategies and assist the person with diabetes to problem solve in order to integrate their medication regimen into their daily life. Rubin, R.R. (2005). Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med 118(5A), 275-345.
19. There are many reasons why people do not take their prescribed medication as advised. Health professionals can help people remember to take their medicines by doing the following: Check that people understand when and how they should take their medicine Do not just ask them if they understand; ask them when they will take the medicine Be sure they understand the benefits of the medicine—people may not have any symptoms of diabetes or feel at all ill; therefore unlikely that the medicine will make them “feel better” Be sure it is understood that the medicine is having a beneficial effect inside the body Wherever possible keep dosing to once or twice a day; it has been shown that the more often a person has to take medication during the day, the greater the likelihood that doses will be missed Try to use generic brands, if they are available, as they are usually less expensive; sometimes people reduce the frequency with which they take a medication or stop taking it altogether because they cannot afford it Ensure that people know what to expect in terms of side effects, and that these might only be short term; thus people will be more likely to continue with the medicine (another reason people stop is that they did not like the side effects) Rubin, R.R. (2005). Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med, 118(5A): 275-345.
20. This slide shows the proposed targets for most people with diabetes. Targets however should always be tailored to the person and adjusted as necessary. Note to the educator: Underline the following key points to course participants: Hypoglycaemia remains the limiting factor in achieving a normal blood glucose range Treatment goals and strategies to achieve the target range must be tailored to co-morbidities and the individual’s ability to perceive and manage hypoglycaemia Targets for older people, children and during pregnancy need to be adjusted from those shown on the slide IDF Clinical Guidelines Task Force. (2005). Global Guideline for type 2 diabetes. Brussels. IDF Clinical Guidelines Task Force. (2007). Guideline for Management of Postmeal Glucose. Brussels: International Diabetes Federation. American Diabetes Association. (2010). Standards of Medical Care. Diabetes Care, 33(suppl 1), S19. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab, 32(suppl 1).
21. This slide shows a method of initiating medicine that is well validated in the literature. Most guidelines are now recommending both lifestyle intervention and metformin at the time of diagnosis. If target level blood glucose has not been reached in 2-3 months an additional glucose lowering strategy should be initiated, this could be either starting a basal insulin or a sulphonylurea. If metformin and sulphonylurea does not result in target level BG, basal insulin can be added. If target level BG are still not met then insulin should be changed to a more intensive regimen. Reinforce lifestyle interventions at every visit and check A1c every 3 months until A1c is <7% and then at least every 6 months. The interventions should be changed if A1c is ≥7%. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab; 27(supple 2). Nathan, D.M., Buse, J.B., Davidson, M.B. et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care, 32(1),193-203.
22. This is another method of starting glucose-lowering medicines in type 2 diabetes. This method is not as well validated. It is again a progression to more medication if blood glucose targets are not met within 2-3 months. Nathan, D.M., Buse, J.B., Davidson, M.B. et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care, 32(1),193-203.
23. Achieving target blood glucose levels is important to delay or prevent the development of the long-term complications of diabetes. Diabetes should be treated aggressively. If the targets are not being achieved, medication dose should be increased, or medication from a different class added. There should not be a delay in moving to insulin if this is needed. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diab 2003; 27(supple 2).
24. There are a number of things to consider when treating older people with diabetes. They may have other illnesses for which they are taking other medications. These may affect the efficacy of the diabetes medication. If a person has reduced kidney function, there might be an increased risk of hypoglycaemia as the medication may not be cleared effectively from the body. Safety measures should be taken into consideration regarding remembering to take the medication, and taking the correct medicines at the correct times. When discussing medications, complementary and herbal medications should be considered as well. See Modules 3 - 3
25. In older people, it is very important to avoid hypoglycaemia to reduce the risk of falls and trauma. The following are therefore of the utmost importance: Start low and go slow Choose medicines that are shorter-acting Education is very important for people with diabetes and those caring for them. People should be informed of the reasons behind the importance of eating regularly when taking insulin secretagogues. Importantly, they should also be warned not to double up on medication if a dose has been missed.
26. Notes to the educator: Ask the participants to complete the chart. The answers are: Sulphonylureas - likely to cause hypoglycaemia; likely to cause weight gain; Biguanide – does not cause weight gain; does not cause hypoglycemia; Glitazones – likely to cause weight gain; does not cause hypoglycemia Meglitinides - likely to cause hypoglycaemia; likely to cause weight gain Alpha-glucosidase – does not cause weight gain; does not cause hypoglycemia when taken alone; target post-meal glucose Incretin mimetic agent – likely to cause weight loss not weight gain; targets post-meal glucose DPP-4 inhibitors - likely to cause weight loss not weight gain; targets post-meal glucose
27. Points to emphasise: He is obese therefore you want to be sure he does not gain more weight He will not make further lifestyle changes, so there is no point in waiting to start medication His A1c is 9.5% He is hypertensive and is not being treated; therefore, he should be started on hypertension medication He should be started on combination therapy: Biguanide and possibly a meglitinide – neither will contribute to weight gain Biguanide alone would not be enough as it will only lower the A1c by 1.0-2.0% Another option would be to start on insulin either at night with the metformin, or twice a day; however, AB is a truck driver and some countries may not allow people to have a truck drivers license if they take insulin
28. People who are newly diagnosed with type 2 diabetes should be informed about nutrition and exercise strategies to help improve blood glucose control. When A1cc is above target, there should be no delay in starting blood glucose-lowering medicines to enhance the effect of lifestyle changes. Blood glucose-lowering medicines often are needed in combination and at lower doses. If blood glucose-lowering medicines and lifestyle strategies fail, insulin should be started without delay.