Diabetes - the place for newer therapies in practice
Although glycaemic control is only one aspect of diabetes management, the practice nurse is presented with an ever-increasing choice of hypoglycaemic agents from which to choose. Here is an update on the risks and benefits the nurse should consider before selecting the right option for the individual patient
Diabetes is a condition with significant morbidity and mortality attached. Approximately 2.9 million adults suffer from type 2 diabetes in the UK, and it is thought that there are also around 850,000 people in the UK who have undiagnosed type 2 diabetes. By 2025, it is estimated that 5 million people will have diabetes in the UK.1 The majority of patients (90%) who have diabetes have type 2 diabetes, but both type 1 and type 2 are linked to significant, and life-changing, complications. In fact many people who have diabetes will die of a cardiovascular condition; having diabetes increases the risk of both macrovascular and microvascular disease. It is important to recognise, therefore, that diabetes management requires treatment of multiple risk factors for cardiovascular disease and of these risk factors, glycaemic control plays a smaller part in improving cardiovascular risk than managing lipids and blood pressure effectively.2
It is worrying to note that most of the money spent on treating diabetes is actually used to treat the micro- and macrovascular complications of the condition, rather than on treating the diabetes itself. Effective management of cardiovascular risk is central to improving outcomes and the use of treatments that are well-tolerated by patients should be a key consideration when prescribing. Long-term cost efficacy should be borne in mind as well as short term goals. However, in this article we will focus on glycaemic control and consider some of the newer therapies that are available for improving blood glucose levels. We will also discuss how and when newer agents might be used in a cost-effective way.
Many of the therapies that are used to treat hyperglycaemia are covered by current NICE guidelines.3 However, since these guidelines were published, newer drugs within the classes mentioned by NICE have come to market and we also have brand new classes of drugs which are available to prescribe.
Current advice from NICE is to combine lifestyle interventions with structured education and appropriate drug therapy to improve overall control of blood glucose, lipids and blood pressure. Metformin is the first line therapy unless contraindicated or not tolerated but once the full dose of metformin (2g) is being taken, a wide range of options for additional hypoglycaemic agents are available to choose from. Lately, selecting diabetes treatments feels like a card trick – ‘Pick a number, any number’ – as we consider whether to choose a DPP4, GLP1 and now an SGLT2 alongside older therapeutic options.
For many clinicians the next step after metformin will be to add a sulfonylurea such as gliclazide. However, although gliclazide is generally well tolerated, the sulfonylureas as a class have recognised side effects which make them potentially unpopular with patients – notably the risk of hypoglycaemia, and weight gain,4 which has been shown to offset any improvement in HbA1c.5 The advent of newer agents provides alternatives to sulfonulureas, and they are therefore worth considering these in some patients.
GRAHAM, AGE 44
Graham has T2D and is well controlled on metformin 2g daily and gliclazide 80mg bd. He has no history of hypoglycaemia and he works hard at maintaining a healthy lifestyle. His BMI is 23 and his BP is 123/66. He takes a statin, which keeps his lipid levels within recommended limits: he has a total cholesterol of 3.9mmol/l and an LDL of 1.9mmol/l. His HbA1c is 48mmol/l. Graham is happy with his current medication and there is no need to make any changes at this stage.
SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS
The latest oral hypoglycaemic drug to come onto the market is from a class known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. Currently there is only one drug available in this class – dapagliflozin. It is licensed to use as monotherapy or in combination with insulin or other oral hypoglycaemic agents apart from pioglitazone; this exclusion has been made as a safety precaution as pioglitazone has been linked to a possible increased risk of bladder cancer, and dapagliflozin works on the renal system.
SGLT2 inhibitors lower blood glucose levels by reducing the amount of glucose reabsorbed by the kidneys thus increasing the amount of glucose excreted, inducing glycosuria and reducing glycaemia. The kidneys have receptors which detect sugar in the urine during filtration and return it to the body. Approximately 90% of glucose reabsorption is due to SGLT2 activity and SGLT2 inhibitors block this activity, allowing glucose to pass through the renal system. As a result of the glycosuria that is a feature of the mode of action of this drug, an increase in genitourinary infections such as vaginal thrush and urinary tract infections was seen.6 However, such infections were generally mild to moderate in severity, occurred in the first year of treatment and rarely recurred.
One of the additional findings from trials done with dapagliflozin was that people who were taking it reported weight loss. This is obviously beneficial in type 2 diabetes. In trials, a sustained weight loss of 1.7-3.7kg was seen.6 This is because the treatment inhibits glucose reabsorption to a level equivalent to an energy loss of 280Kcal per day. Hypoglycaemia does not occur unless the drug is added to another drug that is known to carry the risk of hypoglycaemia (such as sulfonylureas or insulin). In view of its activity within the kidneys it is not recommended for patients with moderate or severe renal impairment (eGFR <60ml/min/1.73m). For this reason, it is often more suitable for use earlier in the treatment process, before any renal impairment might occur. Theoretically, however, it can be used at any stage as long as the patient continues to have adequate renal function. This should be tested prior to initiation and 2-4 times a year, depending on the patient and other drugs being taken. The recommended dose of dapagliflozin is 10mg daily and there is no dose adjustment required. Local guidance should be consulted regarding who can initiate this drug before prescribing.
DAVINDER, AGE 49
Davinder is 49 years old and has an HbA1c of 69mmol/l. He has a BMI of 28 and is currently treated with 2g metformin daily. He tries hard with his diet but works as a taxi driver, which he feels makes it hard to sustain change. He needs add-on therapy but does not want anything which might increase his weight further. Ideally he would like to lose some weight. He has normal renal function. Davinder would be suitable for treatment with dapagliflozin.
INCRETIN-BASED THERAPIES
Incretin-based therapies include glucagon-like peptide-1 analogues (GLP-1) and dipeptidyl peptidase 4 (DPP4) inhibitors. Incretin therapies work in different ways to increase the level of GLP-1 in the gastrointestinal system, stimulating insulin release in response to a meal. Although these have been around for several years now, there are newer options and indications that are worth considering. When the updated NICE guidelines on newer therapies were published in 2009 there were only two DPP4 inhibitors, sitagliptin and vildagliptin. These days there are four, with the addition of saxagliptin and linagliptin. NICE states that DPP4s can be considered as an alternative to a sulfonylurea if there is significant risk of hypoglycaemia or its consequences.3 Renal licences have changed since these drugs first came on the market, and they can all be used in renal impairment – although only linagliptin can be used at the same dose from normal renal function through to end stage renal failure. The others can be used in renal impairment as long as doses are adjusted appropriately. However, saxagliptin cannot be used in end stage renal failure at any dose.7
BRENDA, AGE 72
Brenda lives alone. She has had type 2 diabetes for 5 years and watches her diet carefully. Her BMI is 26. She has an HbA1c of 72mmol/l and her nurse has suggested add-on therapy. Brenda is worried about hypos as she lives alone. She also has erratic eating patterns as she spends a lot of time at her allotment. Brenda would suit treatment with a DPP4.
With regard to the GLP-1 analogues, there are now four different types on the market, the twice daily version of exenatide (Byetta), the once daily liraglutide (Victoza) and lixisenatide (Lyxumia) and the once weekly version of exenatide (Bydureon).
Incretin-based therapies have the advantage of being glucose dependent which means their hypoglycaemia risk is low. GLP1s work by stimulating insulin secretion after a meal and reducing post-prandial glucose levels; they also delay gastric emptying and suppress the appetite. Because of this GLP1s have the additional benefit of weight loss in some patients but this benefit may be offset by the possible disadvantage their method of administration, by injection. The long-acting version of exenatide may offer some advantages in that respect, as it only needs to be given once weekly. The drug is held in microspheres and slowly released to prolong the activity of the drug. In order for this to happen, the drug must be mixed just prior to injecting, which may make it a little more fiddly than the pen devices used for the other GLP1s. The presence of these microspheres may also increase the risk of patients developing small nodules under the skin once the injection has been given, and they should be warned of this possibility; nonetheless, many patients may consider these issues a small price to pay to be able to inject just once a week.
GLP1s can, in some cases, be used with insulin but this treatment combination is usually undertaken by specialists in primary and secondary care.
DONALD, AGE 65
Donald has T2D and is housebound following a stroke in his 50s. His BMI is 35 and he struggles to get in and out of his wheelchair at times. He takes metformin 2g daily and gliclazide 160mg daily. He has occasional hypos. He has to rely on others to cook and shop for him. His son visits once a week to give him a bath. His HbA1c is 78mmol/l. Donald could benefit from a GLP1 analogue. Discussions should be had regarding the risks and benefits of this treatment and whether he would prefer to try a once weekly injection, or a once/twice daily regimen.
CURRENT CONCERNS OVER INCRETIN-BASED THERAPIES
There have been some reports in the press recently about the risk of pancreatitis and thyroid or pancreatic carcinoma in people taking incretin-based therapies (GLP1s and DPP4s).8 [See below] However, it is important to point out that these potential side effects, and in particular pancreatitis, had already been identified, and warnings about these risks are included in the summary of product characteristics for each drug. People with diabetes are known to have an increased risk of these conditions anyway. Anyone starting on these therapies should be alerted to the possibility of side effects, as indeed should anyone starting on new treatments for any condition. The FDA and the EMA have both stated that at this time there has been no causal relationship established between exposure to these drugs and pancreatic or thyroid cancer. The FDA also said there was no clear and direct link with pancreatitis. Nonetheless, studies are ongoing and clinicians should be aware of the potential for harm as well as benefit from any drug. NICE recommends that clinicians should discuss the potential benefits and risks of treatment with a GLP-1 analogue with the person to enable them to make an informed decision.3
SAFETY CONCERNS ABOUT GLP-1 THERAPIES IN DIABETES
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has stated that there are ‘no new concerns for GLP-1 therapies identified on the basis of available evidence’.
The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD) and the International Diabetes Federation (IDF) have also reviewed the available data and have found ‘insufficient evidence to modify current treatment recommendations.’
A pooled analysis of 25 randomised controlled trials, published in Diabetes Therapy, found no difference in the incidence of pancreatitis or pancreatic cancer in those patients taking the GLP-1 inhibitor sitagliptin and those who did not.
Engel SS, Round E, Golm GT, et al. Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Therapy 2013;1: 119-145
CONCLUSION
There is an ever-increasing range of therapies available to treat type 2 diabetes and clinicians need to be aware of the potential risks and benefits of all of these treatments in order to ensure that people with diabetes can make an informed choice regarding their options. Diabetes is a cardiovascular disease and while glycaemic control is important, it is just one facet of care that should encompass lifestyle changes, management of blood pressure and lipids to reduce the risk of long-term complications.
REFERENCES
1. Diabetes UK (2012) Diabetes in the UK Available at http://www.diabetes.org.uk/Documents/Reports/Diabetes-in-the-UK-2012.pdf
2. Yudkin JS, Richter B, Gale EA. Intensified glucose lowering in type 2 diabetes; time for a reappraisal Diabetologia 2010; 53:2079-85
3. NICE (2009) Type 2 diabetes. Available at http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf
4. Wright A, Burden AC, Paisley RB et al .Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UKPDS 57 Diabetes Care 2002;25:330-6
5. McEwan P, Evans M, Kan H, Bergenheim K. Understanding the inter-relationship between improved glycaemic control, hypoglycaemia and weight change within a long-term economic model. Diabetes Obes Metab 2010;12(5):431-6.
6. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial Lancet 2010;375: 2223–33
7. Gadsby R. Prescribing DPP4 inhibitors: Are there any clinically relevant differences? Primary Care Cardiovascular Journal 2012; 5(4):167-169
8. Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB (2013) Glucagon-like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus. JAMA Intern Med 2013; 17:534-9.
