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Author: Alison GRAY
Folder: Therapeutics
Filename: Discussion C Edmunds-
Submitted: Tue, Nov 02 2010, 11:40 AM
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Paper ID: 31025633
Suspected Sources
[1] Another student's paper: Author: Hazel LOWE; Submitted: Thu, Jun 14 2007, 8:57 PM; Filename:
SPECAIL STUDY ESSAY .doc; REFERENCES.doc
[2] http://www.annals.org/content/138/5/383.full
[3] http://www.annals.org/content/146/12/878.full
[4] http://www.glucagon.com/sitagliptin.html
[5] http://www.ncbi.nlm.nih.gov/pubmed/14662691
[6] http://lib.bioinfo.pl/meid:43570
[7] http://lib.bioinfo.pl/meid:243230
[8] http://www.aafp.org/afp/2004/0415/p1961.html
Paper Text
Case Discussion 2: Therapeutics Patient Summary: A 60-year-old woman with Type 2 diabetes, obesity and hypertension presented to the GP for a diabetic review due to high HbA1c result. Her most recent HbA1c result was 8.7% with her last three results ranged from 8.1% to 8.9%. Liver function, urea and electrolyte blood results were normal. She has no history of microalbuminuria, retinopathy or neuropathy and no history of a cardiovascular event or associated symptoms. She has recently lost 2-3kg in weight. She monitors her blood glucose at home but could not provide details of the results. She does not smoke and drinks less than 1-2 units weekly. She is being treated with Metformin 1000mg twice daily, Glipizide 10mg twice daily and Sitagliptin 100mg twice daily for her diabetes. For her hypertension she is on Amlodipine 5mg daily, Bendroflumethiazide 2.5mg daily and Perindopril Erbumine 8mg daily. She is also on preventative medication of Aspirin 75mg daily and Simvastatin 20mg daily. Family history includes Type 2 diabetes with her mother, a history of stroke and ischaemic heart disease with her father and sister. On examination she has a BMI of 28 kg/h2 and a blood pressure of 140/70 mmHg. Cardiovascular, respiratory, abdominal and neurological examinations were all normal. Discussion: The current diabetic target is a HbA1c of <7.0% with a non-diabetic range of 4.0-6.0%. This patient is not achieving her target HbA1c and needs her medication reviewed to achieve this. There is good guideline set out by SIGN and also the Tayside Prescribing Guide as to the ideal medication for treating Type 2 diabetes. 1,2 In all patients diagnosed with Type 2 diabetes, management should start with appropriate lifestyle changes. This has been shown to be one of the most beneficial and cost effective management options particularly in those patients that have impaired glucose intolerance but a risk of developing full Type 2 diabetes. Those patients who maintain a BMI <25 kg/m2 reduce their risk by up to 31% over a 6 year period. 3 Lifestyle changes have also been shown to be responsible for a risk reduction of up to 58%. 4 This patient has tried to optimise her lifestyle factors. The first-line medication is Metformin, which belongs to the Biguanide class of medications. It acts to inhibit gluconeogenesis and glycogenolysis within the liver’s hepatocyte cells preventing the release of glucose into the blood. It also stimulates GLUT receptors on the hepatocyte cell surface, this promotes the transportation of glucose into the cells. Increased intracellular glucose in turn stimulates the enzyme glycogen synthase for cellular production and storage of glycogen. Slow absorption of Metformin occurs from the gastrointestinal tract with a peak blood level achieved between 4 and 12 hours, after ingestion. Once absorbed it is not metabolised and remains unchanged until excreted by the kidneys. The normal half-life is 6.5 hours but it is important to realise that patients with poor renal function can accumulate Metformin due to a decreased clearance rate. This patient is also on ACE inhibitors, which are cautioned due to their effect on renal function. However aggressive control of cardiovascular risk factors are important in patients with Type 2 diabetes as their overall morbidity and mortality from cardiovascular disease is higher. 5 Side effects are another consideration with this Metformin it can commonly cause gastrointestinal upset with nausea and stomach pain. It can also cause lactic acidosis and a https://safeassign.blackboard.com/view-report-display2.do?paperId=31.
metallic taste. This patient suffered some side effects but managed to reach the recommended maximum dose. It is possible to go up to 2500mg with small benefits but as this patient has suffered side effects a second line medication was indicated. 6 The second-line medication is a Sulfonylurea such as Glipizide as in this patient. This stimulates the release of insulin from functioning beta cells within the Islets of Langerhan. This is achieved by its binding to ATP-dependant K+ channel on the beta cells resulting in a more positively charged cell membrane causing Ca2+ voltage gated channels to open allowing an rise in intracellular calcium. The increase to intracellular calcium causes more insulin production and release by the cells. Other beneficial effects include sensitisation of the beta cells to glucose, decreased insulin clearance and less systemic lipolysis (limiting the gluconeogenesis pathway). This class of medication causes increased insulin levels as a direct response to a rise in systemic glucose, for example post- prandial. Greatest benefits are seen when it is taken 30 minutes before a meal, with peak plasma concentration reached between 1-3 hours, and glycaemic control maintained for up to 24 hours. It is metabolised within the liver to inactive conjugates and excreted in the urine, its half-life is 2-4 hours. This patient had not suffered any side effects including dizziness, drowsiness, nausea, vomiting and constipation. Two important issues with this drug are weight gain and hypoglycaemic episodes. In many type 2 diabetics weight is an issue, as such giving drugs that can increase weight is not ideal, however Glipizide has been found to have less effect on weight than other Sulfonylureas, which in this patient is good as she is slightly overweight. 7 There is also evidence to support the increased incidence of hypoglycaemic episodes with patients on these medications. 8 The maximum dose of Glipizide is 10mg twice daily, which this patient is currently on. There is some scope for her to try a different Sulfonylurea, however the alternative would be Glibenclamide, which has a similar efficacy as Glipizide. However Glibenclamide has been shown to have a higher rate of secondary heart failure and cause a higher incidence of hypoglycaemia. 9 Considering this patient’s cardiovascular risk factors changing may not been beneficial and has the potential to be harmful. Another alternative to Sulfonylureas is Repaglinide, which is as effective as Sulfonylurea drugs. Its main advantage is a decreased incidence of hypoglycaemia, and their metabolism by the liver; to an extent enabling use in chronic kidney disease. 7 Not much data has been published but to date most shows little difference between Repaglinide and Sulfonylureas. 10 Another aspect to consider is that Repaglinide is more expensive, Glipizide costing 36.5p/daily as opposed to £1.04 daily at maximum doses. The third line medications are Thiazolidinediones and Dipeptidyl Peptidase 4 inhibitors (DPP-4 inhibitors). DPP-4 inhibitors (this patient is on Sitagliptin) acts by increasing incretin levels. Incretin hormones include Glucagon-like-peptide 1 (GLP-1) and Glucose Dependent Insulinotrophic Polypeptide (GIP) that are released by the gastrointestinal tract to increase insulin levels in response to a rise in blood glucose. Insulin secretion is stimulated in beta cells using cAMP signalling pathways. Incretin also acts to decrease glucagon conversion in the liver. Common side effects are headaches, nausea, skin reactions, and hypersensitivity. There are rare reports of DDP-4 inhibitors causing pancreatitis and theories that they may allow some cancers to progress, but this has not yet been proven. 11 Peak blood levels are reached 1-4 hours after dose. It is metabolised in the liver and excreted in the urine and has a half-life of approximately 12 hours. Two studies have shown that adding a DDP-4 inhibitor, specifically Sitagliptin, to either Metformin has given significant results in control of HbA1c. When added to Metformin 47% of patients achieved a HbA1c <7%. 12 The recommended dose is 100mg daily, which is what this patient is taking without success. Thiazolidinediones have been rejected due to this patient’s cardiovascular risks. Although not contraindicate they have a tendency for increasing fluid retention and causing the emergence of previously undiagnosed cardiac failure. 13 This patient is currently following all of the appropriate and recommended oral medications without achieving her target HbA1c. She has also attempted to control her lifestyle factors. Although it is possible to try different preparations of oral medications, particularly a Sulfonylurea it is unlikely to give her the control she requires. As is the eventual outcome with many Type 2 diabetics, her management needs to look towards injectable insulin or GLP-1 agonists, something she was not keen on considering. Substitution of naturally produced insulin does hold some benefits and disadvantages. There has be a 1.5 to 3.5% reduction in HbA1c levels when insulin is started in combination with Metformin. 14 In this patient the type of insulin used would be important, a moderate to long acting preparation once a night before bed would be preferable due to its simplicity. This regime would supplement the basal insulin level, and this also decreases the likelihood of hypoglycaemic episodes due to a lower insulin dose. 15 The main disadvantage to starting insulin is that most patients suffer from a slight weigh increase of approximately 3 kg. This means that lifestyle control becomes even more important and should be emphasised to the patients. It has been proven that where oral hypoglycaemics are unsuccessful a regime such as this can achieve a HbA1c <7% simply and safely. 16 GLP-1 agonists offer another option but must be started and managed by a specialist. In conclusion, the management of Type 2 diabetics that are not achieving control with oral medication is complicated, partially due to the many options that are available. This patient is not keen to use injected medication and as such every option should be explored before it is used. Unfortunately injected medication is probably inevitable because it offers good long-term control, which will slow disease progression. As such it is important to communicate the need for control and the simplicity of such an option to this patient. It is also
important to explain the systemic consequences if control is not achieved so she can make an informed decision
on her future care.
References:
1. [ 1; 71% ] NHS Tayside Diabetes Management Clinical Network. Accessed 27th Oct 2010.
2. SIGN 116. . Accessed 28th Oct 2010.
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in preventing NIDDM in people with impaired glucose tolerance. [ 3; 100% ] The Da Qing IGT and Diabetes
Study. Diabetes Care. [ 3; 100% ] 1997;20:537-44.
4. , , , , , , , , , , ,; [ 3; 100% ] . Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects
with impaired glucose tolerance. [ 3; 73% ] 2001 May 3;344(18):1343-50.
5. Laakso M, Lehto S: Epidemiology of macrovascular disease in diabetes. Diabetes Rev 5:294–315, 1997 6. , , ,
,. Efficacy of metformin in type II diabetes: [ 3; 70% ] results of a double-blind, placebo-controlled, dose-
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response trial. 1997 Dec;103(6):491-7. 7. Sheehan MT. Clin Med Res. 2003 Jul;1(3):189-200. 8. , , , ,. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. 2008 Nov;31(11):2086-91. Epub 2008 Sep 9. 9. . Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. 1994 Oct-Dec;8(4):201-3.
10. , , , , ,. Comparison of the effects of three insulinotropic drugs on plasma insulin levels after a standard meal.
2002 Aug;25(8):1271-6.
11. ,. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes. 2010 Sep;35(9):509-13.
12. , , , ,; [ 4; 100% ] . Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing
pioglitazone therapy in patients with type 2 diabetes: [ 4; 100% ] a 24-week, multicenter, randomized, double-
blind, placebo-controlled, parallel-group study. [ 4; 100% ] 2006 Oct;28(10):1556-68.
13. , , , , , , , , , , ,. [ 5; 100% ] Thiazolidinedione use, fluid retention, and congestive heart failure: [ 6;
100% ] a consensus statement from the American Heart Association and American Diabetes Association. [ 5;
100% ] October 7, 2003. [ 5; 100% ] 2003 Dec 9;108(23):2941-8.
14. , , , ,. A comparison of intermediate and long-acting insulins in people with type 2 diabetes starting insulin:
[ 7; 79% ] an observational database study. 2010 Nov;64(12):1609-18. doi: 10.1111/j.1742-
1241.2010.02520.x. Epub 2010 Oct 4.
15. , ,. Clinical decisions. [ 8; 74% ] Management of type 2 diabetes. 2008 Jan 17;358(3):293-7.
16. , ,. The treat-to-target trial: [ 6; 100% ] randomized addition of glargine or human NPH insulin to oral
therapy of type 2 diabetic patients. [ 6; 68% ] 2003 Nov;26(11):3080-6.

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