Download Case Discussion 2: Therapeutics

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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 4.06.0%. 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
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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 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
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increasing incretin levels. Incretin hormones include Glucagon-like-peptide 1 (GLP1) 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 halflife 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:
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1. NHS Tayside Diabetes Management Clinical Network.
http://taysidedn.dundee.ac.uk/Default.aspx Accessed 27th Oct 2010.
2. SIGN 116. http://www.sign.ac.uk/pdf/sign116.pdf. Accessed 28th Oct 2010.
3. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet
and exercise in preventing NIDDM in people with impaired glucose tolerance.
The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-44.
4. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, IlanneParikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M,
Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group.
Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects
with impaired glucose tolerance. N Engl J Med. 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. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of
metformin in type II diabetes: results of a double-blind, placebo-controlled,
dose-response trial. Am J Med. 1997 Dec;103(6):491-7.
7. Sheehan MT. Current therapeutic options in type 2 diabetes mellitus: a
practical approach. Clin Med Res. 2003 Jul;1(3):189-200.
8. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Metformin,
sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or
hypoglycemia: a nested case-control analysis. Diabetes Care. 2008
Nov;31(11):2086-91. Epub 2008 Sep 9.
9. Harrower AD. Comparison of efficacy, secondary failure rate, and
complications of sulfonylureas. J Diabetes Complications. 1994 OctDec;8(4):201-3.
10. Cozma LS, Luzio SD, Dunseath GJ, Langendorg KW, Pieber T, Owens DR.
Comparison of the effects of three insulinotropic drugs on plasma insulin
levels after a standard meal. Diabetes Care. 2002 Aug;25(8):1271-6.
11. Pathak R, Bridgeman MB. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the
Management of Diabetes. P T. 2010 Sep;35(9):509-13.
12. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019
Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin
added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24week, multicenter, randomized, double-blind, placebo-controlled, parallelgroup study. Clin Ther. 2006 Oct;28(10):1556-68.
13. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le
Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R.
Thiazolidinedione use, fluid retention, and congestive heart failure: a
consensus statement from the American Heart Association and American
Diabetes Association. October 7, 2003. Circulation. 2003 Dec
9;108(23):2941-8.
14. Gordon J, Pockett RD, Tetlow AP, McEwan P, Home PD. A comparison of
intermediate and long-acting insulins in people with type 2 diabetes starting
insulin: an observational database study. Int J Clin Pract. 2010
Nov;64(12):1609-18. doi: 10.1111/j.1742-1241.2010.02520.x. Epub 2010 Oct
4.
15. Goldberg RB, Holman R, Drucker DJ. Clinical decisions. Management of type
2 diabetes. N Engl J Med. 2008 Jan 17;358(3):293-7.
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16. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized
addition of glargine or human NPH insulin to oral therapy of type 2 diabetic
patients. Diabetes Care. 2003 Nov;26(11):3080-6.