Saturday 19 August, 2006

How to start oral hypoglycaemic therapy

Posted in General Practice, Medicine, Michael Tam, Wards at 14:10 by Michael Tam

Original article by: Michael Tam :: Printer friendly

Type 2 diabetes mellitus is common, and will become more so with the expanding Australian waistline. The large government funded Australian Diabetes, Obesity and Lifestyle Study (AusDiab) revealed that there are almost a million people over the age of 25 years with diabetes (1). Even more startling is that almost 1 in 4 Australians over the age of 25 either have diabetes or impaired glucose metabolism (impaired glucose tolerance or impaired fasting glycaemia) (1).

Oral hypoglycaemic agents are the first line therapy for patients diagnosed with type 2 diabetes mellitus if lifestyle modifications are insufficient. One or more of these agents should be commenced (except for those who present with non-ketotic hyperosmolar coma whereby insulin should be used).

In a nutshell (2):

Asymptomatic hyperglycaemia

  • metformin (monotherapy preferred) or
  • sulfonylurea (monotherapy or with low dose metformin)

Symptomatic hyperglycaemia and/or obesity

  • metformin (monotherapy) or
  • metformin with sulfonylurea

See below for details

Aim for a target of:

HbA1c < 7.0%

and

Fasting blood glucose < 6.5 mmol/L


Comment:
There are many too many oral hypoglycaemic agents to choose from for each to be covered in depth. This article will by large only discuss the medications that I commonly use; i.e., metformin and gliclazide. Both are off patent, inexpensive (to the patient and to the public health system) and of proven effectiveness.

Starting metformin

Metformin is the most commonly used oral hypoglycaemic agents and it is the first line oral hypoglycaemic agent. It is the only remaining biguanide on the market. Interestingly enough it is derived from guanidine, found in “French Lilac” or Galega officinalis, a plant used since the Middle Ages for relieving the symptoms of diabetes mellitus (3).

Start with:

metformin 500 mg daily or twice daily initially

Increase dose by 500 mg every 1-2 weeks according to symptoms and morning fasting blood glucose levels.

Maximum dose: 2.0 – 2.5 g per day

  • The dose of metformin should be titrated up every 1-2 weeks. The glycaemic target if a HbA1c of less than 7.0% with an average fasting blood glucose level of 6.5 mmol/L.
  • When starting metformin simultaneously with a sulfonylurea, use the “starting” dose of the sulfonylurea and aim to titrate up the dose of metformin first.
  • Titrating example:
    • 500 mg daily, then
    • 500 mg bd, then
    • 500 mg mane and 1 g nocte, then
    • 1 g bd, then
    • 1 g mane, 500 mg midi, 1 g nocte (or 850 mg tds)

The most common side-effects that tend to limit its use are gastrointestinal; nausea, vomiting and diarrhoea (4). Fortunately, they are usually transient. As such, “start low and go slow” is good advice, especially for the elderly.

Lactic acidosis is a very rare but serious side-effect from metformin. It becomes more common with the degree of renal dysfunction and with age. The estimated number of cases is 0.03 per 1000 patient years (or 1 case per annum in 30,000 patients) with a 50% mortality rate (4).

Trade names for metformin hydrochloride in Australia include: Chem mart Metformin, Diabex, Diabex XR (slow release), Diaformin, Formet, GenRx Metformin, Genepharm Metformin, Glucohexal, Glucomet, Glucophage, Glucovance (metformin with glibenclamide), Terry White Chemists Metformin

Starting a sulfonylurea

Sulfonylurea agents have been around for decades. The most commonly used sulfonylureas today are “second generation” agents that are more efficacious and with fewer side-effects. Sulfonylurea drugs should be considered as second-line agents and to be used in conjunction with metformin or as monotherapy if metformin is contraindicated or not tolerated. Sulfonylureas as a class are the most efficient at quickly reducing hyperglycaemia so are particularly useful in those patients with marked symptomatic hyperglycaemia.

As a rule of thumb, most sulfonlyurea agents can be started at half a tablet, daily or twice daily though please read the product information.

I recommend:

gliclazide 40 mg daily or twice daily initially

Increase dose by 40-80 mg every 2 weeks according to symptoms and morning fasting blood glucose levels.

Maximum dose: 320 mg per day

  • The dose of gliclazide should be titrated up every 2 weeks. The glycaemic target if a HbA1c of less than 7.0% with an average fasting blood glucose level of 6.5 mmol/L.
  • Doses of up to 160 mg can be given as a single daily dose though divided doses (twice daily) should be used after that.

Sulfonylurea agents are more likely to cause hypoglycaemia compared to metformin so they must be used with care.

Trade names for gliclazide in Australia include: Chem mart Gliclazide, Diamicron, Diamicron MR (slow release), GenRx Gliclazide, Gyade, Mellihexal, Nidem, Terry White Chemists Gliclazide

About thiazolidinediones (or the “glitazones” )

In Australia, the thiazolidinediones should be considered to be “third line” agents. They work well but should probably only be used if there is a contraindication or intolerance to either metformin or sulfonylureas, or as an adjuct when maximal therapy has been reached with the other classes. Its disadvantages include (2):

  • Expensive;
  • a significant period of time is required before maximal hypoglycaemic effect (6-8 weeks);
  • contraindicated in heart failure;
  • not available on the PBS as monotherapy.

About the slow release formulations

Both metformin and gliclazide come in “slow release” preparations. The advantage to the patient is that these preparations simplify the dosing regimen from divided doses to a single daily dose, and generally also simply the titrating process.

The disadvantage is that both slow release metformin and slow release gliclazide are proprietary and the cynic would argue that their release is a marketing ploy to recapture the market after the expiration of the original patent. I do not believe that there is any substantial evidence that the once daily formulations are any “better” in terms of endpoints or side-effect profile.

Dose conversion:

metformin SR 500 mg = metformin 500 mg

gliclazide SR 30 mg = gliclazide 80 mg

  • metformin SR 500 mg tablet = Diabex XR
  • gliclazide SR 30 mg tablet = Diamicron MR

Reference articles

(1) Dunstan D., Zimmet P., Welborn, T., et al. Diabesity & Associated Disorders in Australia – 2000. The Australian Diabetes, Obesity and Lifestyle Study (AusDiab). [download PDF :: 884 Kb]

(2) Twigg, S. Individualising initial therapy for hyperglycaemia in type 2 diabetes. Medicine Today (Update on diabetes). September 2005.

(3) Galega officinalis. Wikipedia. Last updated: 9 June 2006. [Link]

(4) Diaformin (metformin hydrochloride). MIMS Online. Last updated: 20 January 2006.

Please read the disclaimer

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18 Comments »

  1. ashwani said,

    respected sir
    i want to information about metformin sustained release tablet (properties,solubility,ph,marketed product,exipient etc).
    so reply me early.
    thanks
    ashwani

  2. Michael Tam said,

    In Australia, there is only one formulation of slow release metformin hydrochloride and it is sold under the trade name “Diabex XR”. It is produced by Alphapharm Pty Ltd.

    With regards to product information, the following is an extract from MIMS Online: [PDF :: 102 Kb]

  3. ahmed said,

    thanks Dr Michael for this important informaion
    and i want to ask about the maximum dose of gliclazide MR 30mg
    thank you again

  4. Michael Tam said,

    The maxium dose of gliclazide SR is 120 mg (i.e., 4 x 30 mg tabs) per day.

  5. David Geer said,

    Very useful overview – Thanks

  6. dear sir, My wife is a Diabetic 2 Mellitus..on DIAFORMIN 500mg x 2, twice a day…her glucose is between 6 & 7 fasting .she is experiencing for the past 4 weeks diahrea in the morning which necessitates Immodium. and body weakness.which distresses her.. she is also on EFEXOR SR 75 mgr 1 x daily..
    for her anxiety condition… IS IT POSSIBLE THAT THJE DIAFORMIN IS THE CAUSE OF THE DIARRHEA, OR IS THIS CAUSED BY THE EFEXOR SR ?… ( SHE IS TAKING BOTH TABLETS ALREADY FOR 5 YEARS WITHOUT ANY PROBLEM SO FAR UNTIL 4 WEEKS AGO WHEN THIS HAPPENED.)..),.The Endocrinologist is unsure and wants to try DIAMICRON MR SR 30mg x 1 daily to see if the diarrhea stops I AM WORRIED ABOUT SIDE EFFECTS/HYPOS ETC…Please advise.Thanks

  7. Michael Tam said,

    Firstly: read the disclaimer.

    Remember that I am not your regular physician. I do not have all the clinically relevant information. The below is simply my opinion on the limited information that you have provided me.

    The plan that you state that your Endocrinologist wants to try (i.e., try changing metformin to gliclazide to see if it makes a difference to the diarrhoea) sounds quite reasonable to me.

  8. Elle Kerlin said,

    I was diagnos of diabetic 2, 1995. I have used different tablets to control my blood glucose. The latest is Diaformin500…since 1998, twice a day. I
    take also Adalat Oros for my blood pressure. My problem is my skin so sensitive..I have seen 3 doctors,prescriptions is just a relief, I want treatment.,,The itch and rashes attacks me mostly after dinner. Help me.. what is causing this skin problem.. mostly in my fingers now.
    5 months ago.. my whole body..so frustrating and embarassing.. Looks like I have eczema, friends avoid to be near me. I take telfast 180mg.. to stop scratching.

  9. Michael Tam said,

    There is insufficient information there for me to make any reasonable suggestion on what might be going on. If you have had a long term and persistent disorder of your skin, then it seems reasonable for you to see a dermatologist.

  10. Dhofar said,

    what is different of gliclazide XR with diamicron MR?
    what is brand name of gliclazide XR?

  11. Michael Tam said,

    Firstly:
    SR = “slow release” = XR = “extended release” = MR = “modified release”

    In Australia, there is at present only one brand of slow / extended / modified release form of gliclazide. That is “Diamicron MR”.

    So, gliclazide SR/XR/MR = Diamicron MR.

    However, I prefer to use generic, rather than trade names in my articles which is why I refer to it as gliclazide SR (slow-release).

  12. Mary said,

    Dr Tam

    Why is it that Diabex XR is specified to be taken with evening meals? I understand that you take Diabex with meals to improve tolerability but why in the evenings? My question arises from the fact that Diabex (not the controlled release drug) can be taken at any time of the day with meals.

    Thanks in advance.

  13. Michael Tam said,

    Diabex XR (slow release metformin) is designed for once daily dosing. I’m not entirely certain why evening dosing is recommended but I believe that (i) it is better tolerated at night (generally the larger meal) and (ii) it helps reduce glucose levels overnight (metformin inhibits gluconeogenesis in the liver). Morning dosing would lead to the lowest metformin levels overnight and in the early morning which is when gluconeogenesis occurs due to the overnight fast.

    • Mary said,

      I speculated it had to be something to do with the drug concentration in the blood. Your reasoning makes perfect sense to me.

      Thank you Dr Tam.

  14. ATN said,

    i am presently taking 80 mg of glycazide combined with 500 mg metformin twice daily. yet my sugar levels are not reducing even with diet. i have been advised to take exermet 560 mr. kindly advise. thanks
    atn

  15. Micheala said,

    Dear Dr Tam,

    is it any difference between diamicron and Diamicron MR in Australia?Or is the same medicationunder different name? Or does Diamicron exist at all?
    Thanks for answer.
    Michaela

    • Michael Tam said,

      “Diamicron” is the brand name for gliclazide and produced by Servier. Previously, Diamicron was available in both the standard and extended-release formulations. I believe that Servier has withdrawn their standard formulation (80 mg tablet) from the market. So yes, “Diamicron” no longer exists as Servier only producesd “Diamicron MR”.

      The standard formulation of gliclazide is still produced by other companies.

      http://www.pbs.gov.au/pbs/search?term=gliclazide

  16. elina said,

    hello doc. tam ,im 32 yrs old. im taking metformin hydrochloride sometimes if thre is none metformin hypoglycaemic. what is the difference between the two?why is it after taking metformin you will feel very hungry?and why is it takes before meal?


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