Diabetes mellitus Guidelines for starting a patient on oral hypoglycaemic agents

1. Patients will usually have been on supervised diet for up to 3 months and will have inadequate control of blood glucose (Fasting blood glucose > 7 and a 2 hour post prandial > 10 mmol) and HbA1c > 6.5%.
2. Occasionally a newly diagnosed patient presents in quite a fulminant manner with marked weight loss, high blood (>20mmol) +/- ketones. Intercurrent illness may be a feature (UTI, chest infection, acute MI, malignancy)
   • Such patients are likely to be either a late onset Type I (LADA) or Type 2 diabetic with relative hypoinsulinaemia. 
   • Initial stabilisation on bd insulin may be necessary. 
   • Subsequent tentative withdrawal of insulin and substitution using OHAs may be feasible in Type 2 patients following a period of good glycaemic control (+ treatment of precipitating illness).

Which oral agent?

Metformin: 

This is the first line agent in all Type 2 diabetic patients because insulin resistance is the major pathophysiological feature of this condition.

Caution

• Renal failure: Contraindicated in subjects with Cr > 200.
  Note: Lactic acidosis is a very rare cause of fatality in subjects using Metformin -20 per million. Metformin should be temporarily discontinued in patients with Cr >120 with acute circulatory decompensation such as
  • Severe dehydration caused by intercurrent illness (N+V/pneumonia) 
  • Acute MI Acute CVA 
  • Acute Ischaemic limb.
• Hepatic failure
  • Patients with poorly controlled Type 2 diabetes commonly have moderate disturbance of LFTs associated with fatty liver (ALT, gammaGT and Alk phosphatase up to two times upper range normal.)
  • Metformin can be used providing no evidence to suggest more serious cause for liver enzyme derangement. In these circumstances LFTs should be monitored to ensure that LFTs improve after period of improved glycaemic control.
  • In established liver disease due to alcohol or other. Metformin should not be used.
• Alcohol
  • Metformin should be avoided in patients with alcohol dependency syndrome.
• Heart Failure
  • Metformin is contraindicated in subjects with decompensated heart failure. In subjects in whom heart failure is well controlled on combination of diuretics, ACE inhibitor etc - it is safe to use Metformin.
• Preconception, pregnancy and breast feeding
  • Metformin is contraindicated in patients who are planning to become pregnant. Good glycaemic control should be achieved by conversion to insulin therapy.
  • During pregnancy Metformin is contraindicated 
  • Breast feeding - Metformin is contraindicated ·
•  Radiological Imaging Procedure - Metformin should be discontinued for certain procedures - (see protocol)

Dose of Metformin

To avoid occurrence of GI side effects we recommend gradual introduction of Metformin.

• 500mg od for 2 weeks 
• 500mg bd for 2 weeks 
• 500 mg tds 

Maximum dose of Metformin is 1gm tds or 850mg bd if compliance with tablets is an issue. (see 'Stepped Approach' protocol.)

Sulphonylureas

These agents stimulate insulin secretion by the beta cell. Most patients with Type 2 diabetes are hyperinsulinaemic but because of coexisting insulin resistance - endogenous insulin levels are not sufficient to achieve euglycacmia.

Consider sulphonylurea treatment First line in patient who cannot tolerate Metformin. Second line with Metformin

Because of insulin stimulating affect -> risk of hypoglycaemia. Avoid long-acting sulphonylurea in elderly patients (Glibenclamide and Gliclazide). May stimulate appetite and cause weight gain - this can worsen insulin resistance and accelerate B cell failure.

Tolbutamide 

• Safe effective for use in the elderly and may be used in liver impairment as it is metabolised and inactivated in the kidney (100% excretion in the urine).
• Caution 
  Reduce dose in renal failure. 
• Large tablet which some may find difficult to swallow. Dose 500mg - 2gms in divided doses. (Twice a day is satisfactory) - (see 'Stepped Approach' protocol).

Glibenclamide 

• Caution 
  May cause significant hypoglycaemia in the elderly or those with impaired liver or renal function (50% excretion in bile) Dose 2.5mg - 15mg (once or twice a day) - (see 'Stepped approach' protocol).

Gliclazide 

• Intermediate acting - more expensive than Glibenclamide or Tolbutamide. (65% excretion in urine). 
• Dose 40 - 320mg (see 'Stepped approach' protocol)

Rosiglitazone

• Mode of action
  This is a thiazoledodione. Mode of action is via activation of a nuclear hormone receptor PPART present in muscle, liver and adipose - altering expression of key genes involved in carbohydrate metabolism. The net effect is to improve insulin sensitivity.
• When to use
  Consider Rosiglitazone as third line when combination treatment with maximum tolerated Metformin and sulphonylurea fails to achieve adequate glycaemic control (HbA1c < 7.5)
  • All three agents cannot be used together.
  • Preferred third line combination comprises maximum tolerated Metformin and Rosiglitazone 8mg daily* especially in obese subjects i.e. stop suiphonylureas (aim to reduce and stop over 4 weeks following introduction of Rosiglitazone 4mg od).
  • Rosiglitazone can be tried second line in combination with maximum tolerated sulphonylurea in subjects who cannot tolerate Metformin or in whom Metformin is contraindicated. (Only use Rosiglitazone 4mg daily in combination with sulphonylurea)
  • Third line combination treatment comprising maximum tolerated sulphonylurea and Rosiglitazone can also be tried in a few instances where Metformin is poorly tolerated in combination with sulphonylurea i.e. substitute Rosiglitazone instead of Metformin.
• Dose
  Starting dose is 4mg od and can be increased to 8mg od in combination with Metformin only (after 8 weeks). Glucose lowering is observed within 4 weeks - maximum effect seen at 8-12 weeks.
• Cautions
  LFTs should be checked at baseline. Rosiglitazone is contraindicated if ALT ( x 2 upper limit of normal. LFTs should be checked every 2 months for 1'~ year and Rosiglitazone stopped if ALT rises ( x 2 upper limit of normal.
• Contraindications
  • Severe renal impairment 
  • Cr > 500 
  • Heart failure 
  • Liver failure (see above) 
  • During breast feeding or pregnancy

Acarbose

• This is an alpha glucosidase inhibitor - acts by delaying the digestion of carbohydrate in the intestine, therefore reducing post prandial excursions in blood sugar.
• Usually used third line in combination with Metformin and Sulphonylurea.
• Caution 
  During the first few days or weeks of treatment the patient may experience increased flatulence, loose stools, abdominal cramp - particularly if the meal has contained sugar or sucrose containing foods.

Recommended regime for commencement on Acarbose:- (available as a patient leaflet)

You have been advised to start a new tablet called ACARBOSE. You should start taking it as follows:   Weeks 1-2  1/2 tablet (25mg) once daily  Weeks 3-4 1 tablet (50mg) once daily Weeks 5-6 1 tablet (50mg) twice daily Weeks 7-8 1 tablet (50mg) three times a day Week 9 onwards 2 tablets (100mg) three times a day.          Stay on this dose until you see the doctor again. The tablets should be swallowed whole or chewed with the first mouthful of food. If you experience any bowel symptoms (e.g wind) return to the previous dose and try increasing the dose again after another 2 weeks.

Source: Northumbria NHS Health Care Trust diabetes protocol

• Brad Cheek: last updated Dec 2006
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