Sulphonylureas

These are insulin sensitising drugs that activate the transcription factor PPARgamma. Transcription factors regulate expression of a number of other genes. Pioglitazone is the only one of this class to be recommended by the Tayside team, in the light of ongoing concerns about the safety of rosiglitazone (see below).

  • The main effect of glitazones is to increase insulin sensitivity by promoting differentiation of pre-adipocytes to adipocytes. This has the adverse effect of increasing fat mass with an average weight gain of 3-4 kg.
  • Sulphonylureas can be used with all other oral agents and insulin.
  • Longer acting sulphonylureas (glibenclamide, chlorpropamide) are not used routinely. In patients established on these agents their use should be reviewed in the elderly due to decreased renal excretion and subsequent increased risk of hypoglycaemia and should also be avoided in renal impairment (eGFR<60 ml/min).
  • A sustained-release formulation of gliclazide is available (Diamicron-MR) and may be useful to increase concordance in patients who frequently omit their teatime dose(s). However, the tablet burden is not lessened and care should be taken in prescribing and explanation as 30mg of Diamicron-MR is equivalent to 80 mg of the standard formulation (i.e. maximum dose 120mg daily).

Repaglinide and nateglinide were introduced as a different class of drug – “Prandial glucose regulators” yet they work via the sulphonylurea receptor and are essentially short acting sulphonylureas designed to be taken with meals to promote prandial insulin release. These agents are not routinely used in Tayside but could be used in place of traditional sulphonylureas.

 

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Thiazolidinediones (Glitazones).

These are insulin sensitising drugs that activate the transcription factor PPARgamma. Transcription factors regulate expression of a number of other genes. Pioglitazone is the only one of this class to be recommended by the Tayside team, in the light of ongoing concerns about the safety of rosiglitazone (see below).

  • The main effect of glitazones is to increase insulin sensitivity by promoting differentiation of pre-adipocytes to adipocytes. This has the adverse effect of increasing fat mass with an average weight gain of 3-4 kg.
  • In the 2008 NICE guidelines, glitazones are recommended second line only in patients intolerant of sulphonylureas or where hypoglycaemia with sulphonylureas is an issue. In patients treated with sulphonylureas and metformin, thiazolidinediones should be considered as an alternative to insulin only when there is fear of insulin, the use of insulin would affect employment or it is anticipated that large insulin doses would be required.
  • Pioglitazone is available as a fixed-dose combination tablet with metformin (Competact) which may be used in decreasing tablet burden and improving concordance with therapy.
  • A key side effect of this agent is fluid retention causing ankle oedema and an increase in hospital admissions with heart failure. Although the glitazones do not diminish left ventricular contractility, they are contraindicated in patients with heart failure/ LV dysfunction (echocardiography recommended where there is clinical uncertainty)
  • Pioglitazone is licensed in the UK for use with insulin but because of the risk of fluid retention this should only occur in exceptional cases and under close specialist supervision.
  • Following new evidence and the recent circulation from the MHRA suggesting harm from rosiglitazone compared to pioglitazone, we now recommend that in Tayside, patients who are currently treated with rosiglitazone should be changed to pioglitazone. Those on rosiglitazone 4mg should change to pioglitazone 30mg; those on 8mg rosiglitazone should convert to 45mg pioglitazone; those on 'Avandamet' should change to 'Competact' but be aware that a small reduction in metformin dose will result.
  • Thiazolidinediones have been associated with an increased risk of fracture in women. Although the numbers experiencing fractures in the trials is very small, it is recommended that these drugs are avoided in those with high fracture risk.

Because of fatal hepatotoxicity with a previously-available glitazone (troglitazone), initial licensing of glitazones required regular monitoring of LFTs. This has since been relaxed as there appears to be no concern with pioglitazone

 

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Acarbose

This is an inhibitor of intestinal alpha glucosidase. It delays digestion of starch and sucrose and hence reduces the increase in blood glucose levels following a carbohydrate rich meal. It can cause flatulence and diarrhoea and although popular in the Far East is now little used in patients on Western diets. Acarbose can be used with all other oral agents.

Incretin mimetics/DPP-4 inhibitors.

These are new to the UK in 2007. The incretin hormones (GLP-1, GIP) are produced by the small intestine in response to a nutrient stimulus (meal). They act on the pancreas to promote insulin secretion in a glucose–regulated manner. So in effect they are like sulphonylureas, except that they only promote insulin secretion when the glucose is high. The incretins also act centrally to decrease appetite, and they slow gastric emptying causing early satiety.

Two types of new drug utilise this pathway; GLP-1 mimetics and DPP-4 inhibitors.

  • Two GLP mimetics are licensed and approved by SMC. Exenatide is a twice daily s/c injectable and liraglutide is a once daily injectable. Both improve HbA1c and cause weight loss. In a head to head comparison liraglutide was more effective at lowering HbA1c and was associated with less nausea than exenatide. Liraglutide is approved for use as a third-line agent in combination with metformin and a sulphonylurea, or metformin and a thiazolidinediones as an alternative to insulin therapy in those who are obese (BMI>=30kg/m2) and in whom weight loss is desirable. Exenatide is not approved for use with thiazolidinediones. GLP-1 mimetics are not suitable for patients who require insulin therapy. Liraglutide is not licensed for use with moderate renal impairment (eGFR<60ml/min); whereas exenatide can be used in moderate renal impairment but not severe renal impairment (eGFR <30ml/min). For moderate renal impairment dose escalation of exenatide from 5ug to 10ug should proceed conservatively. As with all therapies other than metformin, GLP-1 mimetics should be stopped if adequate glycaemic control is not achieved within 3-5 months (at least 0.5%(5.5mmol/mol).
  • DPP-IV breaks down GLP-1 in vivo, so these drugs enhance the effect of naturally produced GLP-1. Their advantage over GLP-1 mimetics is their oral bioavailability; however they are less potent at lowering glucose and do not have the beneficial weight effects seen with these agents, although they are weight neutral.  Three DPP-IV inhibitors are approved for use within Scotland; sitagliptin, vildagliptin and saxagliptin. Both vildagliptin and sitagliptin are available as combination tablets with metformin.  The gliptins have been approved by SMC for restricted use in patients when the addition of a sulphonylurea to metformin  is not appropriate and are an atternative to thiazolidinediones. Other combinations currently approved for us in Scotland are outlined below:

 

  Added to          
 

Metformin

(M)

Sulphonylurea

(SU)

 M+SU M+TZD

Combination

tablet with

metformin?

 Monitoring?
Sitagliptin  

ü

  

ü

ü

  x  

ü

  *
 Vildagliptin  

ü

ü

  x  x

ü

 LFTs 3

monthly for

1 year
 Saxagliptin

ü

  x  x  x  x  x

 

  •  Vildagliptin should be used cautiously in NYHA I & II heart failure, and is contraindicated in NYHA III & IV heart failure (due to limited data on these groups). Also, vildagliptin should not be used in moderate to severe renal impairment (i.e. CKD stages 4 and 5). Sitaglitpin also should not be used in moderate to severe renal impairment, but liver function test monitoring is not required and heart failure is not a contraindication. In a Cochrane systematic review the HbA1c reduction seen with these agents was 0.6 – 0.7%, less than is seen with metformin or sulphonylureas. They represent an alternative to other agents such as the glitazones.
  • Liraglutide, exenatide, sitagliptin and vildagliptin and saxagliptin have been accepted for use within NHS Tayside and further prescribing information for these agents is available within the Tayside Area Prescribing Guide (TAPG)listed under the appropriate letter.

 

Prescribing in renal impairment

 

Mild

(eGFR 50-80)

Moderate

(eGFR 30-50)

Severe

(eGFR 19-30)

End

stage/Dialysis
Metformin

ü

ü

(half maximal dose

below eGFR

45ml/min)

 x  
Gliclazide

ü

ü

x (although only 5%

of gliclazide is

excreted in urine)

 x
Pioglitazone

ü

ü

ü

ü

(eGFR>4ml/min)
Sitagliptin

ü

 x    
Vildagliptin

ü

 x    
Saxagliptin

ü

 x    
Exenatide

ü

ü

 x  
Liraglutide

ü

(>60ml/min)		 x    

 

For further information on the prescribing of oral hypoglycaemic drugs see:

 

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