Trip Answers

Question answered:04/04/08

We have interpreted this question to mean which oral glucose lowering drug  would be the safest to use in diabetic nephropathy.

 

The CKS guideline on glycaemic control in diabetes includes the following information concerning renal impairment:

 

• “Metformin should be avoided in people who are at increased risk of lactic acidosis:
o People with a serum creatinine concentration greater than 130 micromol/l, which is indicative of renal impairment [RCGP, 2002]. The manufacturers recommend avoiding metformin use in people with a creatinine clearance less than 60 mL/min [ABPI Medicines Compendium, 2005a].
o People with clinical conditions associated with poor tissue perfusion and hence tissue hypoxia (e.g. sepsis, respiratory failure, recent myocardial infarction, heart failure, hepatic impairment other than mildly elevated serum aminotransferase levels) [RCGP, 2002; BNF 52, 2006].
o Women who are pregnant (in any trimester) or breastfeeding.

 

• Metformin should be avoided in acute conditions that may alter renal function, such as [ABPI Medicines Compendium, 2005a]:
o Dehydration
o Severe infection
o Shock
• Metformin should be withdrawn during periods of suspected tissue hypoxia [Jones et al, 2003]. People will normally be referred for hospital admission, as insulin therapy will need to be substituted.”

 

And:

 

• “Avoid sulphonylureas in people at increased risk of hypoglycaemia, such as those who:
o Have severe renal impairment (some experts may use low doses and monitor)
o Have severe hepatic impairment (some experts may use low doses and monitor)
o Are pregnant (there is risk of neonatal hypoglycaemia if used in the third trimester)
o Are breastfeeding (theoretical risk, as data are limited).”

 

In relation to the glitazones, CKS states:

 

"Glitazones should be avoided in people with cardiac failure or a history of cardiac failure as they may cause fluid retention, which may exacerbate or precipitate heart failure [CSM, 2004]. The incidence of cardiac failure is increased when glitazones are combined with insulin [MHRA, 2007]." [1]

 

A second guideline, one by the International Diabetes Federation, notes in its chapter on glucose control:

 

“Standard care
OA1 Begin oral glucose-lowering drugs when lifestyle interventions alone are unable to maintain blood glucose control at target levels (see Glucose control levels). Maintain support for lifestyle measures throughout the periods of use of these drugs. Consider each initiation or dose increase of an oral glucose-lowering drug as a trial, monitoring the response in 2-6 months.

 

OA2 Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimize discontinuation due to gastro-intestinal intolerance. Monitor renal function and risk of signifi cant renal impairment (eGFR <60 ml/min/1.73 m2) in people taking metformin.”

 

“…Lactic acidosis is a rare complication (often fatal) of metformin therapy in people with renal impairment. Gastro-intestinal intolerance of this drug is very common, particularly at higher dose levels and with fast upward dose titration. Some sulfonylureas, notably glyburide, are known to be associated with severe hypoglycaemia and rarely death from this, again usually in association with renal impairment. Thiazolidinediones can cause fluid retention and are contra-indicated in the presence of higher grades of heart failure.” [2]

 

Of interest also is an article on thiazolidinediones and diabetic nephropathy, published last year. The author, Sarafidis notes in the abstract:

 

“Diabetic nephropathy is an important public health issue and a major challenge for modern nephrology, as it is the primary cause of end-stage renal disease. In addition to established risk factors for diabetic nephropathy progression (ie, hyperglycemia and hypertension), current knowledge suggests that other factors can be involved. Population studies show that insulin resistance and hyperinsulinemia are also associated with chronic kidney disease, and several background mechanisms could explain this relationship. The hypoglycemic class of thiazolidinediones that act through reduction of insulin resistance were found to protect against renal injury in diabetic animals and to reduce urinary albumin excretion in patients with type 2 diabetes and microalbuminuria. This renoprotective action is supported by relevant studies showing that thiazolidinediones act beneficially on most of the players involved in diabetic nephropathy progression. Recent studies have raised uncertainty about the cardiovascular safety of thiazolidinediones. After the latter issue is resolved, however, it would appear very interesting to conduct specific studies in patients with overt diabetic nephropathy to determine the effect of these agents on proteinuria and kidney disease progression.” [3]

 

Given the specialist nature of this query, the NLH Primary Care Q & A Service would recommend seeking further advice from the Medicines Information Service or by contacting a local specialist. Should you wish us to refer this question to the Medicines Information service, please let us know via the ‘Contact Us’ link: http://www.clinicalanswers.nhs.uk/index.cfm?action=contact

 

References
1. CKS. Diabetes – glycaemic control. (http://www.cks.library.nhs.uk/diabetes_glycaemic_control)
2. International Diabetes Federation. Chapter 9: glucose control. (http://www.idf.org/webdata/docs/GGT2D%2009%20Oral%20therapy.pdf)
3. Sarafidis PA. Thiazolidinediones and diabetic nephropathy: need for a closer examination? . J Cardiometab Syndr. 2007 Fall;2(4):297-301. (Abstract:   Please note the full text article can be read following free registration at: http://www.lejacq.com/myRegistration.cfm)

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