Management if patient intolerant of metformin in type 2 diabetes

Metformin is generally the first line treatment in type 2 diabetes. Consider a sulphonylurea (or occasionally insulin) as first line if phenotype is unusual for type 2 diabetic (thin type 2 diabetic - this may represent a patient presenting with latent autoimmune diabetes of adulthood (LADA) (see notes))

• if patient unable to tolerate metformin as first line therapy then (1):
  
  
  • either initiate a sulphonylurea e.g. gliclazide, or,
    • pioglitazone, or,
    • gliptin, or,
    • SGLT2 inhibitor - NICE state that an SGL2 inhibitor may be used instead of a gliptin if a sulphonlyurea and pioglitazone are contraindicated (1)
      
      
  • if initiating a sulphonylurea then monitoring blood sugars (BM) will be required; if gliptin then BM monitoring is not routine but 'testing may be required if hypoglycaemia suspected' (5)
    
    
  • if initiating pioglitazone at 15mg od then no BM monitoring will be required
    
    
  • for gliptin then various daily preparations are available
    
    
  • for a sulphonylurea then titrate dose based on prebreakfast BMs
    • for example - initate gliclazide 40mg with breakfast - monitor prebreakfast BMs aiming for 5-8 mmol/l; review patient in 2 weeks with check BMs; if BMs satisfactory then continue present dose and recheck HbA1c in 2 months; if BMs high then increase dose of gliclazide to 80mg od and then review with check BMs in 2 weeks; aim for checking prebreakfast BMs daily whilst titrating initiating dose of sulphonylurea; once BMs stable then continue with dose
      
      
  • check HbA1c in 2-3 months to assess control - note that if on a glitazone improvement in glycaemic control is slower and so checking HbA1c in 3 months is reasonable
    
    
• step2: initial escalation of therapy
  
  
  • if glycaemic control is suboptimal (HbA1C > 7.5% (58 mmol/l))
    
    
    • on other alternative first line therapy to metformin
      
      
      • if on pioglitazone then increase dose to 30mg per day - note that glitazones are associated with weight gain and increased heart failure risk; the maximum dose of pioglitazone is 45mg per day and it may be necessary to titrate the 45mg dose if a repeat HbA1c after increasing the dose to 30mg is not satisfactory
        
        
      • if on a sulphonylurea then consider uptitrating the dose if not on maximal dose - be aware of risks of hypos
        
        
      • in general, check HbA1c in 2-3 months to assess control after each change in dose - note that if on a glitazone improvement in glycaemic control is slower and so checking HbA1c in 3 months is reasonable. Note that a sulphonylurea may be titrated based on BM monitoring and so there may be a series of dose adjustments before a dose is stabilised and then an HbA1c would be requested 2-3 months after a stable dose has been achieved
        
        
      • if on gliptin then other agent will be required as no dose titration available
        • can be combined with sulphonylurea or glitazone at this stage; be aware of hypoglycaemia risk with gliptin and sulphonylurea combination
          
          
      • first intensification with an add on therapy if initial therapy not metformin If HbA1c rises to 58 mmol/mol (7.5%):
        • Consider dual therapy with:
          
          
          • a DPP-4 inhibitor (gliptin) and pioglitazone, or,
            
            
          • a DPP-4 inhibitor (gliptin) and an SU (sulphonylurea), or,
            
            
          • pioglitazone and an SU
            
            
        • support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)
        • check HbA1c in 2-3 months to assess control - note that if on a glitazone improvement in glycaemic control is slower and so checking HbA1c in 3 months is reasonable
          
          
      • further escalation of therapy
        
        
        • if glycaemic control is suboptimal (HbA1C > 7.5% (58 mmol/l))
          
          
        • at this stage NICE suggest that treatment will be with either:
          
          
          • a DPP-4i (gliptin) and pioglitazone, or,
            
            
          • a DPP-4i and an SU, or,
            
            
          • pioglitazone and an SU
            
            
        • NICE suggest that i f HbA1c rises to 58 mmol/mol (7.5%):
        • consider insulin-based treatment
        • support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)
          
          
      • check HbA1c in 2-3 months to assess control
        

Notes:

• LADA
  • patients with LADA are relatively 'insulin deficient' rather than 'insulin resistant'. These patients do not have the classic type 2 diabetic phenotype. These patients are likely to require insulin earlier in their management compared to 'insulin resistant' diabetics. Caution is required in management of these patients because insulin therapy may be indicated from diagnosis of diabetes in these patients if presenting with persistently high blood glucose values
    
    
    
• hypoglycaemia risk
  • hypoglycaemia risk is highest with sulphonylurea treatment. Other agents described (metformin, pioglitazone, gliptin, SGLT2 inhibitors) have lower risk of hypoglycaemia than sulphonylureas. The risk of hypoglycaemia must be considered in patients where the person is at significant risk of hypoglycaemia or its consequences (for example, older people and people in certain jobs [for example, those working at heights or with heavy machinery] or people in certain social circumstances [for example, those living alone])
    
    
• weight gain
  • gliptin therapy is weight neutral and metformin often causes weight loss. Pioglitazone and sulphonylureas are associated with weight gain. Incretin mimetic treatment is associated with weight loss in many patients. SGLT2 inhibitor use is associated with weight loss
    
    
• hypoglycaemia and driving
  • YOU MUST INFORM TO THE DVLA IF:
    • You suffer more than one episode of severe hypoglycaemia (needing the assistance of another person) within the last 12 months. For Group 2 drivers (bus/lorry) one episode of severe hypoglycaemia must be reported immediately.
    • You must also tell us if you or your medical team feels you are at high risk of developing hypoglycaemia
    • You develop impaired awareness of hypoglycaemia. (difficulty in recognising the warning symptoms of low blood sugar) You suffer severe hypoglycaemia while driving An existing medical condition gets worse or you develop any other condition that may affect you driving safely
    • please check the DVLA website for latest advice

Reference:

• 1) NICE (May 2017). Management of type 2 diabetes.
• 2) DVLA (February 2014). At a glance guide to the current medical standards of fitness to drive
• 3) NICE (June 2013). Dapagliflozin in combination therapy for treating type 2 diabetes.
• 4) NICE (June 2014). Canagliflozin in combination therapy for treating type 2 diabetes.
• 5) Management of Type 2 Diabetes. An evidence based consensus guideline based on NICE guidance. South, Central and North Manchester Hospital Trusts (Accessed 29/9/14).