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6.1.1 - 6.1.2.3 Insulin, oral antidiabetic drugs, biguanides

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6.1.1 Insulin

6.1.1.1 Short-acting Insulin

Human soluble insulin (Actrapid; Insuman Rapid)
Human soluble insulin infusion (1 unit per ml)
Insulin aspart (Novorapid)
Fast-Acting Insulin Aspart (FIASP) – specialist use only
Insulin lispro (Humalog)

Standard insulin infusions are prepared by pharmacy in syringes for named patient use. Insulin is adsorbed into PVC bags and so should be administered in a syringe, separately to other infusions.

See NICE TA 151'Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus'.


Notes:

1. Insulins must be prescribed by brand name rather than generically.

2. Species of origin (e.g. pork, beef, human) should be specified, and should not be changed in the absence of clinical indications for a switch.

3. The presentation, eg vials, penfill cartirdge, disposable should also be specified.

4. Although the product literature for insulin syringes and needles recommends single use, in practice many patients re-use them.

5. Only insulin syringes must be used for the measuring and administering of insulin.

6. Analogue insulins e.g. insulin lispro (Humalog), insulin aspart (Novorapid) are genetically engineered insulins with rapid onset and relatively short duration of action. They may be suitable for use just before meals by those patients on multiple dose regimens. They are more expensive than other short acting insulins. Biphasic analogue insulins (e.g. Humalog Mix 25, Novomix 30) are also available. These should only be initiated by a specialist in diabetes.

 

6.1.1.2 Intermediate and long acting insulins

Insulatard
Insuman Basal
Humulin I
Insulin degludec (Tresiba) - see note
Insulin glargine (Lantus) - see note
Insulin detemir (Levemir)
Insuman Comb 15, 25, 50
Humalog mix 25
Humalog mix 50
Novomix 30

Notes:

1. Insulin glargine - This is the first long acting insulin that is a clear solution. This may lead to confusion with short acting insulins. A 300 units/ml form is available for specialist initiation for patients with recurrent severe hypoglycaemic attacks.

2. Consider a long-acting insulin analogue (insulin detemir or glargine) in people:

  • who do not reach their target HbA1c because of significant hypoglycaemia, or
  • who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached, or who cannot use the device needed to inject NPH insulin8 but who could administer their own insulin safely and accurately if a switch to a long-acting insulin analogue were made, or
  • who need help from a carer or healthcare professional to administer insulin injections and for whom switching to a long-acting insulin analogue would reduce the number of daily injections.

 See also:

NICE NG28: Type 2 diabetes

Glucose control in type 2 diabetes (Derbyshire guidelines)

 3. Insulin degludec is an ultra-long-acting insulin analogue reserved for diabetes specialist initiation only. It is appropriate for use in patients with significant noctural hypoglycaemia or loss of hypoglycaemic awareness, despite using long-acting analogue insulins, and who would otherwise be candidates for IV insulin pump therapy. A 200 unit /ml pen is also available for patients who are insulin resistant and require high doses of insulin (> 150 units/day) in preference to using the unlicensed Humulin R (500 units/ml).   

6.1.2    ORAL ANTIDIABETIC DRUGS

6.1.2.1 Sulphonylureas

Glibenclamide tablets
Gliclazide tablets, MR tablets 
Tolbutamide tablets

Notes:

In general, the following guidelines should be followed:

1. Glibencamide should be avoided in the elderly due to increased risk of hypoglycaemia.

2. Patients with significant ketonuria and/or weight loss usually require insulin. Specialist referral is recommended.

3. Overweight asymptomatic patients should initially be managed by diet alone. If treatment targets are not met, metformin should be considered.

4. Sulphonylureas should be used for symptomatic patients who are not overweight, and do not have significant ketonuria.

With the exception of tolbutamide (which is 'weaker'), the sulphonylureas are equipotent in maximum doses. There is therefore little justification for changing drugs within this class if control deteriorates. Gliclazide is mainly metabolised by the liver; this may be a desirable feature in patients with renal impairment. Tolbutamide tablets are large and may be difficult for older patients to swallow. Other newer sulphonylureas are more expensive and offer no particular advantages over those listed above.

5. Sulphonylureas may be given in combination with metformin. Sulphonylureas should not be given in combination with each other.

6. Patients who remain poorly controlled on both a sulphonylurea and metformin should normally be considered for insulin.

 

6.1.2.2 Biguanides

Metformin tablets, SR tablets, oral solution

Notes:

1. Metformin should always be introduced gradually. The starting dose should normally be just 500 mg once daily, which should be gradually increased to 850mg tds (or the highest tolerated dose) unless treatment targets are met on a lower dose.

2. Metformin SR tablets are available for patients who are intolerant of this slow upward dose titration.

3. Metformin is also used in the treatment of hirsutism or subfertility in patients with Polycystic Ovarian Syndrome. For these conditions, initiation of treatment should be by a specialist consultant only.

4. Metformin.is contra-indicated in severely reduced kidney function (GFR < 30ml/min) – the SPC gives helpful advice - see table below:

Renal impairment
GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

GFR (mL/min  Total maximum daily dose
(to be divided into 2-3 daily doses
)
 Additional considerations
 60-89 3000 mg IR;

2000 mg MR

Dose reduction may be considered in relation to declining renal function. 

45-59  2000 mg  

Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin. 

The starting dose is at most half of the maximum dose.

30-44 1000 mg 

As above

<30    -

Metformin is contraindicated.

 

6.1.2.3 Other anti-diabetics

Pioglitazone tablets (diabetes specialist only)
Lixisenatide injection (diabetes specialist only) - first-line GLP-1 mimetic
Liraglutide injection - second-line GLP-1 mimetic - see NICE TA 203 (diabetes specialist only)
Exenatide injection - third-line GLP-1 mimetic - (diabetes specialist only)
Empagliflozin tablets (diabetes specialists only) - preferred SGLT-2 inhibitor – see NICE TA 336 and NICE TA 390; see notes
Dapagliflozin tablets (diabetes specialist only) - see NICE TA 288; NICE TA 390 and NICE TA 418; see notes
Canagliflozin tablets (diabetes specialist only) – see NICE TA 315 and NICE TA 390; see notes
Sitagliptin tablets – see note
Linagliptin tablets – see note

Notes

1. The GLP-1 mimetics (lixisenatide, liraglutide, exenatide) are indicated in type 2 diabetes mellitus in combination with metformin and/or sulphonylureas in patients not achieving adequate glycaemic control on maximally tolerated doses of these agents, and have a BMI ≥ 35kg/m2. These agents should only be continued if there is a beneficial metabolc response: at least a 1.0 percent point reduction in HbA1c at 6 months, and a weight loss of at least 3% at 6 months occurs and is maintained. Lixisenatide is the first-line preferred agent.

2. Exenatide - if this agent is used, the twice daily formulation is preferred. The prolonged-release (once weekly) form may be a suitable option for patients that would otherwise have been considered for daily home visits from the nursing team - see NICE TA. This formulation is classified as BROWN in the local Traffic Light System.

3. NICE guidelines state that pioglitazone and rosiglitazone should be used in type-2 diabetes mellitus where combination therapy is required, in patients who cannot tolerate or have contra indications to the use of either metformin or a sulphonylurea. These should be used as third-line agents in type 2 diabetes. Pioglitazone is preferred as it appears to have a better risk/benefit ratio. Rosiglitazone was withdrawn in October 2010 by EMA/CHMP.

4 Cases of cardiac failure have been reported when pioglitazone has been used in combination with insulin, especially in patients with risk factors for the development of cardiac failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. See Drug Safety Update January 2011.

Also, pioglitazone has been linked with a small increased risk of bladder cancer; it should not be used in patients with active bladder cancer or a history of bladder cancer, and in patients with uninvestigated haematuria (see Drug Safety Update August 2011).

5. Acarbose is not included. It is poorly tolerated, and is expensive.

6. SGLT-2 inhibitors: Canagliflozin requires a GFR of >45ml/min to be effective. Dapagliflozin - efficacy is dependent on renal function; it is not recommended if eGFR <60ml/min. Use is restricted due to lack of long-term efficacy / safety data. Weight loss may be a useful attribute.

SGLT2 inhibitors have been associated with serious and life-threatening cases of diabetic keto-acidosis (DKA).  See MHRA DSU also PRAC recommendations

Canagliflozin may be associated with an increased risk of lower limb amputation, primarily of the toe. Careful monitoring of patients on the drug is advised, especially those with other risk factors: previous amputation, existing peripheral vascular disease, neuropathy. Dehydration and volume depletion may increase this risk, so carefully monitor all patients for signs and symptoms of water or salt loss, and ensure patients are well hydrated ( see DSU). Consideration should be given to stopping the drug if the patient develops foot complications. Whilst there is no evidence of an increased risk with other SGLT2 inhibitors (dapagliflozin, empagliflozin), data is limited, and the risk may  well apply to these agents as well. Further information is available here.

7. DPP4 inhibitors (gliptins) eg, sitagliptin have a limited role in the management of type 2 diabetes mellitus. There is poor evidence of effectiveness and there are more cost effective options available, eg, GLP-1 mimetics. They should only be continued if there is a reduction of ≥5.5mmol/mol (0.5% points) in HbA1c after six months treatment. Linagliptin is an alternative DPP4 inhibitor for patients with renal or hepatic impairment as no dosage adjustment is necessary.  The MHRA has warned of the risk of acute pancreatitis. See the Drug Safety Update September 2012.

For link to BNF section: 6.1.1 Insulins