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Diabetes - Treatment with Oral Hypoglycaemic Agents

Diabetes - Treatment with Oral Hypoglycaemic Agents

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Aims of Treatment

Non-Insulin Oral hypoglycaemics are used in the management of Type 2 diabetes when dietary measures and lifestyle are not sufficient.
Optimal glycaemic control is the overall goal if achievable without unjustifiable risk. Treatment targets need to be individualised taking into account the age of the patient and comorbidities.
Maintaining near normoglycaemia in the early stages of Type 2 diabetes has a legacy protective effect against long term complications in later years when compared to delayed optimisation after loss of control.

Hypoglycaemic therapy should not be delayed in patients who are symptomatic.

In overweight patients early intervention with Metformin should be considered.

Refer all female patients to diabetes specialist team if they are planning pregnancy (urgently if already pregnant)

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Treatment with Oral Hypoglycaemic Agents

Guidance given here is for general information only. For definitive and up to date guidance please refer to the British National Formulary

See - NICE Guidance in the Useful Resources and Links section

 

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Commonly used Oral Hypoglycaemic Agents

Metformin

Action: increases insulin sensitivity by increasing peripheral utilisation of glucose and decreasing gluconeogenesis.

Clinical Use:

 

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First line treatment to maximum tolerated dose if BMI >25 (BMI >23 South Asian)

 

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Must be taken with or after food

 

Contraindications: renal impairment (serum creatinine >150umol/l EGFR <31mls per minute), history of lactic acidosis, hepatic impairment, advanced CCF.

 

Caution: use of iodine containing x ray contrast media (see - Special Circumstances Guideline), breast feeding.

Side-effects: Mainly gastrointestinal. Gradual introduction may improve tolerance. . Consider slow release preparation if side effects problematical.

 

Sulphonylureas

Action: increases insulin secretion by stimulating residual pancreatic beta cell activity.

Clinical Use:

 

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Consider as first line drug for patients who are not overweight, or in whom Metformin is contra-indicated or not tolerated or in combination therapy.

 

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Take before food

Contraindications: Type 1 diabetes, severe hepatic and renal impairment, porphyria, pregnancy, breast-feeding.

  Caution: Sulphonylurea potency may be affected by other drugs: Rifampicin may reduce efficacy while systemic antifungals may enhance.

Side effects: Predominant side effect in clinical practice is hypoglycaemia, especially with longer acting agents and in the elderly. Patients must be counselled regarding risk of hypoglycaemia.

 

Prandial Glucose Regulators (glinides)

Action: stimulate insulin release through a rapid onset of action and short duration of activity.

Clinical Use: to use instead of Sulphonylureas in:

  • Renal impairment
  • Postprandial hyperglycaemia
  • Varied meal pattern; tendency to miss meals (can omit dose)

Contraindications: Type 1 diabetes, severe hepatic impairment, pregnancy and breast-feeding

Side effects: rare hypoglycaemia, Patients must be counselled regarding risk of hypoglycaemia

 

Pioglitazone

Action: increases insulin sensitivity by reducing peripheral insulin resistance,.

Clinical use:

 

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Can be used as monotherapy in overweight patients when metformin not tolerated or contraindicated.

 

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Also as dual therapy in addition to metformin or sulphonylurea or as triple therapy with the other two.

 

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Effects of dosage change take 6-8 weeks to occur.

 

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Check liver function before use and periodically thereafter

 

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Combination preparations with metformin are available

Contraindications: history of heart failure; uninvestigated macroscopic haematuria, previous or active bladder cancer, pregnancy, breast feeding and hepatic impairment.

Caution: increased risk of bone fractures, particularly in women.

Side effects: fluid retention, weight gain.

 

GLP-1 Agonist (Glucagon Like Peptide-1)

This class of injectable agents was introduced in 2007 for use in Type 2 diabetes. Their actions include stimulating the insulin response to glucose and preventing glucagon release after meals. They have central effects on satiety and can promote weight reduction in the obese.

Caution: Concerns have been raised about associations between GLP1 agonists and DPP4 inhibitors with pancreatitis and carcinoma of the pancreas. As of July 2013 there is an international consensus that these agents still have a place in therapy. Patients should be counselled.

ADA/EASD/IDF Recommendations for Clinicians and People with Diabetes Concerning the use of Incretin Therapy and Pancreatic Disease (June 2013)

Bedfordshire JPC recommends specialist assessment and initiation for these agents.

 

DPP4 Inhibitors (Gliptins)

This class of oral agents potentiates the action of endogenous action of GLP-1 and so can only be used in Type 2 diabetes. They stimulate insulin response to glucose and prevent glucagon release after meals. These agents are generally well tolerated with fewer gastrointestinal side effects than GLP-1 agonists and are weight neutral.Several gliptins are available: for patients with renal impairment linagliptin (no dose reduction) or saxagliptin (dose reduction required) are appropriate

Caution: Concerns have been raised about associations between GLP1 agonists and DPP4 inhibitors with pancreatitis and carcinoma of the pancreas. As of July 2013 there is an international consensus that these agents still have place in therapy. Patients should be counselled.

ADA/EASD/IDF Recommendations for Clinicians and People with Diabetes Concerning the use of Incretin Therapy and Pancreatic Disease (June 2013)

 

Sodium–Glucose Cotransporter-2 (SGLT-2) inhibitors

SGLT2 inhibitors lower blood glucose by preventing reabsorption of glucose after filtration in the kidneys producing glycosuria. They rely on normal renal function to work and should not be prescribed if the eGFR is <60 ml/min or if loop diuretics are being used or in patients who are volume depleted. They also appear to have a beneficial effect on weight and blood pressure. Patients should be counselled on the increased risk of genitourinary infections.

NICE has recommended the use of glifozins in therapy in an equivalent place to DPP4 inhibitors.
NICE TA288 - Dapagliflozin
NICE TA315 - Canagliflozin
NICE TA336 - Empagliflozin
 
Rare but serious, sometimes life-threatening and fatal, cases of diabetic ketoacidosis have been reported in patients on SGLT2 inhibitor treatment for type 2 diabetes. In a number of these reports the presentation of the condition was atypical with only moderately increased blood glucose levels being observed. Such atypical presentation of diabetic ketoacidosis in patients with diabetes could delay diagnosis and treatment.
Always consider the possibility of diabetic ketoacidosis in patients taking SGLT2 inhibitors who have non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness.
Inform patients of the signs and symptoms of diabetic ketoacidosis and advise them to seek medical advice immediately if they develop such signs and symptoms.
Stop treatment with SGLT2 inhibitors immediately if diabetic ketoacidosis is suspected or confirmed, and do not re-start treatment unless another clear precipitating factor for the condition is identified and resolved.
Stop treatment with SGLT2 inhibitors temporarily in patients undergoing major surgical procedures or hospitalized due to acute serious medical illnesses. Treatment may be restarted once the patient’s condition has stabilised.
Exercise caution in patients with risk factors for ketoacidosis and inform patients of these factors. These include low reserve of insulin-secreting cells, a sudden reduction in insulin dose, an increased requirement for insulin (due to illness, surgery or alcohol abuse) and conditions that restrict food intake or can lead to severe dehydration.
   

Acarbose

Action: inhibits intestinal alpha glucosidase delaying the digestion and adsorption of starch and sucrose.

Clinical use: postprandial hyperglycaemia

Contraindications: pregnancy, breast feeding, inflammatory bowel disease, partial intestinal obstruction, hepatic impairment, severe renal impairment.

Side effects: flatulence.

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Treatment Choices / Tips for Type 2 Diabetes:

use with NICE Guidance
See - Nice Treatment Algorithm
The treatment plans in this guideline are indicative: it is important to assess the response to agents used and to stop medication if it has failed as well as adding new agents as suggested

If rapid control of hyperglycaemia is required if acutely unwell or severe symptoms or co-morbidities may need early insulin treatment. Usage may be temporary.

Remember that in some patients with newly diagnosed diabetes it may be difficult to differentiate the type of diabetes in the acute stage: Type 1 Diabetes should always be considered. If there is any doubt seek specialist advice, see Emergency Pathways.

Initial Management

Rescue therapy at any phase of treatment may be necessary if an adult with type 2 diabetes is symptomatically hyperglycaemic, consider specialist referral for insulin or a sulfonylurea. Review treatment when blood glucose control has been achieved.

Lifestyle advice plus:

Many patients may benefit from specific adjunctive Obesity Management  at an early stage such as orlistat.

Metformin

  Standard first line treatment unless: very symptomatic and / or low BMI (< 22) / or contraindications.
Give advice about timing of medication (take with or after food to minimise side effects) To improve initial tolerability start with a small dose (eg 500mg od) and increase over a few days to desired dose.
Only use slow release if standard preparation not tolerated when taken correctly.

 

If Metformin contraindicated or not tolerated

  Consider one of the following: -
  DPP-4 inhibitor
  Pioglitazone
  Sulphonylurea
  SGLT2 (licenced for monotherapy: under review by NICE for monotherapy)
   

Sulphonylurea

 

Use as first line if reasons not to use Metformin.
Avoid long acting sulphonylureas (eg glibenclamide) in the elderly
Caution in the obese

Other Oral Agents

 

May be used as monotherapy if metformin or sulphonylureas not suitable. Suggest speak specialist advice.

 

Second Line (First Intensification)

  DPP-4 inhibitor
  Pioglitazone
  Sulphonylurea
  SGLT2
  If symptomatically hyperglycaemic consider rescue therapy
   

DPP4 Inhibitors ('Gliptins')
  .• significant risk of hypoglycaemia particularly in elder people or those with irregular meal patterns
 

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significant postprandial hyperglycaemia
 

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BMI > 28
 

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Weight neutral
 

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Low risk of hypoglycaemia

Sulphonylureas

 

If BMI <28 can add a sulphonylurea to metformin

 

Consider alternative if:

 

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Concerns about further weight gain

 

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Insulin resistance as underlying pathology (central obesity, predominant fasting hyperglycaemia)

 

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Risks of hypoglycaemia; variable life style eg meal / activity / work pattern

Metformin

 

Add to sulphonylurea if not contraindicated

`

Prandial Glucose Regulators ('Glinides')

 

Consider if BMI <28

 

Useful if:

 

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concerns of risk of hypoglycaemia with SU;

 

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variable life style eg meal / activity / work pattern

 

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can manage self titration

Pioglitazone

 

Consider use instead of sulphonylurea if

 

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signs of insulin resistance: BMI >28,

 

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central obesity,

 

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predominant fasting hyperglycaemia

 

Beware contraindications and further weight gain
Low risk of hypoglycaemia

SGLT-2 (Gliflozins)
  Consider use instead of sulphonylurea or DDP4 inhibitor
  • May increase risks of genitourinary infections. Not recommended for use in renal impairment (egfr < 60ml/min) or for use with pioglitazone
  • BMI > 28

 

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Weight neutral or beneficial

 

 

Third Line (Second Intensification)

Consider specialist referral at this stage

Consider additional hypoglycaemic agents in addition to existing treatments.

DPP4 Inhibitors ('Gliptins')

 

If already on metformin and pioglitazone or sulphonylurea:

 

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Use if overweight and do not fulfil criteria for GLP1 agonist

 

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Unwilling to take GLP1 agonist

GLP-1 Agonists

 

Currently only initiated in specialist care (new medication with limited experience to date: potential for wider use in future)

 

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Generally use as an alternative to insulin in patients with BMI >35. Can consider above 30 if exceptional circumstances.

  View See - JPC recommendations

 

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Potential for significant weight loss

 

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Stop if no response at 6 months.

SGLT-2 (Gliflozins)

 

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May increase risks of genitourinary infections. Not recommended for use in renal impairment (egfr < 60ml/min) or for use with pioglitazone

 

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BMI > 28

 

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Weight neutral or beneficial

Insulin

 

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Use earlier if non obese or symptomatic hyperglycaemia

 

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Use in BMI > 30 if clinical situation suggests benefits of better control / safety profile outweigh risks of weight gain.

 

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Other agents contraindicated

 

Basal or Biphasic Insulin?

 

Basal:

 

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BMI >30

 

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Cannot self administer

 

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Predominant fasting hyperglycaemia

 

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Introduction for reluctant patient

 

Biphasic:

 

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Non obese

 

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Daytime hyperglycaemia

 

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Failure of basal insulin despite titration to individual target

 

Fourth Line

Recommend specialist referral at this stage

Intensification of insulin therapy

Human insulins should be used as first choice in Type 2 Diabetes, analogue insulins should be reserved for selected patients with specific requirements.

Basal bolus

Multiple biphasic insulin

Usually continued alongside metformin.

Other combinations of treatment can be used ‘off licence’ but these require specialist assessment and supervision.

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Useful External Links & Resources

View

NICE Guidance 2015

View

Nice Treatment Algorithm 2015

View

NHS E-learning module on safe use of non insulin therapies

View

NICE TA288 - Guidance on Dapagliflozin

View

NICE TA315 - Guidance on Canagliflozin

View

NICE TA336 - Guidance on Empagliflozin

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