Managing type 2 diabetes Flashcards
How many types of antidiabetic agents are there
- 7 oral
- 2 injectable
Sulfonylureas
Sulfonylureas work by stimulating β cell insulin secretion in the pancreas and hence an adequate endogenous reserve of β cell function is required. As β cell function deteriorates over time, the effect of sulfonylureas tends to become suboptimal.
The long-acting sulfonylurea should be avoided in older people due to the risk of hypoglycaemia5. Severe sulfonylurea-induced hypoglycaemia can persist for many hours and is best managed in hospital using an intravenous glucose infusion. Shorter acting Sulphonylureas include Gliclazide & Glimeprimide. Sulfonylureas may cause weight gain, GI disturbance and, rarely, hepatic dysfunction, hypersensitivity reactions and blood disorders.
The use of sulfonylureas in pregnancy and breastfeeding should generally be avoided because of the risk of neonatal and infant hypoglycaemia5.
Sulfonylureas should be used with caution in those with mild to moderate renal impairment, because of the hazard of hypoglycaemia. Care is required to use the lowest dose that adequately controls blood glucose. Avoid where possible in severe renal impairment and use with caution in hepatic impairment5.
Meglitinides
Repaglinide is a rapid-acting insulin secretagogues, which promotes insulin secretion from the pancreas when blood glucose levels are at their highest but not when they return to fasting levels. It therefore reduces post-prandial glucose peaks and, like sulfonylureas, can cause hypoglycaemia.
It has a rapid onset of action and short duration of activity enabling medication to be varied according to eating habits. The dose is omitted if the meal is missed. Repaglinide is more expensive than sulfonylureas and should be reserved for patients who have erratic eating patterns4. There is no licensed non-metformin-based combination containing repaglinide that can be offered at first intensification4.
Adverse side-effects associated with this group of drugs include hypoglycaemia, abdominal pain, diarrhoea, constipation, nausea and vomiting. Hypersensitivity reactions may also occur including rashes and urticaria.
SGLT2 transporters
Canagliflozin, dapagliflozin, ertugliflozin and empagliflozin reversibly inhibit sodium-glucose co-transporter-2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
They are licensed for use in type 2 diabetes as monotherapy and in combination with other antidiabetic agents. There are differing renal function thresholds and doses for SGLT-2 inhibitors use in type 2 diabetes.
Dapagliflozin is now licensed for the treatment of symptomatic chronic heart failure with reduced ejection fraction and chronic kidney disease. Empagliflozin is licensed for the treatment of symptomatic chronic heart failure with/without reduced ejection fraction. Canagliflozin is also now indicated in Chronic renal failure with the 100mg dose licensed down to eGFR 30ml/min in adults with Type 2 diabetes and Diabetic Nephropathy with albuminuria >300mg/day.
The presence of hypovolaemia must be corrected before starting treatment with SGLT-2 inhibitors and patients should report any symptoms of volume depletion, e.g. postural hypotension and dizziness.
SGLT2 inhibitors monitoring
A review by the European Medicines Agency concluded that serious, life-threatening, and fatal cases of diabetic ketoacidosis (DKA)24 have been reported rarely, in patients taking an SGLT2 inhibitor. In 2016, the EMA issued advice to reduce the risk of DKA25.
Healthcare professionals are advised to monitor blood ketone levels 26 during SGLT2 inhibitor treatment interruption, in patients hospitalised for major surgery or acute serious illness. Treatment may be restarted once ketone levels are normal and the patient’s condition has stabilised.
All of the SGLT-2 inhibitors have shown an increased risk of Fournier’s gangrene 27 and a risk of genital infections. Fournier’s gangrene is a rare but serious and potentially life-threatening infection. If suspected, stop the SGLT2 inhibitor and advise patients to seek urgent medical attention if severe pain, tenderness, erythema, or swelling in the genital or perineal area presents, accompanied by fever or malaise as urogenital infection or perineal abscess may precede necrotising fasciitis.
GLP 1 agonists
GLP-1 agonists are known as incretin mimetics as they act by mimicing Glucagon-like Peptide-1 in the gut, which binds to GLP-1 receptors when food is digested, triggering insulin production from the pancreas, inhibiting glucagon secretion and lowering gut motility.
There are currently five GLP-1 receptor agonists available in the UK, (listed in this Diabetes UK table) which are all self-administered by subcutaneous injection, with the exception of Semaglutide which is now also available as an oral formulation
DPP4 inhibitors
Alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin prevent GLP-1 breakdown, resulting in increased insulin secretion and inhibition of glucagon secretion from the pancreas. DPP-4 inhibitors are administered orally, they are weight neutral and they reduce HbA1c by approximately 0.5 to 1%13. All of the DPP-4 inhibitors may be considered as add-on therapy to metformin and/or sulfonylureas if there are contra-indications, intolerances or problems with hypoglycaemia. Furthermore, all DDP-4 inhibitors except alogliptin are licensed for monotherapy, if metformin is inappropriate. Only continue DPP-4 inhibitor therapy if the person has had a beneficial metabolic response (a reduction of at least 0.5 percentage points in HbA1c in 6 months). Alogliptin is the Northern Ireland formulary DPP-4 inhibitor of choice23.
These agents are generally well tolerated with side-effect profiles similar to placebo. A Cochrane review reported an increased risk of infection with sitagliptin and headache with vildagliptin16. DPP-4 inhibitors must not be used in combination with GLP-1 analogues5. If pancreatitis suspected, all DPP-4 inhibitors should be held and stopped if confirmed5. All can cause severe joint pain5. All the DPP-4 inhibitors except linagliptin require dose reduction in moderate and severe renal impairment5.Saxagliptin and alogliptin should be used with caution in moderate to severe heart failure while vildagliptin should be avoided in severe heart failure5
Biguanides
The biguanide metformin lowers blood glucose by inhibiting gluconeogenesis in the liver and enhancing peripheral muscle glucose uptake. Metformin acts in the presence of endogenous insulin; it is only effective if there are some residual functioning pancreatic cells.
Standard-release metformin is the first-line drug of choice for adults with type 2 diabetes in the absence of contra-indications or intolerance. Metformin does not cause an increase in insulin secretion, thus weight gain and hypoglycaemia are less likely than with insulin or sulfonylurea therapy7. The most common side-effect of metformin is gastro-intestinal (GI) intolerance, which may be minimised through slow dose titration over several weeks. Extended-release metformin may be considered if GI side-effects are particularly problematic4.
If monotherapy fails, metformin can be prescribed with all the other antidiabetic agents as combination therapy. Metformin should be used with caution in renal impairment due to the increased risk of lactic acidosis and in hepatic impairment due to the risk of tissue hypoxia. Treatment should be interrupted if dehydration occurs and avoid in conditions acutely worsening renal function, or tissue hypoxia5. Stop metformin if eGFR <30 ml/min/1.73m2
Thiazolidinediones
Pioglitazone is the only glitazone now available, it reduces insulin resistance in the liver and peripheral tissues, leading to a decrease in blood glucose. Side-effects include fluid retention, anaemia, weight gain and altered lipid levels and, rarely, liver dysfunction.
In 2007 a meta-analysis found that glitazones increased the risk of congestive heart failure but not the risk of cardiovascular death8. In January 2011, the MHRA reported cases of cardiac failure when pioglitazone was used alongside insulin10. In August 2011, the MHRA reported a small increased risk of bladder cancer with pioglitazone; however, in patients who respond to treatment, the benefits outweigh the risks11.
The HSC provides a summary of monitoring requirements for commonly used drugs (including glitazones). NICE states that caution should be exercised with pioglitazone due to the increased risk of heart failure, bladder cancer and bone fracture4. Prescribers should review the safety and efficacy of pioglitazone in individuals after 3 to 6 months of treatment. Concomitant use with insulin (risk of heart failure); elderly (increased risk of heart failure, fractures, and bladder cancer)5.
treatment for patients without CVD
Offer Metformin
or
if GI disturbance, offer Metformin M/R
If Metformin contra-indicated, consider:
DPP-4 inhibitor or
Pioglitazone or
Sulfonylurea or
SGLT-2 inhibitor in some people*
Treatment for patients with CVD
Offer Metformin
or
if GI disturbance, offer Metformin MR
and
As soon as metformin tolerability confirmed, offer SGLT-2 inhibitor with proven cardiovascular benefit.
If Metformin contra-indicated, offer SGLT-2 inhibitor alone
stepping up treatment
If at any point, the person’s HbA1c is not controlled below individually agreed threshold, consider switching or adding treatments:
DPP-4 inhibitor or
Pioglitazone or
Sulfonylurea or
SGLT-2 inhibitors may also be an option in dual therapy
If at any point, the person has or develops a high risk of CVD consider switching to or adding an SGLT-2 inhibitor (if not already prescribed).
If at any point, the person has or develops chronic heart failure or established atherosclerotic CVD, switch to or add an SGLT-2 inhibitor (if not already prescribed).
