Glucose Control: Insulin Therapy

(Refer to: Drug Review Insulin for a detailed review of insulin therapy)

Mode of action	Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis
Glycaemic efficacy and indications	Efficacy is theoretically unlimited but in practice may be limited by inadequate education and support, or by side effects (weight gain and hypoglycaemia) Insulin should be used in patients with features of metabolic decompensation (catabolic features, severe hyperglycaemia (fasting glucose > 14 mmol/L, random glucose > 16.5 mmol/L or a HbA1c > 10%) or persistent ketosis at any stage of the disease Insulin should be considered as one of the therapeutic options in patients not achieving adequate glycaemic control on 2 or 3 oral glucose lowering drugs
Cardiovascular outcome trials	UKPDS 10-year observational extension showed a decrease in myocardial infarction in the group where treatment had been intensified using insulin or a sulphonylurea The ORIGIN trial did not show cardiovascular benefit when using a basal insulin analogue in patients with diabetes or intermediate dysglycaemia; it was neutral Multiple studies and meta-analyses suggest that insulin may be associated with adverse cardiovascular outcomes when compared to comparators (metformin and sulphonylureas)
Hypoglycaemia	When used as monotherapy, dual therapy or triple therapy most studies show that the addition of insulin increases the risk of hypoglycaemia The rates of overall and nocturnal hypoglycaemia are lower with long-acting basal insulin analogues when compared to intermediate human insulins (NPH) Analogue basal insulins are preferred when hypoglycaemia is a limiting factor to achieving glycaemic control
Weight	When used as monotherapy or as add on to oral hypoglycaemic agents most studies show that insulin causes weight gain Weight gain over three years in the 4T study was 3.6 kg for basal and 5.7 kg for premix insulin Insulin detemir, however, has been shown in a few studies to either be weight neutral or result in some weight loss in those patients that are overweight or obese
Non-glycaemic benefits	Insulin also promotes protein synthesis, lipogenesis and increases the permeability of cells to potassium, magnesium and phosphate ions
Side Effects and Precautions	Fluid retention, oedema Lipodystrophy Local allergy Systemic allergy Existing cardiovascular disease: there is no evidence for the cardiovascular safety of insulin in patients with established cardiovascular disease, and some studies suggest a possible harmful effect  Avoiding hypoglycaemia takes precedence over intensive glycemic control in these patients
Dosing and prescribing	Starting doses: Basal insulin: Start 10 u at bedtime; monitor fasting glucose; educate the patient to titrate the dose using one of the titration algorithms to achieve fasting glucose targets (Refer to: Figure I below) Premix insulin: When escalating from a basal insulin regimen to a premix regimen, administer two-thirds of the total basal insulin dose in the morning, and one-third in the evening. Educate the patient to titrate the doses using one of the titration algorithms to achieve pre-prandial glucose targets (Refer to: Figure I below) Prescription for insulin must be accompanied with education about handling, storage, injection technique, injection sites, monitoring, titrating and the detection and management of hypoglycaemia
Renal dosing	All insulin preparations are metabolised by the kidneys and will therefore require a dose reduction in patients with renal impairment
Cost	Cost is variable depending on insulin type and dose, and is generally more expensive than oral agents Refer to: Insulin Preparations in South Africa for a complete list of insulins and prices

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)
SEMDSA 2017 Recommendations
Consider insulin as first-line therapy at diagnosis, and at any other point in the course of the disease, in the setting of metabolic decompensation with any of the following features: Catabolism (marked weight loss) Fasting plasma glucose levels >14 mmol/l Random glucose levels consistently >16.5 mmol/l HbA1c > 10% Presence of persistent ketogenesis, ketoacidosis or or hyperosmolar non-ketotic state	C
If insulin is needed at diagnosis, use either pre-mixed insulin twice daily or basal bolus intensive insulin therapy (specialist referral is recommended)	A
Initial insulin therapy at diagnosis is usually temporary, and most patients can be weaned off their insulin with the addition of oral agents  If the patient is not able to transition from insulin to oral therapy reconsider the diagnosis of type 2 diabetes, and refer to a specialist if in doubt	C
Consider adding basal insulin as the third glucose lowering drug in patients not achieving or maintaining their glycaemic targets on a two-drug oral regimen, especially if Targets are unlikely to be achieved with other third line options, and there are adequate resources to support insulin initiation and titration	B
Insulin therapy must be accompanied with intensive patient education and support, which includes (but is not limited to) SMBG and titration instructions, as well as education about the risk of hypoglycaemia	B
Analogue insulins offer some advantages over human insulins and are therefore preferred when the acquisition cost is similar	C
If nocturnal hypoglycaemia is a limiting factor to achieving optimal glycaemic control, consider switching from a human basal insulin to an analogue basal insulin, such as insulin glargine or insulin detemir	B
If glycaemic targets are not being met despite adequate titration of basal insulin, consider combination injectable therapies using a premix, a basal-plus (prandial insulin) or a basal insulin plus GLP-1 receptor agonist combination. Consider the advantages and disadvantages of each option for each individual patient	B
Be aware that insulin therapy is associated with the highest rates of hypoglycaemia and weight gain when compared to other glucose lowering drugs. However this is not a reason to delay or withhold insulin therapy when it is needed	A
Consider referring a patient to an endocrinologist or specialist physician when: Glycaemic targets are unmet with basal insulin doses > 0.8 u/kg or > 60 u daily Glycaemic targets are unmet after 6 months of treatment There is a need for a basal bolus insulin regimen Glycaemic targets are unmet with premix insulin doses > 60 u twice daily	C
Choice of insulins: insulins with the lowest acquisition cost within each class are preferred In each insulin class an insulin analogue is the preferred option if the acquisition cost is similar to that of a human insulin Registered biosimilar preparations are safe and effective. The newer insulins, such as ultra-long acting premixes and U300 concentrated insulins, are not recommended for use at primary care level	C

 

 

Figure I: Independent risk factors for severe hypoglycaemia^17,20

Insulin or sulphonylurea use

Intensive glucose control

Use of 2 or more oral glucose lowering drugs

Older age

Diabetes duration

Hypoglycaemia unawareness

Impaired cognitive function

Low body mass index

Renal impairment

Microvascular complications