Editors

HanneleYki-Järvinen

Insulin Therapy in Type 2 Diabetes

Essentials

Insulin, in adequate doses (10-200 units/day), is an effective means of lowering blood glucose, and hence it prevents retinopathy, nephropathy and neuropathy. It is good to tell this also to the patient.
There are no contraindications for insulin treatment.
Self-monitoring of blood glucose (just fasting glucose when basal insulin is used) and simple self-adjusting of the insulin dose are essential for success.
Insuling therapy can be started in primary care for most patients.
The primary time for administering basal insulin is in the evening, but it may also be some other time of the day, as long as the time remains the same within a few hours.
The target is to reduce the HbA_1c level to 53 mmol/mol (7.0%), or, if there are specific reasons, to a level higher than that.
Meal-time insulins should not be included in modern insulin treatment of type 2 diabetes.
Oral antidiabetic drugs or injectable GLP-1 analogues which are already used may be complemented by basal insulin.

Indications for insulin treatment

Insulin treatment should be started when the treatment of hyperglycaemia with other medications has not been successful (HbA_1c> 53 mmol/mol [7.0%]), they are contraindicated or their adverse effects prohibit their use.
A higher target level may be warranted if the patient has
- recurrent severe hypoglycemias
- short life expectancy
- impairment of cognitive functions, reduced functional capacity
- severe vascular complications
- severe other systemic diseases
Temporarily increased need for insulin
- Transient, serious diseases (e.g. infections, myocardial infarction, aggravation of asthma, etc.) and surgical procedures may increase blood glucose levels so much that temporary insulin treatment is necessary for correcting the imbalance.

Implementation of insulin therapy

Principles

Comparative studies and meta-analyses support combination therapy with oral agents and evening insulin as the insulin treatment regimen of choice in type 2 diabetes Insulin Added on Metformin in Type 2 Diabetes.
Meal-time insulin preparations and premixed insulin preparations increase the occurrence of hypoglycaemias and cause extra weight gain and other trouble, and their use is not evidence-based treatment of type 2 diabetes. Earlier diabetes medication (oral preparations and GLP-1 analogues) does not need to be altered when starting basal insulin treatment.

Basal insulin treatment Long-Acting Insulin Analogues Versus Nph Insulin (Human Isophane Insulin) for Type 2 Diabetes Mellitus, Insulin Added on Metformin in Type 2 Diabetes

Can be carried out by taking basal insulin in the evening between 9 and 11 p.m (see table T1). The insulin may be injected at any time of the day, as long as the time remains each day within the same time window of a few hours.
Snacks do not belong to insulin treatment of a patient with type 2 diabetes. The diet does not need to be changed when starting combination therapy with oral agents and evening insulin if a healthy diet is already followed Lifestyle Education in Type 2 Diabetes.
Basal insulin may be added to any combination of other oral and injectable (GLP-1 analogues) drugs.
A safe initial dose for all patients is 10 units in the evening.
Successful implementation of insulin treatment requires self-monitoring of fasting blood glucose and self-adjustment.
- The patient is given a written simple guide for self-adjustment: increase dosage by 2 units if fasting blood glucose is over 6.0 mmol/l on 3 consecutive mornings.
Teach the patient to recognize the symptoms and treatment of hypoglycaemia and provide instructions on insulin dosage for situations where asymptomatic or symptomatic hypoglycaemia occurs.
- If fasting glucose is below 4.0 mmol/l
  - in 1 out of 3 measurements: no changes to dosage
  - more frequently: reduce dose by 2 units
  - if low fasting blood glucose values still occur, contact a nurse
The insulin dose in type 2 diabetes may vary between 10 and 200 units, depending e.g. on the liver fat content. An average dose is 70 units when a single oral drug is used (1 oral drug equals to approximately 20 units of insulin).
If basal insulin is injected at another time than evening (e.g. in the morning), the dosage may still be adjusted based on the fasting glucose level.
- If the patient is not able to monitor blood glucose him/herself and a nurse visits to inject insulin, it is recommended to determine blood glucose and inject basal insulin before a meal.
If fasting glucose value is not within the target range (5.0-6.0 mmol/l), the HbA_1c target 53 mmol/l (7.0%) will not be reached.
Weight gain during insulin treatment is caused by the correction of hyperglycaemia ("calories earlier lost in urine are now retained in the body") and the higher the blood glucose level before the start of insulin treatment, the greater the gain (1.5 kg / 1 % reduction in HbA_1c) . Basal insulin in itself does not cause weight gain.
Hypoglycaemias occur less frequently when using insulin glargine strength 300 units/ml or insulin degludec strenghts 100 units/ml and 200 units/ml, compared to using insulin glargine strength 100 units/ml or insulin detemir. Moreover, when using the two latter forms, hypoglycaemias occur clearly less frequently than with NPH insulin Long-Acting Insulin Analogues Versus Nph Insulin (Human Isophane Insulin) for Type 2 Diabetes Mellitus.

Simple starting of basal insulin

Start if HbA_1c≥ 53 mmol/l (7.0 %) or above individually set target level in spite of other treatment.

Teach the patient to perform blood glucose self-monitoring if he/she is not already able to perform it.

Let the patient know the benefits of insulin (prevention of problems in the eyes, kidneys and nervous system).

Diet or exercise habits do not need to be changed because of basal insulin.

Initial dose for all patients is 10 units in the evening.

Teach the patient to use the injection device.

Daily monitoring of fasting blood glucose, this may be spaced out to e.g. weekly monitoring when the target has been reached.

Teach self-adjustment: if fasting blood glucose is ≥ 6.0 mmol/l on 3 consecutive mornings, the patient increases the dose by 2 units at home (not if fasting blood glucose is even once < 4.0 mmol/l). If the patient suffers from symptomatic hypoglycaemia, reduce the dose by 4 units. If the patient suffers from recurrent hypoglycaemia, he/she should contact his/her treatment unit.

The dose varies between 10-200 units and is on average 70 units if a single oral drug is used (1 oral drug is equivalent to approximately 20 units of insulin).

Basal insulin can be combined with all oral drugs; with pioglitazone, however, one should exercise caution (risk of fluid retention, not for patients with cardiac failure).

Continuous self-adjustment of insulin dose is required for successful treatment.

Arrange for the patient a possiblity to contact.

Use of GLP-1 analogues with basal insulin

If the patient's fasting blood glucose is within the target (average of fasting measurements 4.0-6.0 mmol/l within an 8-week period), but HbA_1C is above the target 53 mmol/mol (7.0%), a GLP-1 analogue may be added to the basal insulin.
GLP-1 analogue may also be started before insulin. The drugs in this group cause nausea and diarrhoea in some patients. They have beneficial effects on weight despite the improvement of glucose balance and they do not cause hyperglycaemia.
If the patient cannot use a GLP-1 analogue, consider if you can add one more oral preparation (e.g. an SGLT2 inhibitor) to the treatment.

Renal insufficiency

If the patient has renal insufficiency, sulphonylureas should be avoided.
Concerning metformin, either an adjustment of dosage may be required or the drug should be avoided, depending on the severity of renal insufficiency. Consult locally available drug information sources for more details on metformin.
Of the gliptins, linagliptin does not require adjustment of dosage in renal insufficiency. If the patient is already using an SGLT 2 inhibitor, notice the restrictions to use when eGFR is reduced below 60 ml/min/1.73 m² . These drugs may be combined with basal insulin.
If oral antidiabetic drugs are contraindicated, adding a GLP-1 analogue (mild or moderate renal insufficiency) or rapid-acting insulin (all patients, risk of hypoglycaemia) to one or more meals is an option.

Follow-up of insulin treatment

During treatment with evening insulin a fasting blood glucose measurement in the mornings and when hypoglycaemia symptoms appear is sufficient.
A possibility to consult over the phone should be arranged or the normalization of fasting blood glucose level should be followed-up using a remote monitoring system.
Self-adjustment of the insulin dose and the target level of 4.0-6.0 mmol/l for fasting blood glucose should be kept in mind even after the start of the insulin treatment. Once the dose has stabilized, the fasting blood glucose measurement may be performed less frequently, e.g. once a week. The blood glucose balance is assessed by measuring HbA_1c (at least every 3 months) and by monitoring the occurrence of hypoglycaemias.

References

Yki-Järvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Ryysy L, Salo S, Seppälä P. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1992 Nov 12;327(20):1426-33. [PubMed]
Yki-Järvinen H, Kotronen A. Is there evidence to support use of premixed or prandial insulin regimens in insulin-naive or previously insulin-treated type 2 diabetic patients? Diabetes Care 2013;36 Suppl (2):S205-11. [PubMed]
Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab 2015;6(1):19-28. [PubMed]
Rosenstock J, Cheng A, Ritzel R et al. More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: the randomized head-to-head BRIGHT Trial. Diabetes Care 2018;41(10):2147-2154. [PubMed]
Wysham C, Bhargava A, Chaykin L et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA 2017;318(1):45-56. [PubMed]
Marso SP, McGuire DK, Zinman B et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017;377(8):723-732. [PubMed]

section name header

Information ⬇