Endocrinology Metabolism

Early Insulin Usage in the Outpatient Setting

Are you sure the patient has type 2 diabetes mellitus?

Type 2 diabetes mellitus is a progressive condition in which blood sugars rise inexorably over time. This reflects a decline in beta cell function. Patients usually progress from monotherapy, with one oral agent, to multiple agents. Adding insulin to oral therapy in type 2 diabetes is essential when glycemic control is suboptimal. The addition of insulin can result in better glycemic control, as evidenced by a decline in glycated hemoglobin levels. Insulin therapy improves blood glucose control, but this is usually accompanied by weight gain and the attendant risk of hypoglycemia.

Management and treatment of disease

The treatment of type 2 diabetes mellitus has traditionally started with lifestyle modifications followed by a stepwise increase in oral hypoglycemic therapy. In recent years, incretin therapy has been successfully used to improve glycemic control. However, most patients eventually lose control of diabetes and require insulin. The use of insulin is usually postponed and patients experience a prolonged period of hyperglycemia. There is significant clinician inertia towards starting insulin, which is partly related to the complexity of insulin use and patient reluctance to using injections. Adding a basal insulin to oral hypoglycemic therapy is relatively simple and has the advantage of easing a patient into insulin therapy slowly.

Candidates for insulin therapy

All patients with type 2 diabetes who have not achieved goal A1c and who are on maximal oral hypoglycemics and/or incretin therapy should be started on insulin. It is critical that insulin therapy not be delayed. Insulin should be added as soon as there is a trend towards hyperglycemia.

The choice of insulin depends on the type of hyperglycemia experienced by the patient. Patients with high fasting blood sugars are good candidates for adding basal insulin therapy to their oral agents. Patients with mostly post-prandial hyperglycemia will not be adequately controlled with basal insulin alone, and will require prandial insulin. Early use of insulin has been shown to preserve functional beta cell mass.

Basal insulin therapy

The addition of basal insulin therapy to oral hypoglycemic treatment is relatively simple. Basal insulin can be taken as a once-daily dose, as in the case of insulin glargine or detemir, or taken twice daily, as in the case of insulin detemir and NPH insulin.

However, basal insulin therapy added to oral hypoglycemic agents results in good glycemic control in only a small proportion of patients. There is a risk of weight gain and hypoglycemia, albeit at a much lower rate than traditional basal-bolus insulin regimens.

A single evening or bedtime injection of basal insulin with continued use of oral agents lowers fasting blood sugars. There is a beneficial carryover effect on glycemic levels later in the day, resulting in a lowering of glycated hemoglobin. An explanation for this phenomenon is that improvement in fasting sugars reduces glucotoxicity and allows the oral agents to be more effective during the day.

In the past, the only basal insulins available for use, were the intermediate acting insulins NPH and Lente and the long-acting insulin Ultralente. The onset of action of NPH is about 2 hours, and it peaks at about 4 - 6 hours. This puts the patient at risk for nocturnal hypoglycemia.

Glargine and detemir insulins are reported to be peakless, although the latter may have a peak at 3 - 9 hours. These are long-acting basal insulins. Glargine is usually dosed once a day but for most patients, detemir requires twice daily dosing.

The One Pill - One Shot study showed that adding glargine to glimepiride improves glycemic control. The Glargine Treat-To-Target Trial compared the efficacy of glargine to NPH insulin. In this study, oral hypoglycemic therapy was continued, but insulin was added in the form of either glargine or NPH. Insulin was started at 10 units.

Both groups achieved a similar degree of glycemic control (58% vs. 57%), but the group assigned to glargine had a lower frequency of hypoglycemia. In this study there was a forced titration of insulin, based on two preceding fasting blood glucose levels. If the preceding fasting blood sugar level was over 180 mg/dl, the insulin dose was increased by 8 units. If the fasting blood sugar level was between 140 - 180 mg/dl, the increase in basal insulin was by 6 units. If the fasting blood glucose level was between 120 - 140 mg/dl, the insulin dose was increased by 4 units. This forced titration of insulin helped bring the fasting blood sugar levels to goal over a relatively short period of time.

A similar study examined the use of twice-daily detemir insulin to NPH insulin. Oral hypoglycemic therapy was continued in both groups. Approximately 70% of patients in both groups achieved an A1c of <7%. However, the insulin detemir group had significantly lower levels of nocturnal hypoglycemia. Mean weight gain was also lower in the insulin detemir group.

In the APOLLO trial, once-daily basal insulin glargine was compared to thrice-daily prandial insulin lispro in patients with type 2 diabetes who are on oral hypoglycemic agents. The A1c lowering was the same in both groups, but patient satisfaction was higher in the glargine insulin group. Hypoglycemia frequency was also lower in this group.

Practical tactics for starting basal insulin therapy include:

1. Continue oral agents at the same dosage.

2. Add single evening insulin dose (10 units). NPH or glargine can be used.

3. Adjust insulin dose based on fasting blood sugars.

4. Patient can self-monitor blood sugars and increase insulin dose weekly.

5. Increase by 2 units if FBG = 100 - 120 mg/dl

  • Increase by 3 units if FBG = 121 - 140 mg/dl

  • Increase by 4 units if FBG = Over 140 mg/dl

Target FBG should be less than 100 mg/dl. Reduce insulin if FBG is below 72 mg/dl.

Split mix or premix insulin

When a patient has high post-meal blood sugar levels, basal insulin alone will not help achieve goal HbA1c. Premix insulin has the advantage of improving post-prandial blood sugars. Premix insulins are biphasic. They have both a rapid-acting and a delayed-acting component. Premix insulin is usually taken in two doses, prior to breakfast and dinner. Some patients can be started on once-daily split mix insulin at dinner. The second morning dose can be added at a later date.

The advantage of using premix insulin is that it is a relatively simple regimen for patients to use. It also has the advantage of slowly easing a patient into insulin therapy. Once the patient gains confidence with insulin use, it is generally easier to transition them to multi-dose insulin regimens. Hypoglycemia and weight gain are the major side effects of premix insulin.

The 1-2-3 Study demonstrated that optimal dosing of premix insulin can effectively achieve targets for glycemic control. Premix insulin was started at one pre-dinner shot and then titrated up to three shots per day (one before each meal). Approximately 88% of patients receiving the three shots of premix insulin achieved a goal A1c of <6.5%.

The INITIATE trial directly compared biphasic to basal insulin therapy in patients with poorly controlled diabetes who were on oral agents. A greater proportion of patients in the biphasic insulin group achieved goal HbA1c compared to the basal insulin group. However, this control was achieved at the expense of more weight gain and more episodes of hypoglycemia.

There are a variety of split mix insulin regimens available for the treatment of type 2 diabetes:

  • Aspart mix 70/30 insulin

  • Lispro mix 75/25 insulin

  • Lispro mix 50/50 insulin

  • NPH/Regular 70/30 insulin

  • Degludec/Aspart mix 70/30 insulin

For the first three premix insulin combinations, the onset of action is 5 - 15 minutes and the duration of action is 10 - 16 hours. For the NPH/Regular insulin combination, the onset of action is 30 - 60 minutes and duration of action is 10 - 16 hours. Degludec/Aspart is given once or twice a day with the degludec component having a half-life over 24 hours and a duration over 42 hours.

A common starting dose for insulin therapy in patients with type 2 diabetes is 0.15 units/kg body weight/day. However, most patients with type 2 diabetes have insulin resistance and require higher doses to achieve glycemic targets. Most patients require between 0.5 - 1.0 U/kg body weight/day.

A useful strategy would be to start a patient on 10 units of premix insulin, 30 minutes before supper. The other option would be to take 10 units of insulin before breakfast and before supper. Dosage titration is based on blood sugars and should be done on a weekly basis.

The pre-breakfast dose of premix insulin should be adjusted based on the pre-supper blood sugar value. Adjust the pre-supper insulin based on fasting or pre-breakfast blood sugar values. Reduce the total daily dose by 20% if recurrent hypoglycemia occurs.

Further titration of insulin or evaluation of therapy depends on A1c values. Knowing the relative contribution of fasting and postprandial glucose to A1c allows clinicians to make informed decisions about therapy. The relative contribution of fasting glucose to overall glycemia is about 70% in patients with an A1c over 10%. When the A1c is close to target, most of the contribution is from post-prandial hyperglycemia. At that time, increasing basal insulin, which mostly targets fasting blood sugar, is not of much value and puts the patient at risk for hypoglycemia.

If a patient is being transitioned from once daily basal insulin to twice daily premix insulin, then the total dose of basal insulin can be divided by two. Half of the dose is given 30 minutes prior to breakfast and the other half is given 30 minutes prior to dinner. Start the new insulin regimen 18 - 24 hours after the last basal dose of insulin is given.

Patients on degludec/aspart will most likely need to take a short-acting insulin at meals that do not have an injection of degludec/aspart.

Hypoglycemia related to insulin use

Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. It causes morbidity and is sometimes fatal. The barrier of hypoglycemia precludes tight glycemic control in some patients with diabetes. Hypoglycemia begets hypoglycemia. Recurrent episodes of hypoglycemia blunt the physiologic response to a drop in blood sugar, and this results in hypoglycemia unawareness, which can be dangerous.

The condition HAAF (hypoglycemia-associated autonomic failure) has been described in type 1 and 2 diabetes, whereby recurrent hypoglycemia provokes failure of the sympatho-adrenal response and impairment of hypoglycemia awareness. The United Kingdom Hypoglycemia Study Group found that the prevalence of severe hypoglycemia is 7% among patients with type 2 diabetes who have been treated with insulin for less than 2 years. Among patients treated for longer than 5 years, this figure rose to 25%. Estimates of prevalence and incidence may be underestimated, as asymptomatic episodes of hypoglycemia are not recorded.

Research suggests that with increasing age, the symptoms of hypoglycemia may become less intense. In older adults, there is attenuation of autonomic activation in response to hypoglycemia. Hypoglycemia causes functional brain failure that is typically reversed after the plasma glucose concentration is raised. Rarely, it causes sudden death, presumably due to cardiac arrhythmia. If hypoglycemia is prolonged or profound, permanent brain dysfunction and death may result.

Most episodes of hypoglycemia are effectively self-treated by the ingestion of carbohydrates or glucose tablets at a dose of 20 gm of glucose. The glycemic response to oral glucose is transient, typically less than 2 hours. Therefore, ingestion of a snack or meal shortly thereafter is advisable. Clinical improvement should occur in 15 - 20 minutes. Symptoms persist even after blood sugars have been raised, so there is the potential for over-treatment.

Parenteral therapy is necessary in a patient who is unable to take carbohydrates orally. Glucagon, in a dose of 1.0 mg for adults, can be injected subcutaneously or intramuscularly. If intravenous glucose is used to treat hypoglycemia, there is typically only a transient rise in blood glucose, as the effect of insulin is still persistent. After an initial dose of parenteral glucose, oral carbohydrate feeding should be started, if appropriate. This will result in a durable improvement in blood sugar levels.

Patients with impaired hypoglycemia awareness should be educated about prevention and treatment of hypoglycemia. They should be advised to wear medic alert bracelets declaring that they have diabetes. Patients should be advised to check blood sugars before driving. It should be recommended that they have a source of glucose handy at all times to treat potential hypoglycemia. Continuous glucose sensors also help prevent and quickly treat hypoglycemia (For more information, see chapter on Diabetes and Continuous Glucose Monitoring).

Inhalable insulin:

Inhalable insulin (brand name Afrezza) was approved June 27, 2014 for adults with Type 1 and Type 2 diabetes.

What's the evidence?

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Turner, RC, Cull, CA, Frighi, V, Holman, RR. "Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49)". JAMA. vol. 281. 1999. pp. 2005-12.

Holman, RR, Thorne, KI, Farmer, AJ. "Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes". NEJM. vol. 357. 2007. pp. 1716-30.

Meneghini, LF, Rosenberg, KH, Koenen, C, Merilainen, MJ, Lüddeke, JH. "Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study". Diabetes Obes Metab. vol. 9. 2007. pp. 418-27.

Fritsche, A, Schweitzer, MA, Häring, HU. "4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime glargine in patients with type 2 diabetes. A randomized, controlled trial". Ann Intern Med. vol. 138. 2003. pp. 952-9.

Bretzel, R, Owens, D. "Once daily basal insulin glargine vs thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycemic agents (APOLLO): an open randomised controlled trial". Lancet. vol. 371. 2008. pp. 1073-84.

Rosenstock, J. "Basal insulin supplementation in type 2 diabetes: refining the tactics". Am J Med . vol. 116. 2004. pp. 10s-16s.

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Garber, AJ, Wahlen, J. "Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing of biphasic insulin aspart 70/30 (The 1-2-3 study)". Diabetes Obes Metab. vol. 8. 2006. pp. 58-66.

Hermansen, K, Davies, M. "A 26-week randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral hypoglycemic drugs". Diabetes Care. vol. 29. 2006. pp. 1269-1274.

Nathan, DM, Buse, JG, Davidson, MB. "Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes". Diabetes Care. vol. 32. 2009. pp. 193-203.

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"ACE/AACE Consensus Conference on Implementation of Outpatient Management of Diabetes Mellitus: consensus management of diabetes mellitus: consensus conference of recommendations. ACE/ AACE Diabetes Recommendations Implementation Writing Committee". Endocrine Practice. vol. 12. 2006.

Janka, HU, Plewe, G, Riddle, MC. "Comparison of basal insulin added to oral agents vs twice-daily premixed insulin as initial insulin therapy for type 2 diabetes". Diabetes Care. vol. 28. 2005. pp. 254-9.

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