The current therapy guidelines for diabetes mellitus type 2 provide for the use of insulin as initial therapy as well as a later therapy option in monotherapy or in combination with other antidiabetic drugs [1]. This article focuses on the various uses of insulin therapy in the treatment of type 2 diabetes. In particular, the possible combinations of insulin with other antidiabetic agents are discussed.
After Banting and Best were able to isolate insulin from the pancreas of cattle in 1921, insulin was administered to the first children with type 1 diabetes mellitus in Canada in July 1922. Up to this point, all children with type 1 diabetes have died in a relatively short time. Ted Ryder was one of the first people to be treated with insulin in July 1922 – he was five years old at the time and died at the age of 76 without any relevant diabetes complications. Today, thanks to the possibilities of modern insulin therapy, children with type 1 diabetes even have a practically normal life expectancy if the diabetes is well controlled. Insulin has also been indispensable in the treatment of type 2 diabetes for many decades. Insulin is usually used in the treatment of type 2 diabetes when satisfactory metabolic control can no longer be achieved with other antidiabetic drugs. Due to the continuous deterioration of β-cell function during the course of the disease, a considerable proportion of patients with type 2 diabetes must be adjusted to insulin treatment in the longer term.
Insulin as initial therapy in newly diagnosed type 2 diabetes
Intensified insulin therapy (e.g., basic bolus therapy) is a very effective treatment option for newly diagnosed diabetes and derailed metabolic status. Several studies have shown that in patients with an HbA1c >10%, temporary intensified insulin therapy can achieve normal blood glucose levels in a short time and keep patients in remission for longer [2]. For this reason, intensified insulin therapy is highly recommended as a primary treatment option in HbA1c >10% and/or symptomatic patients – for practical reasons, this usually requires hospitalization. Initial intensified insulin therapy leads very quickly to good metabolic control and can be stopped again in the course. A remarkably high proportion of patients who are initially treated with intensified insulin therapy do not need antidiabetic drugs even one year later, because the β-cell function could recover due to the initial insulin therapy. Another advantage of initial insulin therapy is that patients get to know insulin as an effective medication and are not afraid of insulin therapy later on, should insulin therapy become necessary again in the further course of the disease.
Insulin in combination with other antidiabetic agents
Early insulin therapy (basal insulin in combination with metformin): In the national guidelines, metformin is designated as the primary antidiabetic agent in the treatment of type 2 diabetes and is undisputed as the first-choice antidiabetic agent, at least in overweight patients, unless contraindications exist [1]. Based on the guidelines, it is already possible to use insulin as a second antidiabetic drug after metformin. In clinical practice, this early use of insulin is limited to selected situations. The reasons that insulin is rarely used in practice as a second antidiabetic agent after metformin are likely explained by the potential side effects of insulin (weight gain and hypoglycemia) and patients’ reservations about injections. Good candidates for early use of insulin are normal-weight patients with type 2 diabetes and patients with a very elevated fasting value.
Normal-weight or only mildly overweight patients with type 2 diabetes often have poorer insulin secretion than the severely overweight patients in whom insulin resistance predominates. Due to poorer insulin secretion, normal weight patients with type 2 diabetes need to be treated with insulin statistically earlier than overweight patients [3]. Some of these patients are likely to be type 1 diabetics who should be treated with insulin anyway. For these reasons, early use of insulin in normal-weight patients with type 2 diabetes is a rational treatment option.
Another reason to use insulin early in the treatment of type 2 diabetes is high fasting blood glucose levels. For fasting blood glucose control, injection of a long-acting insulin preparation at bed rest or in the evening is still the most effective treatment option. <In the Origin study, fasting blood glucose was shown to be maintained at 5.3 mmol/l for several years with early use of insulin with a single injection of insulin glargine (Lantus®) [4]. The Origin study also showed that early therapy with insulin is safe – cardiovascular events and cancer were no more common in patients treated with insulin glargine (Lantus®) than in the control group. The incidence of severe hypoglycemia was also low: only 1% of patients experienced severe hypoglycemia per 100 patient-years – despite very good glycemic control (average HbA1c 6.2%).
Basal insulin in combination with several antidiabetic agents in the later course of the disease: Typically, insulin is only used in type 2 diabetes when the individual HbA1c target is not reached despite therapy with two to three different antidiabetic agents. The typical initiation of insulin therapy is as a single injection of a long-acting insulin preparation in the evening or at bedtime (“bedtime”) in combination with existing antidiabetic drugs [1]. The following section discusses which antidiabetic drugs can be combined with insulin or which antidiabetic drugs should be discontinued when insulin therapy is initiated.
- Metformin: Metformin therapy is usually continued when insulin therapy is started with long-acting insulin preparations (basal insulin), unless metformin is contraindicated (renal function!).
- sulfonylureas (gliclazide) and glinides (repaglinide and nateglinide): Within the sulfonylureas, gliclazide is the substance that has the lowest potential for hypoglycemia. For this reason, only this substance should be used in combination with insulin from the sulfonylurea group. The combination of gliclazide or the glinides (repaglinide or nateglinide) with long-acting insulin preparations in the evening or “bedtime” makes pathophysiological sense; these preparations can therefore also be continued with long-acting insulin preparations in the evening when insulin therapy is started. If the long-acting insulin preparations are not applied in the evening but in the morning or at noon, the sulfonylureas and glinides should be discontinued on a trial basis to prevent hypoglycemia.
- Glitazone (pioglitazone): Pioglitazone is a drug that increases insulin sensitivity. Fluid retention and weight gain are sometimes possible side effects of therapy with pioglitazone. These side effects occur more frequently in combination therapy with insulin, which is why an attempt to discontinue pioglitazone should always be made when insulin therapy is started.
- DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin): A combination of a DPP-4 inhibitor with long-acting insulin preparations in the evening or at bed rest is a pathophysiologically reasonable therapy. DPP-4 inhibitors can therefore be continued with the long-acting insulin preparation when it is started. All DPP-4 inhibitors are approved for use in combination with insulin; there are (still) differences in reimbursement by health insurers.
- GLP-1 analogues (exenatide, exenatide LAR, liraglutide): In principle, the combination of subcutaneously applied long-acting GLP-1 analogues (liraglutide and exenatide LAR) with long-acting insulin preparations makes pathophysiological sense (at the moment, only liraglutide is approved in combination with basal insulin). The combination of short-acting GLP-1 analogues (exenatide) with long-acting insulin preparations is permitted by the health insurance scheme and makes pharmacological sense, but is rarely used in Switzerland, partly because of the poor tolerability of exenatide.
In the future, it will even be possible to apply long-acting insulin preparations and GLP-1 analogues simultaneously in the same pen.
- SGLT-2 inhibitors (canagliflozin): SGLT-2 inhibitors can be combined with any form of insulin therapy. If insulin therapy with long-acting insulin preparations is started in the evening or during bed rest, therapy with the SGLT-2 inhibitor can be continued.
Intensification of insulin therapy (basic bolus therapy or mixed insulin): If metabolic control is insufficient despite oral antidiabetic drugs in combination with long-acting insulin preparations in the evening, insulin therapy must be intensified. In this case, there is either a switch to a basic bolus therapy or to a therapy with mixed insulin. The following section discusses which antidiabetic agents can be combined with these forms of insulin therapy. In principle, a discontinuation of all other antidiabetic drugs is always justified during intensified insulin therapy or therapy with mixed insulin. The combination of intensified insulin therapy or mixed insulin with other antidiabetic agents must have a favorable effect on metabolic control, insulin requirements, weight, or frequency of hypoglycemia-a favorable effect of the combination can be demonstrated only with a discontinuation trial.
- Metformin: Metformin is often continued even with intensified insulin therapy or treatment with mixed insulin. The main argument for continuing therapy with metformin in these cases is the reduction of insulin requirements in patients with high insulin doses. Whether continuing metformin therapy has a beneficial effect on metabolic control or insulin requirements can be assessed with a discontinuation trial.
- Sulfonylureas (gliclazide) and glinides (repaglinide and nateglinide): Sulfonylureas and glinides should generally be discontinued when a patient is being treated with intensified insulin therapy or mixed insulin to prevent hypoglycemia.
- Glitazone (pioglitazone): In principle, the combination of pioglitazone with insulin should be used very cautiously. In patients with marked insulin resistance (insulin requirement >1E/kgKG), it is necessary in exceptional cases to reintroduce pioglitazone secondarily in combination with insulin therapy. However, if the combination does not lead to a significant improvement in metabolic control, pioglitazone should be discontinued.
- DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin): The combination of DPP-4 inhibitors with intensified insulin therapy or with mixed insulin is not fundamentally wrong, but based on the current data, the cost-benefit ratio is rather unfavorable. The benefit of combining a DPP-4 inhibitor with baseline bolus therapy or mixed insulin therapy is small; in most cases, the DPP-4 inhibitor can be discontinued with these forms of insulin therapy. If, in exceptional situations, combination therapy is to be performed, it is worthwhile to clarify the eligibility for health insurance coverage.
- GLP-1 analogues (exenatide, exenatide LAR, liraglutide): The combination of GLP-1 analogues with mixed insulin or with a basic bolus therapy is currently not yet subject to health insurance coverage in Switzerland, but will probably represent a possible combination therapy in the future.
- SGLT-2 inhibitors (canagliflozin): SGLT-2 inhibitors can be combined with any form of insulin therapy. A favorable effect on metabolic control or a favorable effect on weight and insulin requirements are arguments that may support combining insulin therapy with an SGLT-2 inhibitor.
Prof. Dr. med. Peter Wiesli
Literature:
- Inzucchi SE, et al: Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35(6): 1364-1379.
- Weng J, et al: Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 2008; 371(9626): 1753-1760.
- Matthews DR, et al: UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med 1998; 15(4): 297-303.
- Gerstein HC, et al: Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367(4): 319-328.
CONCLUSION FOR PRACTICE
- Insulin is safe, always effective, never contraindicated, and can be used at any stage of type 2 diabetes; at the latest when individual target values are not achieved with two to three other antidiabetic agents.
- In newly diagnosed type 2 diabetes and derailed metabolic status (HbA1c >10%), temporary intensified insulin therapy (basic bolus) is very effective and can lead to longer-lasting remission of diabetes.
- When insulin therapy with basal insulin is started in the evening, the existing other antidiabetic drugs are continued – pioglitazone is always discontinued in this situation.
- Simultaneous use of more than three different antidiabetic agents (including insulin) is rarely justified.
- In intensified insulin therapy or therapy with mixed insulin, a combination with other antidiabetic drugs must have a demonstrable benefit – the benefit can be verified with a discontinuation trial of the antidiabetic drugs.
HAUSARZT PRAXIS 2014; 9(7): 14-17
