The most modern representatives of basal insulins are ultra-long acting and associated with low hypoglycemia rates. Mixed insulin or combination preparations of GLP-1-RA and a long-acting insulin are good alternatives to the relatively complicated basic bolus system. Regular follow-up, including addressing lifestyle factors, is also an important component of a multifactorial treatment regimen.
About 6.4% of the Swiss population has type 2 diabetes. “A quarter of all patients need insulin,” explains Prof. Roger Lehmann, MD, Senior Physician, at the Department of Endocrinology, University Hospital Zurich, and President of the Swiss Society of Endocrinology and Diabetology (SGED) [1]. Clarification of an insulin deficiency is the most important of the three guiding questions of the SGED Recommendations 2020 (Fig. 1) : 1. does the patient require insulin?.., 2. how is the kidney function?, 3. is it necessary to treat or prevent heart failure? Very high HbA1c levels, evidence of catabolism (e.g., unintentional weight loss), polyuria, or polydipsia are possible warning signs of insulin deficiency. Insulin is never wrong if type 2 diabetes has been present for a very long time and the HbA1c value is >10%, Prof. Lehmann continues. In concrete terms, this initially means the use of basal insulin alone or in the form of a combination preparation of a GLP-1 receptor agonist (GLP-1-RA) and a long-acting insulin (e.g. Xultophy®). In intensified insulin therapy, a basic bolus system is applied or, alternatively, a mixed insulin is used. The SGED guidelines suggest a stepwise approach: “Start with metformin in combination with an SGLT-2 inhibitor or GLP-1-RA. If that is not successful, add the next therapy, and if that is not effective either, add basaslinsulin. Only if that doesn’t work either, more complicated regimens with basal bolus or mixed insulin,” summarizes Prof. Lehmann. In some cases, insulin is also indicated as the first therapy when the criteria for insulin deficiency are met and the HbA1c level is >10%. Another rare indication for insulin is in isolated cases of ketoacidosis with SGLT-2 inhibitors or lactic acidosis with metformin, which should be discontinued and replaced with insulin.
New generation basal insulins: low risk of hypoglycemia
One of the basal insulins already available on the market for many years is NPH (Insulatard®), followed later by Detemir (Levemir®) and Glargin 100 (Lantus®). The representatives of a new generation of basal insulin are Glargin U300 (Toujeo®) and Degludec (Tresiba®). Unlike NPH insulin, these newer insulins have a very flat course of maximum effect. Avoidance of hypoglycemia correlates positively with the variability of an insulin and is an important criterion for basal insulin selection. Glargine U300 (Toujeo®) and Degludec (Tresiba®) are currently the two agents with the longest duration of action and the lowest risks of hypoglycemia. These two most modern representatives of the basic insulins are ultra-long-acting: “Insulin Degludec is effective up to 42 h and has a half-life of 25 h, Toujeo has a half-life of 17.5 h,” the speaker explained. Therefore, it does not matter whether they are administered in the morning or in the evening. However, this can be relevant for the other basal insulins: if someone has a high morning value, the basal insulin should be injected in the evening in these cases; if the morning value is good and hypoglycemia tends to occur at night, administering the basal insulin in the morning is worth a try. In summary: Switching from an NPH insulin to glargine U100 or detemir reduces hypoglycemia rates by 30-60%; switching to insulin degludec (Tresiba®) and glargine U300 (Toujeo®) is associated with an additional 30-50% reduction in hypoglycemia rates. That’s why these are the best insulins, the speaker explained. The CONCLUDE treat-to-target study, which compared the efficacy and safety of insulin degludec (Tresiba®) and insulin glargine 300 E/ml in type 2 diabetic patients pretreated with insulin who had at least one risk factor for hypoglycemia, showed a trend in favor of insulin degludec over insulin glargine 300 E/ml [2].
Mixed insulin and combination preparations as an alternative to basic bolus
The principle of a basic bolus system is that basic insulin prevents the rise in fasting blood glucose levels and bolus counteracts an excessive rise in glucose levels postprandially [1]. The short-acting insulin preparations (Tab. 1) are used with meals containing carbohydrates. As a scheme for the daily dose of insulin, the following rule can be used (box): 0.4 units per kg body weight, half of which as basal insulin and the other half as bolus insulin distributed over meals. 1 unit of insulin is equated with 10 g of carbohydrates. “If blood sugar is very high before a meal, give a little more; if blood sugar is low, maybe eat a little first and then inject the full amount,” the speaker said. Increasing the amount of insulin may also be considered if the patient has a high BMI and a low risk of hypoglycemia. For many patients, implementing a basic bolus system is a relatively complicated matter. Mixed insulins and combination preparations of GLP-1-RA and long-acting insulin are not only easier to use than a basic bolus system, but also have evidence-based efficacy. In a head-to-head study, Xultophy® [3] performed better than basal insulin, with fewer hypoglycemic episodes and fewer injections. Xultophy® is a combination preparation of GLP-1-RA (liraglutide) and insulin degludec. Ryzodeg® three times daily proved to be comparably effective in empirical comparison to baseline bolus in terms of HbA1c, hypoglycemia, weight gain, and amount of insulin required [4]. Ryzodeg® is a combination of a long-acting insulin (Degludec) and a short-acting insulin (Aspart). It is a simple system that can be increasingly used by primary care physicians, the speaker said. Suliqua® is another combination preparation consisting of GLP-1-RA and insulin glargine. “With the basal insulin you cover the basal need, and with the GLP-1-RA you have covered one main meal with the Suliqua®, and with the Xultophy® you have covered all three main meals if possible,” explains Prof. Lehmann.
Which antidiabetic agents are contraindicated with insulin administration?
Pioglitazone, which is now used only very rarely and can lead to an increased risk of heart failure when combined with insulin, should be discontinued, the speaker explained. Sulfonylureas should also be discontinued. All other antidiabetic therapies may be continued if reasonable and approved. The only thing to avoid is a combination of GLP-1 RA and DPP-4 inhibitors, as this does not add any benefit. If target HbA1c levels are not achieved on treatment with 2-3 oral antidiabetics plus basal insulin, there is the option of giving a mixed insulin or a co-formulated insulin (Ryzodeg). Basal insulin combines well with GLP-1. Medication for T2D as well as lifestyle changes should be reevaluated at regular intervals (every 3-6 months) [5]. According to the general SGED therapy scheme in type 2 diabetes, metformin is initially the preferred antidiabetic drug if well tolerated and not contraindicated, except in the following cases: If eGFR is low (<30 ml/min), metformin is contraindicated; DPP-4 inhibitors or GLP-1-RA may be used instead. For eGFR <45 ml/min, the SGED guidelines recommend not using metformin or, if already prescribed, reducing the daily dose and reviewing eGFR two to three times a year [5]. If heart failure is to be prevented and eGFR is above 30 ml/min, SGLT-2-i are the therapy of choice. Metformin should be combined as early as possible with SGLT-2-i or GLP-1 RA, which have additional cardiovascular benefits. Diabetes requires multifactorial treatment, and lifestyle factors (e.g., diet, exercise, smoking cessation) also play an important role. Regarding exercise, there are two conditions that diabetics should prevent: Hypoglycemia and hyperacidity [7]. Particular attention should be paid to the prevention of hypoglycemia, especially in older type 2 diabetics treated with insulin.
Literature:
- Lehmann R: Endocrinology. Prof. R. Lehmann, MD, FOMF Update Refresher, Livestream, June 23-27, 2020.
- Philis-Tsimikas A, et al: Reduced risk of hypoglycaemia and lower HbA1c with degludec compared to glargine U300 in insulin-treated patients with type 2 diabetes, EASD 2019.
- Billings LK, et al: Diabetes Care 2018; 41: 1009-1016.
- Rodboard HW, et al: Diab Obes Metab 2016; 18: 274-280.
- Lehmann R, et al: Recommendations of the Swiss Society of Endocrinology and Diabetology for the Treatment of T2DM, 2020, www.sgedssed.ch
- Swiss Drug Compendium, https://compendium.ch
- Diabetes Information Service, www.diabetesinformationsdienst-muenchen.de
FAMILY PRACTICE 2020: 15(11): 22-24