Some new drugs and new techniques are expected to improve glycemic control in type 1 and type 2 diabetes. In addition to proper medication selection, a patient-centered approach is essential. The motto is no longer to reduce the HbA1c below 6.5% in any case, but to set an individual therapy target.
Prof. Peter Diem, MD, Chief of the Clinic for Endocrinology, Diabetology and Clinical Nutrition at the Inselspital in Bern, sees some new and interesting approaches or improvements to existing techniques in diabetes therapy. However, these new strategies and developments are still largely dreams of the future. “You can no longer push the HbA1c value partout below 6.5% for everyone, but should adjust it individually,” Prof. Diem said. The American Diabetes Association (ADA) and European Association of the Study of Diabetes (EASD) position paper “Management of Type 2 Diabetes” recently summarized the new strategy [1].
The main goal of glucose control remains: A target HbA1c of less than 7% with a preprandial glucose of 130 mg/dl and postprandial of less than 180 mg/dl [2, 3]. This reduces the risk of microvascular complications [4]. But for certain individuals, different recommendations apply: For example, blood glucose should be adjusted more strictly to a target HbA1c of between 6.0 and 6.5% in patients with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. Less stringent HbA1c values between 7.5 and 8.0%, or even slightly higher, apply to older individuals with concomitant diseases or those prone to hypoglycemia.
“The risk-benefit ratio has to be assessed for each patient individually,” said Prof. Oliver Schnell, MD, a member of the Executive Committee of EASD’s Diabetes and Cardiovascular Disease Study Group, at the congress in Paris (see interview on page 27). “There is no one algorithm that applies to all patients.” The patient’s wishes and expectations should also be included in the therapy decision. “If the patient has had diabetes for a very long time and was not well controlled, I choose a less aggressive target, because the benefit is very questionable here,” said Prof. Ulrich Keller, MD, former chief physician of the Department of Endocrinology, Diabetology and Clinical Nutrition at the University Hospital of Basel and currently a diabetologist in private practice there. He also aims for a higher HbA1c value in patients in whom absolutely no hypoglycemia is desired, for example, in elderly frail people in whom a fall could result in serious secondary diseases. In younger patients with a short duration of diabetes, however, he agrees on the lowest possible HbA1c target value – “Because with them, it’s obviously very important that they don’t get any microvascular sequelae.”
The basis of treatment in type 2 diabetes is still lifestyle modification. The ADA and EASD therapeutic recommendations are based on a meta-analysis of 140 head-to-head comparisons and 26 observational studies of diabetes monotherapy and combination therapies [5].
Most drugs and two-drug combinations reduce the target HbA1c by about 1% [6]. Metformin remains the first-line therapy for type 2 diabetes. If a second drug is required, the choice depends on the specific needs of the patient. One can choose between five different preparations. For example, should the patient lose weight, GLP-1 agonists or DPP-4 inhibitors can be used as add-on therapy. According to Dr. med Martin Füchtenbusch, these performed equally well in all studies. If one wants to pay attention to the costs, one should rather choose sulfonylureas as a second preparation, advises Prof. Keller. If a third drug is necessary, various combinations are available. If the patient has an HbA1c above 10-12% at diagnosis, insulin therapy is usually used first to improve glycemic control and then switched to oral antidiabetics.
Bariatric surgery improves diabetes, but long-term effects unclear
For extremely obese patients with poor glycemic control, bariatric surgery could be an option. Diabetes improved markedly in many: in a European study, two years after the start of the trial, more than 75% of patients who underwent surgery had remission, defined as an HbA1c level <6.5% or fasting glucose <100 mg/dl. In contrast, no remission was observed in any of the patients on standard therapy. In the US study, remission was defined as <6.0%; this was achieved by 12% of patients on standard therapy and over 36% of those who underwent surgery [7, 8]. However, Prof. Diem warns against exaggerated euphoria: “It is not yet clear whether patients remain cured of diabetes in the long term.” This is because in some cases the positive effect of the operation seems to disappear again [9, 10]. “In addition, we don’t yet know whether the surgery will have a long-term effect on cardiovascular events,” Prof. Diem said. It has also not yet been sufficiently investigated whether not only extremely obese but also “normally” overweight people benefit from bariatric surgery and what the benefit-risk ratio would be for adolescents or young adults.
New drugs with a different mechanism of action
Some new preparations could come onto the market in the coming years. These are, on the one hand, sodium glucose cotransporter-2 (SGLT2) inhibitors. With the help of SGLT2, 90% of the glucose is reabsorbed in the kidneys. SGLT2 inhibitors increase renal excretion of glucose, thereby decreasing blood glucose levels, independent of insulin levels [11]. However, the German Institute for Quality and Efficiency in Health Care (IQWiG) recently stated that, to date, an additional benefit of the SGLT2 inhibitor dapagliflozin, which is approved in the EU and the USA, has not been proven compared with the previous standard therapy [12]. Other SGLT2 inhibitors are still in earlier stages of clinical development [13]. Any new preparation must be convincingly better than the previous ones, says Prof. Keller. “It might work well for patients who absolutely don’t want to inject insulin or where you want to avoid hypoglycemia at all costs.” Other studies are looking at how SGLT-2 inhibitors work in type 1 diabetes. DPP4 inhibitors have so far shown only a moderate effect in type 1 diabetics [14]. Linagliptin, a new DPP-4 inhibitor, is eliminated by the kidney only to a small extent and dose adjustment in patients with renal insufficiency is not necessary [15].
New approaches via glucagon, glucokinase or interleukin-1.
Confusion is sometimes caused by the similar-sounding names GLP-1 analogs, glucagon receptor antagonists, and glucokinase activators. Newer GLP-1 analogs work longer than existing ones and need to be given only once per day or per week. People even try to implant them so that they work for months.
Glucagon receptor antagonists are not yet as well developed. In type 2 diabetics who already have elevated blood glucose due to insulin resistance, glucagon blockade may reduce hepatic glucose release and thus be of therapeutic benefit. Newer glucagon receptor antagonists are reported to have better pharmacokinetic properties than previous molecules [16]. “Within twelve weeks, the HbA1c value dropped by 1.5%,” reports Dr. Füchtenbusch from the Diabetes Research Group at Helmholtz Zentrum München. However, there would be two major problems: First, inhibition blocks hypoglycemic counterregulation. Second, the body needs the glucagon receptor for fat metabolism to bring fats into beta-oxidation. “In some cases, triglycerides and cholesterol rose enormously in the patients and they developed a fatty liver, so I am very skeptical,” is Dr. Füchtenbusch’s assessment.
Glucokinase activators increase the affinity of glucokinase for glucose. Thus, they stimulate the secretion of insulin and promote the uptake of glucose into the liver and the metabolism of sugar [17]. Other drugs are in even earlier stages of development [18]. For example, compound 264W94 blocks the apical sodium-dependent bile acid transporter (Asbt) in the intestine. Two weeks after oral therapy in rats, 264W94 increased bile acid excretion in feces and thus GLP-1 in blood. Both HbA1c and glucose levels decreased [19]. Another approach is anti-inflammatory interleukin-1 receptor antagonists. The disadvantage of the short half-life should be improved by fusion with recombinant human albumin [20].
Better insulin pumps and new insulins
Technological advances mean that insulin pumps for type 1 diabetes now operate with fewer errors than in the past and ensure better blood glucose control [21]. With the newer programmable pumps, you can calculate the amount of bolus insulin needed, have the basal rate programmed, or have the amount automatically adjusted for unusual situations such as illness or physical exertion. Nevertheless, some patients forget to apply their insulin bolus before eating, resulting in postprandial hyperglycemia [22]. Insulin patch pumps are small, self-adhesive devices on the skin that you fill with insulin and wear directly on your body. The device (Pod) administers bolus and basal insulin via a small cannula according to instructions programmed by the patient into a wireless companion device. The patch pump has the advantage that the cannula is inserted only once at a time. Various patch pumps are currently being developed, some of which can be controlled via cell phone.
There are also new preparations or application techniques for insulins. The ultra-long-acting insulin degludec (Tresiba®, approved in Japan) improved blood glucose similarly to insulin glargine with comparable insulin doses. It appears to cause nocturnal hypoglycemia somewhat less frequently. Whether this is also the case in daily use remains to be seen [23, 24]. A buccal insulin spray has been studied in recent years. However, often the results could not be replicated in others. Good randomized trials are lacking, and such a spray appears to be approved only in Ecuador to date [25]. Other scientists are trying to increase the absorption of short-acting insulin to make it work even faster. With the InsuPad, this is done by means of heat (38 or 39.5 °C). This is to increase blood flow and insulin is to be absorbed more quickly into the blood. The small studies to date showed that it lowered blood glucose faster than without the pad [26]. In addition, there are other techniques that make insulin act more rapidly, such as adding hyaluronidase to rapid-acting insulins or vitamin D to insulin aspart or pegylation [27].
On the way to the artificial pancreas
If diabetics measure blood glucose frequently, this can lower HbA1c levels [28–30]. The patient and physician can use it, for example, to detect phases of hypoglycemia and adjust the insulin dose. New devices for self-monitoring of blood glucose ( [SMBG]), which should measure more accurately, are currently being developed. In 2010, a study showed that eleven out of 27 devices did not provide sufficiently accurate measurement results [31]. Devices that continuously determine subcutaneous glucose concentrations (continuouse glucose monitors, [CGM]) constantly show the patient with type 1 diabetes his or her glucose levels. There are warning signals by which one can detect outliers of glucose concentration even in phases when the patient normally does not measure, for example during sleep. CGM allows the patient to see more directly the effect of lifestyle changes on blood glucose [32, 33]. CGMs can reduce periods of hypoglycemia as well as fluctuations in blood glucose [34]. Until now, CGMs have to be used in combination with SMBG to calibrate the measured values before a therapy decision is made. The current optimal blood glucose control and insulin supply is considered to be the combination of CGM with continuous insulin infusion via pump (continuous subcutaneous insulin infusion, [CSII]) [35].
Even better is a completely closed system, a so-called artificial pancreas. The patient wears two devices on the body: the sensor measures the glucose level, and the pump administers insulin. A computer – the artificial pancreas – calculates how much insulin is needed. The “closed loops” systems are tested in studies where the systems performed well [36, 37], but they are not yet used in practice. There are still some problems, says Prof. Diem. On the one hand, this would be the accuracy of the glucose measurement in the fatty tissue, and on the other hand, today’s insulins usually only take effect after 15-40 minutes, during which the blood glucose can already change again, Prof. Diem continued. Hyperglycemia caused by catheter occlusion or computer miscalculations could also be dangerous.
A vaccination for type 1 diabetics
Prof. Anette-Gabriele Ziegler, MD, Director of the Institute of Diabetes Research, Helmholtz Zentrum München, hopes to be able to protect babies at high risk for type 1 diabetes with a vaccination in a few years. In a study of older children who showed signs of an autoimmune response, disease progressed more slowly in vaccinated than in placebo vaccinated children [38, 39]. Currently, an additional study is being conducted with two- to seven-year-old children at high risk for diabetes [40]. “If, as we hope, the vaccination protects against diabetes, we want to vaccinate babies as a next step,” says Prof. Ziegler. “We know that the immune system is messed up many years before the onset of the disease, so we need to start very early with vaccination.”
For years, researchers have pursued two other approaches to treating type 1 diabetics. On the one hand, they try to transfer stem cells from which new insulin-producing beta cells are to develop, and on the other hand, pancreatic or beta cells from deceased persons are transplanted. “After the first studies, we were very euphoric,” recalls Prof. Diem. Now, however, it is known that the new stem cells can also be destroyed by diabetes. “And we don’t have the donors for the transplants,” says Prof. Diem. “We probably won’t know which of the three paths is best for another 10 to 20 years.”
Felicitas Witte, MD
Literature list at the publisher
HAUSARZT PRAXIS 2013; 8(6): 27-29
