In previous articles, we began to talk about the principles of treatment for type 2 diabetes mellitus (DM). In this article, we continue the discussion of drugs that are used in the treatment of this disease. Thiazolidinediones
Thiazolidinediones reduce insulin resistance in adipose, muscle tissue and the liver, increasing the level of transcription of insulin-sensitive genes in the cells of these tissues. Advantages: thiazolidinediones control blood sugar and reduce HbA 1c hemoglobin by about 1%. Clinical studies have shown that thiazolidinediones practically do not differ in effectiveness from sulfonylureas, however, they maintain the level of hemoglobin HbA 1c at the level of 17.19.
Side effects: in rare cases, the toxic effect of thiazolidinediones on the liver is noted. It is necessary to control the levels of liver enzymes before taking these drugs and periodically during treatment. Taking thiazolidinediones can cause swelling and anemia.
The results of a comparative study of ADOPT, which compared the effect of a number of drugs on the progression of type 2 diabetes and its outcome, demonstrate that taking thiazolidinediones causes a greater weight gain than taking sulfonylureas. In this case, the peripheral rather than the central type of fat deposition prevails. Patients should be warned that when taking thiazolidinediones, they should expect weight gain, despite the efforts to reduce it, which they will make in accordance with the general recommendations for diabetes control.
In 2007, in a meta-analysis of studies on the effect of rosiglitazone on the occurrence of myocardial infarction, it was concluded that taking this drug increases the risk of developing this disease by 43%. In 2009, the RECORD study showed that taking rosiglitazone increases the risk of heart failure and fractures (mainly in women) 20 .
In September 2010, the European Medicines Agency recommended suspending permission to sell rosiglitazone, as recent studies and accumulated data have confirmed that it increases the risk of developing cardiovascular disease (CVD) 21 . In July 2011, the same agency recommended that rosiglitazone not be prescribed to patients with bladder cancer or macroscopic hematuria (blood in the urine) with an unclear history of etiology. Considering the fact that some risk factors are related to age, the benefit / risk ratio should be carefully analyzed before prescribing such drugs to elderly patients and during treatment 22 .
Thiazolidinediones are contraindicated in patients with a history of heart failure, as well as with an increased risk of fractures.
Possible benefits for patients
In the 6th version of the clinical guidelines for the treatment of type 2 diabetes mellitus of the National Institute of Health and Improvement of Medical Services of Great Britain (NICE), thiazolidinediones are recommended in the following situations:
- As a second-line therapy with inadequate glycemic control (maintaining hemoglobin HbA 1c at a level of ≥6.5% or at a different, higher level as agreed with the patient) and with a significant risk of developing hypoglycemia or its consequences (for example, in older patients or representatives of certain professions (such as working at height or with heavy equipment), as well as for treating patients in certain social conditions (for example, single and self-serving).
- As a third-line therapy (when prescribing drugs containing metformin as a first-line drug and sulfonylurea derivatives as second-line drugs), if it is not possible to provide adequate glycemic control (maintaining hemoglobin HbA 1c at a level of ≥ 7.5% or at another , at a higher level as agreed with the patient) and if the patient cannot be prescribed insulin.
- Thiazolidinediones can be prescribed in combination with insulin therapy if the patient has previously experienced a marked decrease in blood glucose in response to treatment with thiazolidinediones, or if the patient receives high doses of insulin, but cannot achieve effective glycemic control.
Achievements in the field of drug treatment
In recent years, there have been several advances in the medical treatment of type 2 diabetes. New drugs available to patients include:
- dipeptidyl peptidase-4 inhibitors (DPP-4);
- glucagon-like peptide-1 analogues (GLP-1);
- insulin glargine and insulin detemir.
Glucagon-like peptide-1 analogues (GLP-1)
Analogues of glucagon-like peptide-1 (GLP-1) have a therapeutic effect due to the incretin effect. The hormones of incretin were first discovered when it turned out that when glucose was ingested, there was a more pronounced stimulation of insulin production than when the same level of glucose was achieved after its intravenous administration.
Glucagon-like peptide-1 is produced in the ileum in response to food intake. It has the following effects on various organs and cells of the body:
- pancreatic beta cells – increases glucose-dependent insulin secretion;
- stomach – helps to slow the emptying of the stomach;
- liver – reduces the level of glucagon, which, in turn, reduces the release of glucose by the liver;
- alpha cells – reduces the secretion of glucagon after eating.
- Promotes a feeling of fullness and reduces appetite.
Advantages: drugs reduce the level of HbA 1c hemoglobin by about 1% in 6 months and provide effective weight loss – a maximum of 5% for the same period 23 .
Side effects: against the background of treatment with GLP-1 analogues, dose-dependent, short-term adverse events such as nausea and vomiting are most often observed . After appropriate consultations with patients before treatment, with the withdrawal of the drug, nausea usually does not occur. Over time, the severity of symptoms decreases in almost all patients.
There is evidence to suggest that therapy with GLP-1 analogues may increase the risk of developing pancreatitis. When treating patients at risk of developing pancreatitis (gallstones, alcoholism, hypertriglyceridemia), these drugs should be prescribed only if the possible benefits of the therapy outweigh the potential risk.
Possible benefits for patients
The NICE Institute recommends the use of glucagon-like peptide-1 analogues as a third-line therapy as an addition to drugs containing metformin (first-line therapy) and one of the sulfonylureas (second-line therapy) with inadequate glycemic control (maintaining hemoglobin HbA 1c at a level of ≥7 , 5% or at a different, higher level, as agreed with the patient) if the following conditions exist:
- With a body mass index (BMI) of ≥35.0 in patients of European descent (adjustments are needed for representatives of other ethnic groups) and the presence of specific psychological or medical problems associated with obesity.
According to the NICE recommendations, it is worthwhile to continue therapy with these drugs for more than 6 months only if the patient has a positive metabolic reaction (decrease in HbA 1c hemoglobin level by at least 1.0 percentage point and weight loss of at least 3% of the initial value).
When a positive reaction to glucagon-like peptide-1 analogues is achieved , a dose reduction of other oral preparations may be required in order to reduce the risk of hypoglycemia. At the moment, there is no data on the safety of long-term administration of GLP-1 analogues.
Dipeptidyl Peptidase-4 Inhibitors (DPP-4)
Another way to increase insulin secretion by the pancreas through the incretin system is to block the activity of the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors bind to individual regions of the active center of the dipeptidyl peptidase-4 enzyme and thereby prevent its binding to glucagon-like peptide-1 (GLP-1), which leads to the breakdown of this peptide hormone. As a result, the level of GLP-1 rises.
Advantages: DPP-4 inhibitors have been shown to reduce HbA 1c hemoglobin levels by 0.6–1.1%. These drugs have a glucose-dependent effect, and the risk of developing hypoglycemia when taking them is lower than when taking other oral drugs.
Side effects: DPP-4 inhibitors are usually well tolerated by patients and, very importantly, do not cause weight gain.
Possible benefits for patients
One of the DPP-4 inhibitors can be prescribed as a second or third line therapy in addition to a sulfonylurea preparation or preparations containing metformin with insufficient glycemic control (maintaining hemoglobin HbA 1c at a level of ≥6.5% or at another, higher level as agreed with the patient) if:
- the patient is at significant risk of developing hypoglycemia or its consequences;
- further weight gain will result or increase serious problems associated with obesity;
- it is impossible to provide adequate glycemic control (maintaining hemoglobin HbA 1c at a level of ≥7.5% or at a different, higher level as agreed with the patient), and the patient cannot be prescribed insulin.