According to the algorithms of the American Diabetes Association / European Association for the Study of Diabetes and the International Diabetes Federation (Fig. 1), the choice of glucose-lowering therapy depends on the current and target level of glycated hemoglobin (HbA1c). Starting treatment of type 2 diabetes usually includes a recommendation on lifestyle changes (as close as possible to the so-called “healthy”) and taking metformin. In case of failure of prescribed therapy, tablets of glucose-lowering drugs (TSSP) are combined and injections of GLP-1 analogue / mimetic or insulin, usually of prolonged action, can also be added. Within the framework of this algorithm, sulfonylurea derivatives (PSM) of the second generation are preferable to the first generation, due to the lower risk of hypoglycemia.
The long-acting sulfonylurea derivatives of the first generation, such as chlorpropamide, often caused hypoglycemia and other side effects, including fluid retention, hyponatremia, and their effectiveness changed unpredictably when combined with various drugs and alcohol. Second-generation PSM — gliclazide, glipizide, glibenclamide, and glimepiride (third-generation PSM), on the contrary, are usually safer and less likely to cause hypoglycemia. For example, in a study comparing glipizide with PSM of the first generation, hypoglycemia during treatment with glipizide was 23% less common.
International Recommendations for the selection of glucose-lowering therapy in patients with type 2 diabetes.
As mentioned earlier, T2DM develops because increased insulin secretion is not able to compensate for insulin resistance (relative insulin deficiency). In this regard, the goal of treating diabetes is, on the one hand, a decrease in insulin resistance so that persistent insulin secretion can compensate for it, and on the other hand, it is necessary to somehow stimulate or restore depleted insulin secretion. Note that the stimulation of secretion does not imply the restoration (normalization) of the function of beta cells, but on the contrary, it may be accelerated in the background of stimulation, which will be discussed below.
The constantly expanding range of glucose-lowering drugs for the treatment of T2DM complicates the algorithm for selecting the optimal drug therapy, at the same time certain basic principles remain unchanged. First of all, treatment begins with an attempt to reduce insulin resistance, which the recommendation recommends in the algorithm is “modification of lifestyle”, which implies a decrease in body weight in people with obesity and an increase in physical activity, which, as is known, increases insulin sensitivity. In addition, from the moment of detection of diabetes mellitus, it is recommended to prescribe treatment with metformin, the main mechanism of action of which is to increase the sensitivity of the liver to insulin action. Assign a minimum dose of metformin, if necessary, gradually increasing to the maximum within 1-2 months.
Such a rather aggressive drug therapy for the first time revealed T2D differs significantly from the previous recommendation of trying first to limit oneself to a “change in lifestyle”. It is justified by the identified positive effects of metformin in the treatment of early disorders of carbohydrate metabolism (impaired fasting glucose and impaired glucose tolerance), which was shown in our studies (see above). However, not all patients tolerate metformin well, in addition, it has a whole range of contraindications that are not uncommon in an elderly patient with type 2 diabetes. Attempting to prescribe metformin to the maximum possible number of patients with diabetes mellitus can undermine the local health budget in cases of limited resources, since in Russia they provide free diabetes medication with diabetes patients. In this regard, a number of Russian and foreign diabetologists offer a more restrained approach to treatment with metformin, which I share and which consists of the following. If, for the first time diagnosed with T2DM, the squamous glycemia is <8 mmol / l and A1c <10%, then we can restrict ourselves to the appointment of “lifestyle changes”. And only if, after 3-4 months of diet therapy and the expansion of physical activity, A1c will not become less than 7%, then metformin is added to the treatment. Otherwise, treatment of type 2 diabetes without hypoglycemic drugs continues, but against the background of regular, once every three months, control of the A1c level.
From the foregoing it is clear that the second cardinal component of the treatment algorithm for T2DM is the A1c level, which in this connection becomes a routine (!) Method of research. Unfortunately, in Russia, the introduction into clinical practice of this method is still difficult because of its high cost. However, without it, the modern practice of treating diabetes is virtually impossible.
The borderline A1c level of 7% was chosen because a number of studies showed a significant increase in the risk of developing diabetes complications at A1c level ≥ 7%. Attempts to introduce more ambitious treatment goals – A1C <6.5% or even <6% – into crash therapy practice have failed: in some studies where such goals were set, the risk of cardiovascular death increased. The reasons for this are not yet fully disclosed.
Medicinal treatment of type 2 diabetes is divided into two levels:
- Traditional drug therapy, tested by long practice and relatively inexpensive, the basis of which are metformin, sulfonamides and insulin.
- Treatment, which includes recently entered the market of pharmaceutical drugs with a short period of introduction into wide clinical practice and, due to restrictions in the production of generics, expensive.
If treatment with metformin, aimed at reducing insulin resistance, is ineffective (A1c <7%), then with the traditional approach two different treatment options are possible, aimed at overcoming the threshold of insulin resistance by increasing the blood insulin concentration (step 2 in Fig. 5.7): 1 ) the appointment of sulfonamides or glinides (interacting with sulfanilamide receptors of beta cells) to stimulate insulin secretion to a level above the insulin resistance threshold; 2) the appointment of basal insulin (NPH, Lantus, Levemir) to increase the concentration of exogenous insulin in the blood above the threshold of insulin resistance. At the same time, metformin is not canceled, since it did not reduce insulin resistance to the level that provides the goal of treatment (A1c <7%), but it is assumed that it still increased insulin sensitivity, and this, in turn, reduces the required increase in concentration insulin in the blood by sulfonamides or exogenous insulin.
Treatment with metformin in combination with sulfonamides is the cheapest, but hypoglycemic reactions and weight gain are often observed against it. Level A1c on this combination can be reduced by 1%.
Treatment with glinides is especially effective in case of hyperplycaemia, but drugs of this class have a weak sugar-lowering effect, and they are only effective as starting therapy with drugs that interact with sulfanilamide receptors, for example, with isolated high postprandial hyperglycemia. The A1c level when joining glinides to metformin decreases by 0.4-1%. Unfortunately, a common mistake remains the appointment of a combination of sulfonamides with glinides, which, although not sulfonamides, interfere with their action by competing for binding to a common sulfanilamide receptor on a beta cell. So, a patient with type 2 diabetes can receive either only sulfonamides, or only glinides, but not a combination of these drugs!
