Insufficient evidence of benefit for colesevelam in glycemic control in type 2 diabetes

Insufficient evidence of benefit for colesevelam in glycemic control in type 2 diabetes

General information: what is glycemia in diabetes

Type 2 diabetes is characterized by a constant deterioration of beta cell function, so treatment should be dynamic, involving a gradual increase in drug intervention as the disease progresses.Ideally, the blood glucose level should be maintained within the limits close to normal: before meals, blood glucose is 5-7 mmol/l and glycated hemoglobin (HbA1c) is less than 7 %. However, exclusively hypoglycemic therapy does not provide adequate treatment for patients with type 2 diabetes. It is necessary to monitor the level of lipids and blood pressure.

Aggressive glucose reduction is not the best strategy for a wide range of patients. For example, in patients with a high risk of cardiovascular disease, lowering HbA1c levels to 6 % or lower may increase the risk of cardiovascular disaster.

Type 2 diabetes therapy should be based on individual risk stratification. Research by a team of scientists led by Frida Morrison, published in Archives of Internal Medicine, 2011, showed that patients who visit an endocrinologist every two weeks, blood glucose, HbAc1 and LDL levels fall faster and are better controlled than patients who visit a doctor once a month or less. A significant contribution to the success of treatment is made by the patient himself, following a diet and following lifestyle recommendations.

Pharmacotherapy of type 2 diabetes

Early initiation of type 2 diabetes pharmacotherapy improves glycemic control and reduces the likelihood of long-term complications.As for the question of how to treat type 2 diabetes and what specific medications to use, everything will depend on the chosen treatment regimen.
Type 2 diabetes mellitus (type 2 diabetes mellitus) is characterized by hyperglycemia, which develops due to a combination of disorders, including:

  • tissue insulin resistance;
  • insufficient insulin secretion;
  • excessive or inadequate glucagon secretion.

Poorly controlled type 2 diabetes is associated with microvascular, neuropathic complications. The main goal of therapy for patients with type 2 diabetes is to eliminate symptoms and prevent or at least prolong the development of complications.

The drug of choice for monotherapy, as well as the leading drug of combined treatment for type 2 diabetes, is Metformin. Its advantages include:

  • efficiency;
  • the lack of weight gain;
  • low probability of hypoglycemia;
  • low level of side effects;
  • good tolerability;
  • low cost.

The dose of Metformin is titrated for 1-2 months, determining the most effective method of selection. The therapeutically active dosage is at least 2000 mg of Metformin per day. To reduce the risk of side effects from the gastrointestinal tract, the drug is taken during or after meals several times a day.

Metformin reduces the risk of developing dementia associated with type 2 diabetes. This was proven in a large-scale 2013 study involving 14,891 patients, divided into four groups depending on which drug they took. Throughout the experiment, patients received monotherapy with Metformin, sulfonylureas, thiazolidinediones, and insulins. Within five years of starting Metformin treatment, dementia was diagnosed in 1,487 (9 %) patients. This is 20 % lower than in the sulfonylurea group and 23 % lower than in the thiazolidinedione group (data from Colayco DC, et al., diabetes Saget journal, 2011).

Two-component treatment regimen

If during 2-3 months of Metformin monotherapy it was not possible to achieve a stable decrease in blood glucose levels, another drug should be added. The choice should be based on the individual characteristics of the patient. According to the recommendations of the American Association of clinical endocrinologists, published in the journal Endocrine Practice in 2009, it is better to give preference to:

DPP-4 inhibitors – when glucose levels rise both on an empty stomach and after eating;
GPP-1 receptor agonists — with a significant increase in blood glucose after eating;
thiazolidinediones — in the treatment of patients with metabolic syndrome and / or non-alcoholic fatty hepatosis.

Withdrawal of oral medications and insulin monotherapy for type 2 diabetes is associated with weight gain and hypoglycemia, while combined treatment reduces these risks.

If two-component therapy is ineffective, another third hypoglycemic drug is added within 2-3 months. This can be:

  • an oral drug that belongs to a different class of hypoglycemic agents than the first two components of the treatment regimen;
  • insulin;
  • injectable exenatide.

Drugs of the thiazolidinedione group are not recommended as a third means of the scheme. Thus, the data of the American Association of endocrinologists indicate an increased risk of myocardial infarction in patients taking rosiglitazone. Therefore, it is recommended to prescribe only to those patients who are unable to control glucose levels with other medications.

In patients at high risk of cardiovascular disease, lowering HbA1c levels to 6 % or lower may increase the risk of cardiovascular disaster. For example, a study of a group of 44,628 patients conducted by American scientists led by Danielle C. Colayco showed that patients with HbA1c levels less than 6% had cardiovascular problems 20 % more often than patients with an average HbA1c level of 6-8 %.
Published in the journal Diabetes Care, 2011

An experiment conducted by the ACCORD (Action to Control Cardiovascular Risk in Diabetes) research group showed that a drop in HbAc1 levels below 6 % in patients at risk led to an increase in five-year mortality from myocardial infarction.

Data from researchers led by Gerstein HC, published in the new England journal of medicine, 2011

In relation to another well — known thiazolidinedione-pioglitazone – there was also alarming information about an increased risk of developing bladder cancer while taking it. The American Association for drug control FDA does not recommend prescribing pioglitazone to patients with a history of bladder cancer.

GPP1-receptor agonists have a different mechanism of action from other hypoglycemic drugs. They mimic endogenous incretin HPP-1 and thus stimulate glucose-dependent insulin release. In addition, GPP1 receptor agonists help reduce glucagon levels.

The combination of exenatide-the most famous drug of this group-with one or two oral (for example, Metformin and / or sulfonylureas) attracts with its simplicity and high efficiency.
Insulin as a Supplement

Many patients with type 2 diabetes who cannot be controlled with oral hypoglycemic medications need insulin therapy. The combination of oral medications that lower sugar and insulin in type 2 diabetes effectively reduces blood glucose levels.

To oral hypoglycemic agents, it is advisable to add a single morning injection of insulin of medium or long duration. This approach can provide better glycemic control with smaller doses of insulin.

A group of British scientists led by Nicholas a Wright (Nicholas a Wright) in a six-year randomized study proved that the abolition of oral medications and insulin monotherapy for type 2 diabetes is associated with the likelihood of weight gain and hypoglycemia, while combined treatment reduces these risks. The experimental data was published in Internal Medicine in 1998.

Insulin can be used in individuals with severe hyperglycemia, as well as temporarily prescribed during General illness, pregnancy, stress, medical procedure or surgery. With the progression of type 2 diabetes, the need for insulin increases and may require additional doses of basal insulin (medium and long-term duration of action), as well as the introduction of bolus insulin (short or fast action).

When deciding with which oral hypoglycemic agents it is better to combine insulin, you should follow the General principles of building a multi-component treatment regimen for type 2 diabetes. It is known, for example, that the addition of insulin before bedtime during treatment with Metformin leads to weight gain twice as often as combined treatment with insulin and sulfonylureas or double insulin monotherapy (data from H. Yki-Järvinen L. Ryysy K. Nikkilä, Internal Medicine, 1999).

Against the background of treatment with bolus insulin, it is necessary to cancel oral medications that increase insulin secretion (sulfonylureas and meglitinides). At the same time, Metformin therapy should be continued.

Douglas Badenoch
I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I've been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it.. Ha! Hence The National Elf service.

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