Algorithm for the treatment of type 2 diabetes: a position statement of Brazilian Diabetes Society

The Brazilian Diabetes Society is starting an innovative project of quantitative assessment of medical arguments of and implementing a new way of elaborating SBD Position Statements. The final aim of this particular project is to propose a new Brazilian algorithm for the treatment of type 2 diabetes, based on the opinions of endocrinologists surveyed from a poll conducted on the Brazilian Diabetes Society website regarding the latest algorithm proposed by American Diabetes Association /European Association for the Study of Diabetes, published in January 2009. An additional source used, as a basis for the new algorithm, was to assess the acceptability of controversial arguments published in international literature, through a panel of renowned Brazilian specialists. Thirty controversial arguments in diabetes have been selected with their respective references, where each argument was assessed and scored according to its acceptability level and personal conviction of each member of the evaluation panel. This methodology was adapted using a similar approach to the one adopted in the recent position statement by the American College of Cardiology on coronary revascularization, of which not only cardiologists took part, but also specialists of other related areas.

Considering the great controversy raised by the recommendations at the recent ADA/EASD algorithm, the Brazilian Diabetes Society (BDS) decided to evaluate the opinions of its members, through a survey conducted on the BDS' website during ten days, in November 2008 [1,2]. Two hundred and seventeen associates (endocrinologists) completed this survey. Table 1 shows the percentages of answers to the proposed questions to BDS' associates.

General conclusions about the survey results
The results showed that the majority of the brazilian endocrinologists do not agree with the guidelines proposed by the ADA/EASD algorithm regarding the use of glitazone, GLP-1 analogs and DPP-IV inhibitors in the treatment of Type 2 Diabetes.
Considering the need for an algorithm reflecting the opinion of Brazilian endocrinologists, the Brazilian Dia-betes Society decided to develop this position statement, whose recommendations shall be dictated by the technical panel assessments, named by the entity and also by the results obtained from the survey.

Results of the controversial diabetes argument acceptability assessment
In addition to the feedback from associates obtained through the survey and in order to provide a more robust basis to the algorithm proposed for the treatment of type 2 diabetes, the Brazilian Diabetes Society obtained the opinions of a panel formed by renowned Brazilian specialists regarding recommendations, guidelines and controversial arguments on the treatment of type 2 diabetes in international literature.
The correlation between scores and their corresponding acceptability levels, as well as the analytical interpretation of results, are summarized in table 2. Table S1, Additional file 1 shows the relation between controversial matters assessed and their respective bibliographical references and the average level of acceptability for each controversial matter, following the calculation methodology as defined in the previous item.

Module 3
New SBD algorithm proposal for the treatment of type 2 diabetes

Laboratory goals for characterization of good glycemic control
The desirable goal for A1C, as defined by the previous position statement in 2007, recommended A1C levels < 6.5%. In this new Position Statement, the recommended A1C goal was redefined to <7.0% as shown in table 3. However, according to the ADA's 2010 statement, in patients with a history of severe hypoglycemia, patients with limited life expectancies, children, individuals with comorbidities, those with longstanding diabetes, advanced age and those with advanced microvascular or macrovascular complications" intensive glycemic control may outweigh its benefits. But for patients with short duration of diabetes, long life expectancy, and no significant CVD a level of A1c even lower than the general goal of <7%, has been suggested if this can be achieved without significant hypoglycemia or other adverse effects [3][4][5].
Regarding tolerable levels for laboratory goals, they were defined based on the recommendations contained in the bibliographical references [3][4][5].

New SBD algorithm proposal for treating type 2 diabetes
The new algorithm proposal for the treatment of type 2 diabetes was developed based on the premises and assessments conducted through the survey with SBD members and the assessment of conclusions from the panel of specialists ( Table 4). The presentation format of the new algorithm proposal was developed taking as fundamental reference the recommendations by the Joslin Diabetes Center & Joslin Clinic and also by the American Association of Clinical Endocrinologists [6][7][8][9].. The present algorithm was completed before the publication of the recent AACE/ACE algorithm [10]. As pointed out in the recent AACE algorithm safety, efficacy and effectiveness must be the priorities and in developing countries like Brazil cost of medications is an important barrier and could Influence the treatment.

Summary of therapeutic profile of drugs used for treating type 2 diabetes Comparative efficacy and potential of A1C reduction of different therapeutic interventions
The various therapeutic interventions present different levels of comparative efficacy and of potential of A1C reduction. Such facts must be taken into account when determining the best therapeutic strategy for each patient (table 5) [11,12].

Summary of therapeutic profiles of drugs used for treating type 2 diabetes
The main features of therapeutic profiles of drugs used for treating type 2 diabetes are summarized in table 6 [13,14].

Fixed combinations of oral antidiabetic drugs
Due to its convenience and comparatively lower prices, fixed-combination therapies for treating diabetes are being made available more frequently. There are many presentations of combined treatments, including two oral agents in the same package, however with separate pills (table 7) or a single pill containing both active agents in the same formulation (table 8).

Action profile of human insulin and human insulin analogs
Basically, there are three commercial presentation forms of insulin in the Brazilian marketplace: 1) human insulin in monotherapy; 2) human insulin analog in monotherapy; 3) biphasic human insulin analogs.
The addition of insulin to patients with type 2 diabetes must be done as soon as the patient did not reach the target of HbA1c [15]. No definitve conclusions regarding the association between insulin therapy with glargine [16] and malignancies were established. Table 9 summarizes the main features of the action profile of insulin preparations available.
Biphasic insulin analogs have a long-acting insulin component, in a formulation combined with a short-acting insulin component, as shown in table 10

Treatment cost estimate for various therapeutic options
The concept of Evidence-Based Medicine recognizes three main components to help physicians define therapeutic conduct: the evidence of research per se, the clinical expertise of physicians and patient preferences. Treatment cost must be one of the fundamental factors for patients to fulfill their right of choice in due proportion, in the concept of evidence-based medicine [17].
We added two website suggestions for physicians to obtain information about drug costs for consumers of the therapeutic options they intend to prescribe. In both references, prices are displayed in different rows expressing the costs of each drug, considering the incidence of distinct tax rates, which vary according to Brazilian states.    For the physician, the desired piece of information is the maximum retail price (MRP), which may be found in the last row to the right in price tables.

Links to browse drug prices
http://portal2.saude.gov.br/BPS/visao/consultapublica/ publico_interno_item.cfm [18] Using the internal resource of research to obtain the desired price http://www.elomedico.com.br [19] Requires previous and free subscription. Search for item "drugs/prices" on the left row in the homepage   Metformin (Glifage®, others) Reduces primarily the hepatic glucose production and fights insulin resistance. High potential of A1C reduction (2%). Gastrointestinal intolerance. Does not cause hypoglycemia. May promote mild weight loss. Contraindicated in case of renal dysfunction.

Glitazones -Rosiglitazone (Avandia®) -Pioglitazone (Actos®)
Primarily fight insulin resistance and reduces hepatic glucose production. Increases muscle, fatty tissue and liver sensitivity to insulin. Intermediate A1C reduction potential (0.5 -1.4%). Promote hydric retention and weight gain, increasing the risk of heart failure. Also increase the risk of fracture. Recent results of studies such as RECORD and BARI 2D indicate that rosiglitazone does not increase the risk of infarction and CVD.
Incretin mimetics and DPP-4 inhibitors -Exenatide (Byetta®) -Vildagliptin (Galvus®) -Sitagliptin (Januvia®) This is a new therapeutic class for treating diabetes, whose mechanism includes stimulating beta cells to increase insulin synthesis and action on pancreatic alpha cells, reducing glucagon production. Glucagon has the effect of increasing glycemic levels. Average potential of A1C reduction (0.5 -0.8%, depending on the basal A1C value). Do not cause hypoglycemia but gastrointestinal intolerance and pancreatitis have been described (exenatide and sitaglipitn) [13,14].
This table represents only a partial relation of commercial medications of various drugs and does not represent a specific recommendation of any commercial brand.