Сахарный диабет 2 типа: время изменить концепцию

«The most entrenched conflict of interest in medicine is a disinclination to reverse a previous opinion»

John S Yudkin.

is quite surprising, but more than a century after type 2 diabetes mellitus (T2DM) had been identified and the first treatment modalities were tried, this disease remains not only one of the biggest problems in the world, but its "epidemic" has now become a "pandemic". The paradox is obvious: on the one hand, governments and the «Big Pharma» spend billions of dollars each year on the «anti-diabetic war», on the other hand, diabetes becomes stronger, younger and continues its quick-paced spread throughout the world [1].

Given the traditional point of view which characterizes the disease as a progressive, incurable condition, one may understand the frustration health care providers (HCPs) and patients feel without being able to see the «light at the end of a tunnel». Nowadays, the notion that something might be wrong with our understanding of T2DM, grows stronger and stronger. Otherwise, why aren't we succeeding? Multiple studies, especially the recent ones (ACCORD; ADVANCE; VADT), convince us that the whole concept of type 2 diabetes doesn't work: none of these studies has found a significant benefit in aggressive glucose lowering, in terms of cardiovascular (CV) events, although there was a reduction in microvascular complications [2–5].

Moreover, recent comprehensive meta-analysis [6] persuasively proved that: intensive HbA1c lowering did not show significant differences for all-cause mortality and cardiovascular mortality when compared with conventional glycaemic control. Targeting intensive glycaemic control reduced the risk of microvascular complications while increasing the risk of hypoglycaemia.

The question remains: is there an alternative way of understanding and treating this highly complicated syndrome we call «Type 2 diabetes»?

A history

The second half of the 20th century was undoubtedly a «historical» period for Diabetology. It's remarkable, but over a century ago, the only treatment of T2DM was prolonged fasting (i.e., calorie influx restriction) combined with consumption of pure alcohol (i.e., stopping gluconeogenesis). This may sound amusing, but perhaps the physicians of the past had a far better understanding of the T2DM pathogenesis than we have today.

Type 1 diabetes mellitus 

It seems almost unbelievable to the modern generation of HCPs, but until 1993, when the DCCT study was first published [7], there was no consensus regarding the benefits of intensive treatment of type 1 DM. In many countries, including Europe and USA, endocrinologists didn’t believe there were any benefits to intensive treatment and accordingly, didn’t make the efforts to strictly control their type 1 patients. Interestingly enough, it was the Russian (Soviet) school of endocrinology [8] who pioneered a concept of strict diabetes control in type 1 diabetes persons.

Type 2 diabetes mellitus

The euphoria of victory that came with the glucocentric theory («beat the sugar and save the patient») and tight glycemic control in T1DM was soon extrapolated on T2DM. However, the UKPDS study, published in 1996, had demonstrated little more than modest achievements: in spite of significant reduction in microvascular complications, no significant improvement in macrovascular endpoints was observed in the group with well-controlled diabetes. [9]. UKPDS and other studies, conducted in the late 20th century, suggest that direct extrapolation of rules implicated in T1DM management to the treatment of T2DM is incorrect. Nonetheless, during the next 10 years, most opinion-leaders in the field of Diabetology continued to insist on «intensification» of therapy in T2DM. It is quite difficult to understand the underlying motivation of those leaders, many of whom continue this «intensification» mantra to this day. Their obstinacy became almost «religious» (J. Yudkin), going against a growing body of evidence regarding the virtual bankruptcy of this «Intensification theory» [10].

Type 2 diabetes: myths and reality

Cardiovascular disease remains the main cause of the higher mortality in T2DM patients, but it is yet unknown whether intensive glycaemic control is superior to conventional glycaemic control for reducing mortality and cardiovascular disease in patients with T2DM [6, 11].

Nowadays we can observe a true revolution in terms of diabetes management and understanding of the underlying processes in its pathogenesis. This comprises three main events that «changed the diabetes world»:

• Development of incretin–based therapies;
• Implementation of CGM-systems;
• Advancement of bariatric surgery.

However, when one looks at the «Position Statement», one might think that time had stopped, for many of the points are not definite and very little is essentially new [12]. 

There is a feeling that authors try to slowly ward off the glucocentric theory and substitute it with some «Patient-centered» concept. «After Metformin, there are limited data to guide us»– is this an actual position statement meant to guide the endocrinologists of the 21th century? Yet another citation from this paper reads the following: «Combination therapy with additional 1–2 oral or injectable agents is reasonable, aiming to minimize side effects where possible». What should HCPs conclude from such a «guideline»? 

So, let us analyze the main myths about T2DM.

THE FIRST MYTH: «We should fit our therapies to the patient's needs»

According to EASD Position Statement, «Ideally, a treatment program should be designed specifically for an individual patient, to match the supply of insulin to his or her dietary/exercise habits and prevailing glucose trends, as revealed through self-monitoring. Anticipated glucose lowering effects should be balanced with the convenience of the regimen».

But the problem is that most T2DM patients suffer from diabetes specifically because of their inadequate eating habits and lack of physical exercise. So, would it be wise to fit the therapies – and insulin in particular – to such an unhealthy lifestyle?

«Shared decision making with the patient may help in the selection of therapeutic options»– this is written in the Position Statement, 2012. Unfortunately, patient-derived information is not always complete and may even misguide a clinician [13].

So, what unbiased data do we have? HbA1c is a surrogate marker, incapable of reflecting what really happens with the patient right now. Unfortunately, self-monitoring is hardly a reliable source as well, for many of our patients wouldn't adhere to the recommended SMBG algorithm or might even present us with deliberately misleading results [14]. Obviously, decisions made without objective information, are mostly wrong. They will remain so, or may even become worse, should we allow patients to actively affect them.

THE REALITY

Many of T2DM patients don't know (while some do not even want to know) what they really need. UKPDS proved the importance of therapeutic training with evidence from a conventional treatment group, which failed to control their diabetes. Undoubtedly, we should fit the therapies to the patient’s eating/exercise habits in T1DM. Regarding T2DM however, the facts are diametrically opposed.

In summary: by allowing the T2DM patients to intervene in making clinical decisions, we risk pushing them into a vicious cycle of overtreatment due to the progressing consequences of their inadequate lifestyle, where iatrogenic complications may be severe or even fatal (ACCORD study is an appropriate example) [5].

THE SECOND MYTH: «Diabetes is a progressive incurable disease»

Evidence, which continues to grow nowadays, tells us that it is not the full truth. The truth is that this process is in fact reversible. It is especially interesting, that the reversibility, theoretically and practically, may occur at any stage of the disease. For instance, if we put our glucotoxic patient on a short-term intensive insulin therapy, we provide the β-cell with «rest», raising the probability of rehabilitating the β-cell function, which would result in a remission of diabetes. If we start GLP-1 analogues and the patient normalizes his body mass, then, remission of diabetes may be achieved, or, at the very least, the patient will be able to reverse his insulin dependency (we may call it the «insulin-weaning effect» of GLP-1 analogues).

Furthermore, if our T2DM patient undergoes bariatric surgery, the effect would likely be an 80% cure of diabetes. In other words: T2DM is not only a «slowly progressive», but is also a «rapidly regressive» disease – the outcome ultimately depends on how we manage diabetes. Indeed, we may prescribe the patient some secretagogue which would result in β-cell apoptosis and exhaustion combined with weight gain, thus, converting his diabetes into an «incurable and insulin dependent» disease. Alternatively, we may choose one of the modern approaches, thus protecting his pancreas and restoring his glucose tolerance.

Progressive decline of β-cell function in the UKPDS

In 1995, results of a 6 year-old follow-up study in the UK Prospective Diabetes Study were reported. Although the patients who received intensive treatment maintained significantly better glycemic control, all groups showed progressive hyperglycemia over the 6 years of the study, with associated decrease in β -cell function (Fig. 1).

Insulin secretion deteriorated in patients who were allocated to and remained on a diet therapy, with a significant decrease from 1 to 6 years (53% to 26%; p <0.0001). Those on sulfonylurea therapy displayed an increase in β-cell function during the first year of therapy (46% to 78%) which subsequently significantly decreased to 52% (p < .0001) by year 6. Patients who were allocated to Metformin therapy also had an increase in β-cell function in the first year which deteriorated after the 6th year (66% to 38%), and was similar to that seen in patients treated with diet alone [15]. 

Potential for improvement of β-cell function

One of the potential benefits of treatment with incretin agonists is the capability of these agents to affect β-cell function and probably mass. For example, evidence from mice model studies supports the stimulating effect GLP-1 analogues have on β-cells [16].

By now GLP-1 effects on glucose homeostasis in humans is well studied (fig. 2) [17-20]. GLP-1 is secreted by the L‑cells in the small intestine after a meal [17-20], decreasing the functional load of the β-cell while improving their response on glucose stimulation [17, 19]. GLP-1 reduces insulin resistance (and, therefore, β-cell workload):

• Regulates the rate of gastric emptying so that nutrients from the meal are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, thus reducing the glycemic peak [17, 19];
• Decreases postprandial glucagon secretion from pancreatic α-cells, which helps maintain the regulatory balance between insulin and glucagon [20];
• While reducing postprandial glucagon secretion, GLP-1 has an indirect beneficial effect on beta-cell workload, due to decrease in postprandial hepatic glucose output [20];
• Influences the central nervous system, resulting in increased satiety and consequentially in a reduction of overall food intake [18].

THE REALITY

In many patients with T2DM, progressive obesity has an iatrogenic nature. Thereupon, nowadays T2DM is not a «one-way ticket». Our patients have the right to be informed that T2DM can not only be a «slowly progressing», but also a «rapidly regressive» disease.

Remission of diabetes

Induction of T2DM remission is the primary goal of modern Diabetology; a number of scientific groups have made progress on this ground. For example, a study, published by an Israeli team, showed that short-term insulin pump therapy was able to induce remission in 9 out of a total of 13 (69.2%) patients with newly diagnosed T2DM, thus fully restoring glycemic parameters [21]. Normoglycemia was obtained within a few days with an insulin dose of 0.6+/-0.06 U/kg/24H and maintained for 9 to > 50 months (median +/- SE, 26 +/- 4.8 months) on diet alone. Body weight remained unchanged in all patients. 4 (30.8%) patients were considered therapeutic failures in this study. In summary, this pilot study suggests that short-term intensive insulin pump therapy has potential to induce remission in newly diagnosed T2DM patients, who failed to respond to dietary measures.

THIRD MYTH: «Intensification of therapy is necessary if the patient doesn’t meet the criteria for good glycemic control» – anent the polypharmacy 

According to the EASD Position Statement, after Metformin: «Combination therapy with an additional 1–2 oral or injectable agents is reasonable, aiming to minimize side effects where possible» [22]. Following such guidelines, HCPs are forced to prescribe an array of drugs in stark contradiction to the principle of minimizing adverse drug interactions.

A telling illustration to the prominence of the polypharmacy problem is the report, published by the Department of Anthropology at Michigan State University [23]. Researchers analyzed the management of patients with T2DM and hypertension in 44 primary care centers in Michigan during 2009 and 2010. They conducted interviews with 58 physicians, nurse practitioners, and physician assistants, observed 107 clinical consultations with 12 clinicians in 6 clinics, and interviewed 70 patients treated by those 12 clinicians. 

Out of the total of 70 patients, 62 (89%) said they took multiple medications, while 36 (51%) were taking 5 or more medications, a threshold commonly used to define polypharmacy. Such medication use reflects a world-wide trend of prescription, where drug use in US alone has increased 6-fold since 1990. Adverse drug reactions reported by the Food and Drug Administration tripled between 1995 and 2005. In addition, lower diagnostic guideline criteria introduced over the years have resulted in an increase in the number of people diagnosed with and being treated for chronic diseases such as diabetes, hypertension, and even prediabetes.

A quote from a family practice physician illustrates this phenomenon: «I tell most new diabetics that the sad news is that they’re going to be on 5 meds…. That’s just what’s going to happen because their cholesterol parameters are lower and their blood pressure parameters are lower…» [23].

To help doctors plow through the muck and find the balance between effective treatment of a chronic disease and the risks of polypharmacy, Dr. John S. Yudkin, emeritus professor of medicine at University College, London wrote 10 Commandments for his colleagues. The following is one of the rules: «Thou shalt exercise caution when adding drugs to existing polypharmacy. It’s generally a bad idea to give a patient another drug when a patient is already on a drug. Doing so increases the risk of bad interactions between the drugs. It also increases patient confusion, thereby again increasing risk. So adding one drug doesn’t just introduce the risks named on the pamphlet you get with that drug, because the body is a complex machine, drug interactions are poorly understood, and humans on lots of drugs make mistakes in the use of those drugs».

FOURTH MYTH: «Weight gain is a by-product of therapy»

Role of obesity in type 2 diabetes mellitus

Obesity rates among U.S. adults have more than doubled since 1980, when they were about 15%. At that same time, they have more than tripled among children. Obesity is the satellite of poverty: one-third of adults who earn less than $15,000 per year are obese, compared to one-quarter of those who earned $50,000 or more per year. The correlation between national obesity and national diabetes epidemic is obvious [24].

Obesity is clearly becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Healthcare service use and medical costs associated with obesity and related diseases have increased dramatically and are expected to continue to rise. A variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence upon such risk factors as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state. On the whole, excessive weight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death, because of their impact on the cardiovascular system. 

It is not surprising that the American Heart Association has identified obesity as an independent risk factor. This action should heighten physician awareness about the importance of obesity and stimulate a more vigorous approach to its prevention and treatment [25–27].

Obesity determines the development of insulin resistance. Pathogenetic relationship between these two pathologic entities is detailed in Fig. 3.

Obesity also directly increases the risk for T2DM development (Fig. 4). BMI growth is well established as an independent risk factor for T2DM in women [29].

T2DM therapy is the art of a delicate balance between HbA1c reduction on the one hand, and weight gain on the other hand. It’s worthwhile to keep in mind that each HbA1c reduction by 1% results in almost 16% to 20% reduced risk of CV. Every 5-unit elevation in BMI, however, increases the risk of CV by almost 30%. Thus, body weight gain is a key factor in metabolic syndrome, rather than just a «by-product» of insulin therapy, and therefore, keeping the patient’s weight stable is essential during treatment of diabetes [31].

Weight gain is not the result of a specific type of therapy, but in most T2DM patients it's the outcome of an absolutely inadequate lifestyle. The statement «Most therapies result in weight gain over time» – is wrong. The correct position should be: «Whatever the therapy, diabetes patients gain weight» (Fig. 5).

The influence of diabetes treatment on patients' weight was evident in the UKPDS study: regardless of treatment, patients gained weight [32]. During the 10-year follow-up, patients treated with insulin demonstrated the largest increase in body weight, with an average gain of 4.0 kg more than conventionally treated patients (UKPDS 33). The extent of weight gain in insulin-treated patients observed in UKPDS has been confirmed in subsequent studies. For example, in a 6-month study comparing bedtime insulin glargine with NPH insulin once daily (both agents added to existing oral therapy in a treat-to-target protocol), weight gain at the end of the trial period was 3.0 and 2.8 kg, respectively [34]. 

In the ADOPT study, Rosiglitazone, Metformin, and Glibenclamide were evaluated as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. Rosiglitazone was associated with more weight gain and edema than either Metformin or Glibenclamide [33].

Generally, weight gain is the consequence of increased calorie intake or decreased calorie utilization. It can result from a number of specific factors:

• Poor glycaemic control increases metabolic rate and consequently, improving glycaemic control decreases metabolism. If calorie intake is not modified accordingly, body weight will increase;
• Improving metabolic control reduces glucosuria, thus fewer calories are lost in this manner;
• Normally, insulin suppresses food intake through its effect on CNS appetite control pathways. It has been suggested that this effect of insulin is lost in diabetes patients;
• Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake.

Additionally, beside modifications of calorie intake or utilization, the use of insulin can lead to increased lean body mass through its anabolic nature.

The real condition is as follows: due to blindly added-on therapies many T2DM persons become subjects of vicious cycle or cascade, named «Overtreating-Overeating-Overtreating» (Fig. 6 and 7). 

Benefits of weight loss

Today, in an era of widespread use of bariatric surgery, there is a growing body of evidence proving the beneficial effects of weight reduction on all components of the metabolic syndrome. For example, a study of over 100,000 nurses aged 30 to 55 years of age has found that weight loss of more than 5 kg was associated with a gradual decrease in risk of diabetes mellitus. In the Swedish Obesity Study, among those who underwent gastric bypass and subsequently lost weight, 69% with type 2 diabetes were cured: in the surgically treated group T2DM had disappeared in 72% of the patients after 2 years [35]. In summary, recovery from T2DM was established in 76.8% of the patients who underwent bariatric surgery [36]. However, even bariatric surgery is not an ideal solution: «only» 36% of those who had diabetes at entry remained free of the disorder at 10 years (a nonetheless praiseworthy result), while in the conventionally treated group these percentages were 21% and 13% respectively (DPT study) [37]. 

Hence, T2DM-related β-cell and insulin sensitivity disorder can be reversed, provided that body weight is adequately reduced (Fig. 8) [38].

Concepts in modern Diabetology 

Glucocentric Fervor in Modern Diabetology

It may come as a surprise, but the only popular and well-known definition of T2DM today is: «a chronic progressive disease, characterized by hyperglycemia and gradual β-cell function loss». But let’s look at this process from another point of view. We all know that the main background for T2DM is chronic overnutrition (and obesity as a result) and low physical activity, sometimes close to immobilization (and again, obesity as a result). We also realize that consequent events, namely, insulin resistance, hyperglycemia, glucosuria, metabolic syndrome, result in weight loss, or, at least, slowdown the rate of adiposity.

So, if we look at this process from the pathophysiological point, one may conclude that T2DM can be viewed as nothing more than a physiological reaction of nature to chronic overnutrition. In other words, this is the way our body tries to resist the calorie poisoning. Indeed, the most effective and simple way to do so from a «natural» viewpoint – is to develop insulin resistance (if adipose tissue is incapable of «sensing» insulin stimulus, it won’t be compelled to lipogenesis) and to stop gradually the β-cell function (as lower insulinemia would cause lesser rate of lipogenesis). 

And this is exactly what happens in persons moving from NGT through – IGT – IFG – to T2DM. Hence, nature «makes its choice» between obesity (adiposity) on the one side and hyperglycemia on the other side. As overnutrition, rapid weight gain and their consequences would be more likely to kill the person, it «prefers» hyperglycemia which appears to be the «lesser of two evils». Hence, hyperglycemia would be better viewed as a marker, than a risk factor of CV disease [39]. Fighting hyperglycemia by all means, while our patient’s weight grows, would eventually cause death or, at the very least elevate risk of CV morbidity (ACCORD, ADVANCE and VADAT).

What killed the patients in the ACCORD study? Patients who received intensive therapy gained twice more weight (14.1% vs. 27.8% – more than 10 kg above the baseline) than those who received the usual treatment, accompanied with CVD and mortality-risk increase [5].

Table 1 clearly demonstrates that only antihyperglycemic agents, with a weight–neutral or weight-reductive effect may provide the improvement in CV (cardiovascular) morbidity and mortality. Note the correlation between weight reduction and CV morbidity/mortality. On the other hand, the hypoglycemic agents provide in parallel both weight gain and CV morbidity/mortality. 

Gravicentric concept

The growing mass of evidence confirms the theory of J.S. Yudkin et al. that the «Glucocentric Concept» does not fully stand up to our expectations. We propose the Gravicentric Concept (gravis, Lat. = «heavy») as a supplement or an alternative that is based on theoretical, experimental and clinical evidence for efficacy of modern pharmacotherapeutic and surgical methods of T2DM management, as well as principles of avoiding adverse drug interactions due to polypharmacy. 

Briefly we may summarize man principles of a «Gravicentric» concept in the following way:

The «FIVE NO» rule

• No cascade «add-on» therapies to obese (overweight) patient with a positive weight balance;
• No weight gain allowed regardless the type of treatment;
• No use for all hypoglycemic (only for antihyperglycemic) agents and TZD’s;
• No chronic insulin for morbidly obese patient;
• No supraphysiological (more than 0.5-0.6 U/kg of current body weight) insulin, and no insulin / OAD dose elevation for persons who gain weight.

Strategic objectives

Thus, implementation of a «Gravicentric» concept would imply:

• Weight-loss strategies for all, especially for newly diagnosed T2DM;
• De-intensification of treatment for those who are already treated with multiple medications;
• Use of antihyperglycemic, not hypoglycemic agents;
• Ultimately – to reduce the pharmacologic load on the patient to the minimum, until T2DM remission.

With that in mind, the physician should share his treatment plan with his patient and explain to him the reasoning beyond its every stage. How close the patient will get to the ultimate goal is up to the patient’s and doctor’s desire.

Conclusion

Every endocrinologist today has a part in the Diabetology revolution, which would eventually bring all existing approaches to their proper places. Modern pharmacology (incretin-based therapies), bariatric surgery and new technologies of continuous glucose monitoring (CGM) lead us to an insightful and profound understanding of what actually happens to our T2DM patients. It also gives us the means to control the process in the most effective and safe way possible. There is no doubt that the practical efficiency of the «Gravicentric Concept» must be proved in major, long, randomized trials. At the same time, this «Gravicentric» approach to T2DM management, will probably replace the glucocentric one. It is likely to open the eyes of many HCPs and as a result, help many people with diabetes to regain their health.

The authors declare that there are no conflicts of interest.