Type 2 diabetes mellitus treatment habits in a specialized care setting: the START-DIAB study

1Introduction

Personalized treatment of type 2 diabetes mellitus (T2DM) [1] has now become part of healthcare professional daily practice. It marks a turning point after years of strict, almost mechanical implementation of Evidence Based Medicine (EBM) principles, suggesting the adoption of standardized therapeutic behaviors in line with statistically significant results obtained in quite large, yet selected, populations [2].

Nowadays indeed, in the absence of a single EBM-supported therapeutic gold standard for all diabetic patients, EBM is intended as the most effective integration of best clinical trial outcomes with physician’s experience/skills and patient’s values/expectations. This makes doctors behave explicitly, consciously, and judiciously by sharing their considered therapeutic decisions with their patients [3, 4].

Personalized treatment is strongly required for T2DM because of both inner disease heterogeneity and individually identified goals [5, 6]. Moreover, being individual genetic variability still wide and ill-defined, physicians have to choose drugs based on a series of phenotype-related variables rather than on precision medicine principles [7–9]. To cope with such a difficult task, Italian specialists can rely on specific phenotype- related algorithms stemming from the analysis of the Annals of the Italian Diabetologist Association (AMD), a high quality nation-wide clinical care database of T2DM patients followed up within specialized settings since 2004 [10].

According to those Annals, over 50% Italian people with T2DM fail to meet expected metabolic targets, and some 30% of their newly diagnosed mates display HbA1c levels >8.0% (64 mmol/mol) which is not in line with the best way to avoid/delay complications and related risk factors [10, 11]. This holds true however for many European countries as well, despite the availability of increasingly safe and effective drugs and the rather frequent issue of detailed recommendations by diabetes-related scientific societies [12–14].

Whatever the country or the care setting, both physicians and patients prefer to wait longer that expected for oral treatment intensification [15–17] and, even more, for insulin therapy initiation [18, 19]. In Italy this phenomenon is exacerbated by national legislation stating that every sixth month general practitioners (GPs) have to be allowed by public diabetes care units to prescribe innovative, effective and safe drugs to their individual patients. Italian GPs, in turn, tend to treat freshly diagnosed or low-complexity cases on their own until specialists’ help can no longer be postponed [19–22].

We thus performed this real life six month investigation: its primary outcome was to verify specialists’ treatment attitude towards their freshly referred patients with HbA1c levels >7% (>53 mmol/mol). Secondary outcomes were to i) evaluate the metabolic target attainment rate and ii) identify reasons behind metabolic control failure and iii) six-month follow up changes in blood pressure, BMI, creatinine, and the rate of cardiovascular events, adverse effects and unscheduled diabetes care consultations.

2Subjects, materials and methods

START DIAB was designed as an observational, multicenter study involving 48 public Diabetes Care Units (DCU) having the protocol approved by their own Ethics Committees and the informed consent signed by participating patients. All DCUs had been certified for clinical research and, as members of the AMD Research Network Initiative [23], were highly experienced in randomized clinical trials [11]. Specialists involved in data collection were randomly chosen within them in order to prevent any selection bias. The period under study was September 2014 to May 2015.

2.5Follow-up phase

Three and six months after their first referral (coded as T3 and T6, respectively), all people were seen at their own DCUs (see Fig. 1).

At those selected time points the following data were recorded:

• i) new laboratory test results,

• ii) new clinical events and/or diabetes complications and eventually experienced side effects,

• iii) treatment changes,

• iv) unscheduled visits required to improve diabetes control and/or stop complications,

• v) doctor’s answers to the above mentioned questionnaire (at 6 months only).

Fig.1

Schematic representation of the study protocol.

3Results

Baseline characteristics of the population under study have been already described in Table 1.

Moreover, as shown in Table 2, 976 people were taking a single drug at enrollment – either traditional (n = 969) (i.e. metformin, SUs, repaglinide, TZD and acarbose) or innovative (i.e. incretins; n = 12 only because of to the above mentioned strict Italian prescription policy).

Out of the 1513 people on multiple HAOIs, 10.1% (n = 153) were on innovative drugs combined to traditional ones, the others were on traditional drugs only. However, people recently diagnosed as having T2DM (n = 173) received their first HAOI prescription directly by the diabetologist: 87 were on metformin, the rest on a combination of metformin and incretins.

Tables 2 and 3 clearly show that in 71.8% people with HbA1c >7% diabetologists mostly changed treatment by slightly reducing secretagogues and, to a lesser extent, by increasing incretin utilization (from 13.4% to 33.5%; p < 0.001) and starting insulin (3.8%).

Figure 2 describes the distribution of people with T2DM at T0, according to three arbitrarily chosen ranges of HbA1c (Class A: >7–7.5%; Class B > 7.5–8%; Class C > 8%): the highest rate of CV and other diabetes related complications was found in class C.

Fig.2

Distribution of the absolute number (n) and percentage (%) of people with diabetes complications according to three arbitrarily chosen HbA1c ranges as observed at T0 (A, B, C). The highest rate of CV and other diabetes related complications was found in class C. See text for further details.

As shown in Table 4, however, class C was characteried by a high prescription rate of drugs known for their inner hypoglycemic or cardiotoxic risk (secretagogues) and for renal contraindications (secretagogues, metformin), as opposed to a rather low utilization of notoriously less hazardous incretins. Percent people undergoing no treatment changes increased with increasing HbA1c value.

3.1End of follow-up

Out of the 2489 people wit T2DM enrolled in the study, 2323 (93.3%) were available for analysis after 6 months. 180 unscheduled diabetologist visits and 480 visits by other specialists were recorded.

At the last visit (T6, Table 2) incretin and pioglitazone utilization significantly increased as compared to referral (36.3% vs 13.4% and 24.4% vs 12.1%, respectively, p < 0,0001), and SU utilization significantly, yet slightly decreased (42.9% vs 44.4%, p < 0.05). Metformin was prescribed at about the same rate all the time. 941 people were on one only drug, 1489 on more than one (n = 2 : 900 people; n = 3 : 570 people and n > 3 : 16 people). Still the most frequent association was metformin + glibenclamide (67%). A significant increase in insulin utilization was also observed at T6 as compared to T0 (7.8% vs 3.8%; p < 0.01).

At the 3-month follow-up time point no treatment changes occurred in 43.3% people with HbA1c >7% : 25% among them had cardio-vascular complications and their eGFR ranged 50 to 65 ml/min/1.73m².

Then, as shown in Fig. 3, HbA1c levels went down to 7.3±0.9% and 7.1±0.9% (at 3 and 6 months, respectively p < 0.001) from baseline 8.0±1.0% levels, and reach lower than 7% in 33.1% people at 3 months and in 48.2% people at 6 months (p < 0.001).

Fig.3

Percent variation of the amount of people with HbA1c values above or below 7. Average values±SD at the different time points during follow-up are reported below each colums. * = <0.001 vs baseline (Mantel Haenszel test χ square for columns, and rM-ANOVA plus paired t test for M±SD).

83% people had their hypoglycemic treatment modified at least once during the 6-month period under investigation: 71.8% at T0, 5.7%, between T0 and T3, 27.3% at T3, 4.3% between T3 and T6 and 24.2% at T6, respectively.

Moreover, 91% treatment changes occurring during the study involved the same people already undergoing changes at T0.

4Discussion

As stated by international [24, 32, 33] and national [31, 34] guidelines, T2DM should be addressed according to the “treat to target” principle after suitable lifestyle changes have been strongly and consistently suggested. In fact all DCUS participating in the study knew how difficult it was for T2DM patients to refrain from relying on medications only and spontaneously increasing drug dosage instead of sticking to the appropriate diet all the time. Therefore they used to monitor patient adherence to nutritional recommendations at all referrals and were very active in reinforcing the nutritional message along with trying to make their patientsexercise.

When coming to the medication issue, however, achieving adequate glycemic target is not easy for various reasons, including the complexity of patients and of care itself, hardly attainable targets, therapeutic inertia, poor adherence, and progressive beta-cell functional exhaustion [29, 35]. Therefore intensive and aggressive therapy meant at achieving more stringent glycemic targets is not indicated in all patients and cost-benefit balance has to take into consideration individual life expectancy, disease duration, hypoglycemic risk, chronic complications, as well as, comorbidity severity [32].

The first step is metformin, typically prescribed to all people with T2DM unless contraindicated [24, 31]. However, after a median of 45 months (with some variability) metformin alone is no longer enough [35].

The choice of the second therapeutic step depends on major pathophysiological mechanisms involved in a specific patient. In addition to beta-cell defects and insulin resistance, incretin defects and the increased kidney glucose handling threshold have been identified so far. The latter can be modified by glycosuria-enhancing sodium-glucose co-transporter inhibitors (SGLT2is), which, unfortunately, were not available in Italy at the time of the present study. The former, instead, could be easily treated at that time with incretin mimetic drugs (DPP4is and GLP1-RAs) which are very effective in modulating beta-cell secretion and inhibiting inappropriately high glucagon synthesis and release [36].

Incretins entail virtually no hypoglycemic risk per se, are accepted for use even in case of kidney disease and approved for CV safety Therefore they are more and more often used by diabetologists because of [37–40], as well as, being either neutral (DPP4is) or helpful (GLP1RAs) as for body weight [1]. However, despite providing an interpretation in line with that when dealing with reasons behind their own treatment choices, diabetologists contradicted themselves in everyday practice by going on with secretagogues at a relatively high rate during the 6-month follow-up in people failing to reach the target. The results of our study are in line with what reported in the literature, however, according to which failure to intensify treatment when expected is observed in 50–60% patients, which means in fact that only the 40–50% patients change their medication regimen and some 50% only among them have a chance to reach the target afterthat [41].

Secretagogues were always the most prescribed drugs. Indeed, around 50% of our patients undergoing one or more treatment changes reached the 7% HbA1c target. However, despite attaining unsatisfactory HbA1c levels, some 25% patients had no treatment changes made after their first DCU referral and were characterized by the highest HbA1c values and the highest frequency of complications (see Fig. 2 and Tables 3 and 4). In fact, poorly compensated patients involved in our study displayed the greatest insulin utilization rate – which kept low per se anyway (only 7.8%) – and the highest recourse to incretins, but quite surprisingly, as seen in Table 4, were still mostly prescribed secretagogues (sulfonylureas and repaglinide).

Of course insulin secretagogues, mainly SUs, representing the oldest class of oral diabetes medications, are highly effective in triggering insulin release and controlling glucose levels especially during the first years from diagnosis. However, they have been reported to carry along a much higher rate of secondary failure than other drugs mostly due to long-term exacerbation of islet dysfunction [42, 43]. In addition to that, their use is known to be associated with a slight, yet consistent, weight gain and puts patients at risk for serious hypoglycemic episodes [11, 44, 45]. The rather low cardiovascular safety profile, due to their inner mechanism involving the closure of cell membrane K-ATP channels, is another major aspect to consider with respect to this class of drugs and especially of SUs [46].

Anyway, the finding that 91% treatment changes occurring during the study involved the same people already undergoing changes at T0 somehow brings out how difficult it is for specialists to select the best possible treatment choices in certain cases.

Actually, when interpreting poor metabolic control, diabetologists were satisfied with an HbA1c higher than 7% in 13.9% cases based on individual considerations, but in all the others they identified three main areas of responsibility. One was mostly represented by naturally occurring secondary failure (32.2% cases), another depended on people with T2DM themselves (76.5% cases), mostly including either careless or temporarily worsened lifestyle (52.5% and 44.7%, respectively), unreliability (19.2%), poor compliance (15.3%), self- adjusted dosage after spontaneously occurring adverse effects (4.4%), and, finally, unexpected drug discontinuation (4.3%). The least represented area was clinician’s responsibility (10.6% cases), including mostly treatment changes autonomously decided by GPs (5.5%) and the inability to share multiple drug choices with T2DM patients(4.6%).

Overall all the above suggests that specialists tend to charge their “counterpart” with most of the responsibility for poor treatment results.

Fortunately enough, the rate of side effects and serious complications was quite low and similar to that recorded in our country’s general population [11, 35, 38].

Our study has some limitations. One is the relatively small number of people participating in the study. This can be overcome only by repeating it on a very large diabetic population. The other is given by possible differences among involved diabetologists in terms of clinical experience, which was in fact rather unlikely as (i) the results obtained were consistent with the overall data of AMD Annals Initiative [10, 11] and (ii) all diabetes specialists had been randomly assigned to our study but, having been collecting data for the AMD Annals Initiative for years, constituted a homogeneous group and were fully familiar with the present research task. Another limitation consisted of the expected influence of individual factors on drug choices, including care setting, doctor-patient relationship and economic constraints. With respect to the latter, anyway, all those factors per se cannot be standardized in any studies carried out in real life.

In conclusion, throughout the 6-month follow-up period involved diabetologists monitored their patients and gave them reasoned advice on required lifestyle adherence. In addition, they prescribed a significantly larger amount of safe and innovative drugs than before the first visit at their DCUs, but still displayed a conservative attitude towards diabetes treatment. In fact, traditional and well-consolidated therapies were mostly prescribed despite being endowed with a high risk for hypoglycemia, weight gain and adverse cardiovascular effects. Insulin prescription was less than expected too, in fact, and seemed to be mostly driven by HbA1c values higher than 8% (64 nmol/mol) rather than to a fully convinced adoption of the treat-to-target method.

According to our results, then, a series of mainly cultural barriers have to be highlighted eventually hampering metabolic control in several patients. Specific actions have to be devised and readily taken against too conservative treatment attitudes to improve diabetes outcomes in the upcoming years.

Better tools and greater resources allowing safer intensive glucose lowering strategies may also help specialists implement best practices [47].

Conflict of interest

None to report.

Financial disclosure

No financial support was received for this study. No Authors had any personal, academic or financial relationships that could influence their actions or financial involvement with an organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.