The Standard of Care in Type 2 Diabetes: Re-evaluating the Treatment Paradigm

There is currently a global epidemic of diabetes—something that was predicted decades ago by epidemiologists, who observed substantial increases in the prevalence of type 2 diabetes (T2D) among populations of indigenous people who adopted Western lifestyles [1‐5]. The same trend can be seen in India: in 1990 there was only one state where noncommunicable diseases (including T2D) resulted in more deaths than communicable diseases, while in 2016 more people died of noncommunicable diseases in all 31 states, and diabetes is at the forefront of this trend [6]. Lifestyle is what has driven this change, with decreases in physical activity coupled with increases in fast food consumption, portion sizes, overall calories, carbohydrate consumption, and the intake of sugar and fat, leading to marked increases in obesity and T2D [7‐9].

Hotspots of diabetes in addition to India include the Middle East [10, 11] and China [12, 13]. Indeed, the large populations of India and China mean that they contribute a substantial proportion of the world’s diabetes population. Epidemiological projections predict that diabetes prevalence will more than double by 2030, with the greatest increases occurring in developing countries, particularly in Asia and parts of the Middle East [14]. Given that most of those with diabetes live in the developing world [15], the cost of therapy is a major consideration. While advances in diabetes care are occurring at a fast pace, many of these advances are unaffordable in places like India and China, where many people live below the poverty line.

There is hence an urgent need to address the epidemic of T2D, both in developing countries and in the West. Applying the standard of care in T2D can be an important component of how we address this global challenge.

This article does not contain any studies with human participants or animals performed by any of the authors.

The details of a typical case seen in diabetes clinical practice are summarised in Table 1. When this patient presents to the specialist, he is told that within 6 months of his last examination his glycosylated haemoglobin (HbA1c) has increased from 6.4% to 8.2%, meaning that he has gone from prediabetes to diabetes. He has also gained 7 lb, putting his body mass index into the obese range. The patient tells the specialist that he was recently laid off from his job, and that he hates taking pills. He wants to manage his diabetes through diet and exercise, but the specialist does not want to wait for the diet and exercise to work. The patient says that he doesn’t understand why things have to change, because he feels just as well as he did 5 years ago; the specialist points out that the patient’s latest tests show declining renal function, and that he needs aggressive treatment.

In making decisions about the most appropriate way to manage this patient, several things should be considered: adherence may be an issue for him; his renal function is reduced; he does not have any diabetes-related symptoms, but he is at risk for cardiovascular disease and diabetic kidney disease; and his diabetes is progressing, since metformin is no longer controlling his glycaemia.

The specialist decides to add a SU to the patient’s regimen, starting him on gliclazide modified release (MR). This SU is a good choice for this patient because it has been shown to confer a lower risk of hypoglycaemic events compared with other SUs [16‐20] for similar reductions in HbA1c [16]. Gliclazide MR may be used safely in this patient with impaired renal function, [21] and at risk of cardiovascular disease [22]. Moreover, it’s a once-daily medication, which is likely to increase adherence [23, 24]. Gliclazide MR has not been associated with substantial weight gain [24, 25], which might not be an issue for this patient, and the average HbA1c reduction with SUs is ~ 1.5% [26]. The specialist explains to the patient that initially he’ll be taking half a tablet per day (30 mg), and will eventually increase the dose to two 60 mg tablets per day, if needed. The patient objects to the titration, but the specialist explains why starting at a lower dose is needed to mitigate potential side effects. They discuss hypoglycaemia symptoms, and the specialist asks the patient to be adherent to the medication regimen.

At the follow-up appointment, the patient tells the specialist that he has a new job. The specialist goes through the patient’s most recent tests, which show that he has responded to the SU therapy and now has HbA1c of 7.2%. His kidney function is stable. When asked about adherence, the patient admits to sometimes forgetting to take his medication in the morning, and then taking it at night; the specialists asks him not to do that, since it may increase the risk of hypoglycaemia [27, 28]. The specialist still has some concerns about the patient’s weight, and doesn’t think that diet and exercise alone will fix that, so changes in the patient’s regimen may be warranted.

When considering a change in regimen, there are aspects that should be considered: since T2D is progressive, we know that metformin plus an SU will not be enough for many patients; the patient is employed now, and thus likely to be more active; he is reasonably compliant with his medication, showing a behavioural improvement, so may be open to improving his diet and exercising more; his weight is still an issue, but the fact that he still sometimes forgets his medication and then takes it when he shouldn’t means that hypoglycaemia is still a concern.

In summary, a scenario like the one presented is very common in diabetes clinical practice. SUs are drugs of choice to be used with metformin due to their complementary modes of action [29]. These two drugs remain the most widely prescribed anti-hyperglycaemic agents worldwide [30], and have stood the test of time. Compared to other SUs, gliclazide has a lower risk of cardiovascular disease, a lower risk of hypoglycaemia and weight neutrality. In this particular case, gliclazide is a good choice as sodium glucose cotransporter 2 (SGLT2) inhibitors are generally contraindicated in patients with declining renal function, and DPP4 inhibitors are more expensive and so may not be affordable by many people in developing countries. Eventually one of the newer agents will have to be considered for a patient like this, but we at least know that agents with a long experience of use are effective in this setting.

The excess risks in T2D include death, myocardial infarction/angina, stroke, renal disease and end-stage renal disease (ESRD), retinopathy, neuropathy and heart failure. The mediators of these risks include non-modifiable factors such as age, sex, race and genetics, and modifiable factors such as hyperglycaemia, hypertension, hypoglycaemia, dyslipidaemia, smoking and obesity. Hyperglycaemia is a major risk factor, and there is good epidemiological data, such as National Health and Nutrition Examination Survey data, showing that the presence of hyperglycaemia decreases survival [31]. Mortality data from the UK Prospective Diabetes Study (UKPDS) showed that cardiac death, sudden death and stroke were responsible for 56% of deaths; these deaths could all be considered diabetes related, and are therefore to some extent modifiable [32].

In terms of modifying risk, the UKPDS has also demonstrated that tight control of blood pressure and glucose leads to the greatest reduction in risk of any diabetes-related endpoint [33], including microvascular endpoints [34]. Overall, the intensive glucose policy employed by the UKPDS, which maintained HbA1c at a median of 7% over a follow-up of 10 years from T2D diagnosis, decreased the risk of any diabetes-related endpoint by 12% (p = 0.029) [35]. The risk of myocardial infarction was reduced by 16% (borderline significance p = 0.052), while the risk of microvascular endpoints was decreased by 25% (p = 0.0099) [35]. Subsequent clinical trials that have employed an intensive glucose control strategy include the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the Action to Control CardiOvascular Risk in Diabetes (ACCORD) trials. In ADVANCE, patients were 8 years from diagnosis in both intensive treatment and control groups, with ~ 21% having a history of myocardial infarction or stroke; in this trial, target HbA1c was ≤ 6.5% [36]. Over the 66-month follow-up, the differences in HbA1c between groups evolved slowly (Fig. 1), and while the difference was small, it was statistically significant. The effect of therapy on major microvascular events was significant, in favour of intensive therapy, with a relative risk reduction of 14% (p = 0.01); this reduction was mostly due to the effect on new or worsening nephropathy (21%; p = 0.006), which is a positive signal in terms of ESRD and future risk of major events [36, 37]. Indeed, a subsequent analysis of renal outcomes, including ESRD, demonstrated that intensive glucose control resulted in a significant reduction in the risk of ESRD compared with standard therapy [38]. The ADVANCE Observational (ADVANCE-ON) study followed almost 8500 ADVANCE participants for a total follow-up time of 9.9 years, and found that reductions in the risk of ESRD persisted [39].

In the ACCORD study, the median duration of diabetes was 10 years, and one-third of patients had previous cardiovascular events while 5% had congestive heart failure [40]. ACCORD had a very aggressive target HbA1c of ≤ 6.0%, and the impact of this aggressive treatment was quick but negative. ACCORD was stopped early because of a 22% relative increase in mortality in the intensive therapy group versus the standard therapy group [40]. The patients in ACCORD had a high risk profile, higher than that for diabetes alone, but nevertheless the results of this trial showed that aggressive treatment of hyperglycaemia is not a safe strategy for many at-risk patient groups.

There is a continuum of clinical research from RCTs to real-world observational trial evidence, moving from tightly controlled, homogeneous populations to broad populations such as those seen in usual clinical practice (Fig. 2) [50]. RCTs can overcome potential issues with confounders that can be present in a broader population, while real-world studies help to answer some of the questions that RCTs may not have answered. The main differences in design between RCTs and real-world studies are summarised in Table 2 [51].

In clinical practice there are patients with T2D who have survived even for 50–60 years after their T2D diagnosis; for those patients, the only agents available to them when they were diagnosed were metformin and SUs [77]. Some of those patients are still taking this regimen, demonstrating the long-term efficacy of those older drugs. The WHO recommendations are very appropriate. It is too early to consider not using SUs and metformin because they still do have a place in therapy. Moreover, these drugs are perhaps the only ones affordable by the majority of patients in developing countries like India, where over 70% of patients pay ‘out of pocket’ for medicines [78]. The newer drugs are useful, particularly for specific indications or needs, such as a patient with cardiovascular risk, or a need for weight loss. So having more options for therapy is a positive thing.