Management of Type 2 Diabetes in Developing Countries: Balancing Optimal Glycaemic Control and Outcomes with Affordability and Accessibility to Treatment

References for this review were identified through searches of PubMed for articles published from January, 2015 to November, 2018 by use of the terms “Cost”, “Cost effectiveness”, “Health economics”, “Low income”, “Middle income”, “Maturing country”, “Low resource”, “Glycaemic control”, “Access”, “Affordability”, “Treatment initiation” and “Treatment persistence”, with therapies comprising “Sulfonylurea”, “DPP4i”, “SGLT2i” and “GLP-1RA”. Articles resulting from these searches and relevant references cited in those articles were reviewed.

Achieving and maintaining tight glycaemic control is an essential principle in managing diabetes to avoid related complications [23, 24]. Specifically, early intensive glycaemic control (to achieve an HbA1c value of 7.0% or less) reduces renal complications when compared to standard regimens and has been shown to be safe in terms of cardiovascular outcomes, highlighting its role in the prevention of microvascular complications [25].

Unfortunately, in type 2 diabetes, specifically in the developing world, the opportunity for early intensive intervention is often limited: patients are diagnosed late with increased levels of HbA1c, and morbidity and diabetes-related mortality are high [19, 26]. Indeed, type 2 diabetes is frequently only recognized when life-threatening complications develop [13]. With its increasing prevalence, access to the most effective, well-tolerated therapies that lower blood glucose levels in type 2 diabetes is more important than ever [27, 28].

As a result of its high efficacy in lowering HbA1c, its favourable safety profile, low cost and widespread availability, metformin remains the first-line medication for management of type 2 diabetes [20, 21, 29, 30]. Several options exist when metformin is not well tolerated or becomes inadequate alone in achieving glucose targets, including sulfonylureas and insulin, as well as the newer glucose-lowering therapies SGLT2i, DPP4i and GLP-1RA.

While these novel treatments may offer some advantages over older glucose-lowering agents, especially in patients with established cardiovascular disease (SGLT2i, GLP-1RA), they do come with restrictions, as they are typically costly or less effective (DPP4i, SGLT2i) and have their own share of side effects, such as gastrointestinal disturbances, pancreatitis and infections (SGLT2i) [31].

With this in mind, considering treatment options for patients in restricted-resource settings, this part of the review will focus specifically on evidence for second-generation sulfonylureas, such as gliclazide and glimepiride, as well as newer agents, such as SGLT2i, DPP4i and GLP-1RA.

In the management of type 2 diabetes, treating physicians must consider the risks versus benefits of the chosen therapy. Generally, adverse events associated with treatment of type 2 diabetes (including SGLT2i, DPP4i, GLP-1RA, metformin, insulin and sulfonylureas) include hypoglycaemia, weight gain, infections, nausea and other gastrointestinal events [61]. Long-term safety data collection for newer agents is ongoing.

Sulfonylureas have a well-established safety profile because of their longevity (more than 60 years) in the market [62]. As a result of their mechanism of stimulating insulin secretion, they are associated with a higher risk of hypoglycaemia, weight gain and occasionally cardiovascular complications [63]. However, both efficacy (Fig. 2) and adverse-event profiles differ between the first- and second-generation sulfonylureas [7]. Generalizations for the efficacy and safety of sulfonylureas as a class should, therefore, be avoided [64]. Additionally, despite previous data, a recent prospective study showed no increased risk of severe hypoglycaemia with sulfonylureas [65].

Hypoglycaemia is an important consequence of treatment for diabetes, being associated with both clinical and economic costs. Clinical manifestations, such as falls, dysrhythmias, confusion and neuroglycopenia, are burdensome for the patient and may require medical intervention, resulting in increased resource utilization [66]. Severe hypoglycaemia is also a risk factor for cardiovascular disease in people with type 2 diabetes, as indicated in a systematic review and meta-analysis, supporting the idea that avoiding severe hypoglycaemia is important to prevent cardiovascular disease in this population [67].

In a retrospective study of a large US claims database, use of the DPP4i linagliptin was associated with lower incidence rates of hypoglycaemia compared with sulfonylureas available in the USA in patients initiating therapy as second line after metformin monotherapy [66]. However, information on the type of sulfonylurea used was not available; therefore, intra-class differences in the incidence of hypoglycaemia were not taken into account.

Differences have also been observed in hypoglycaemic risk between different sulfonylureas, which may be explained by variations in their molecular structure [32] and pharmacological profiles [14, 31]. It is known that glibenclamide is long acting and forms active metabolites, which increase the risk for prolonged and severe hypoglycaemia. This risk is less with later sulfonylureas, which have inactive metabolites [68]. Gliclazide is the only one reported in the class that does not bind to Epac2 (exchange protein directly activated by cAMP 2 and also known as Rap guanine nucleotide exchange factor 4), a stimulating factor for insulin exocytosis, and has a reduced risk of hypoglycaemia [32]. Several meta-analyses have compared the risk of hypoglycaemia between different sulfonylureas, with numerous reports of a significantly lower risk of hypoglycaemia with the later-generation sulfonylureas compared with others in the class [14, 31, 69, 70]. In a model-based meta-analysis conducted by Maloney et al., important differences were identified both between and within classes of anti-hyperglycaemic drugs used to treat type 2 diabetes. Despite increased rates of hypoglycaemia with sulfonylureas as a class, the risk was notably lower with gliclazide (Fig. 4) [37], which is also mirrored in the head-to-head GUIDE trial comparing gliclazide with glimepiride [71]. The ADVANCE trial compared intensive blood glucose control using daily gliclazide MR (target HbA1c value 6.5% or less) versus standard blood glucose control (with target HbA1c levels defined on the basis of local guidelines). In the intensive treatment group, 90.5%, 73.8% and 40.5% of participants were treated with gliclazide MR, metformin and insulin, respectively. In the standard treatment group, 1.6%, 67.0% and 24.1% were treated with gliclazide MR, metformin and insulin, respectively. While severe hypoglycaemia was marginally higher in the intensive therapy group, it was still uncommon (2.7% vs 1.5% in the standard-control group; P < 0.001) despite the intensive arm achieving an HbA1c of 6.5% [25]. Additionally, a recent analysis of ADVANCE confirmed that the risk of severe hypoglycaemia associated with the intensive regime did not vary across different levels of kidney function (P = 0.83). This analysis confirmed that the risk–benefit profile of an intensive glycaemic control strategy is consistent across those with both preserved and reduced kidney function [72]. With this in mind, patients with type 2 diabetes can benefit from intensive glucose lowering regardless of kidney function, as long as attention is given to the prevention of hypoglycaemia [72]. Moreover, by providing proper education regarding the signs and symptoms of hypoglycaemia and its prompt management, and subsequent reduction of dosage of the sulfonylurea doses, the problem can be managed, at least in part.

Clinical practice should be evidence-based, although this may not necessarily be the case. In a recent study of general practitioner prescribing practices in England, the authors were surprised to find the continued use of the older sulfonylureas tolbutamide and glibenclamide, despite the recommendation that these agents should not be generally prescribed for the treatment of type 2 diabetes [73]. These findings show that the intra-class variability of sulfonylureas may not have been communicated strongly enough.

Special circumstances, such as fasting during Ramadan (estimated to be observed by 80–90% of Muslims with diabetes), need to be considered when using glucose-lowering therapies, because of the increased risk of hypoglycaemia [14, 31]. This risk varies depending on the agent, with no significant differences in the rate of any hypoglycaemic events observed for gliclazide and the DDP4i vildagliptin in a randomized trial [74]. The trial, which included frequent physician contact and Ramadan-focused advice as part of the intervention, provides reassurance on the use of vildagliptin and gliclazide plus metformin in these circumstances [74].

It has been reported that weight gain is an undesirable consequence of therapy with sulfonylureas [14]. However, variations have again been noted within this drug class. In the UKPDS trial, weight gain of approximately 4 kg was reported in the first 3 years after glibenclamide initiation [23]. In the ADVANCE study, weight gain in the intensive glucose control arm, using gliclazide-based treatment, was reported as less than 1 kg [25]. More recently, the CAROLINA data showed weight gain associated with sulfonylureas to be relatively low, even when compared to a ‘weight neutral’ agent such as the DPP4i linagliptin, with an average between-group difference in weight of − 1.5 kg (95% CI − 1.8, − 1.3) [55].

In both developing and developed countries, cost is an integral part of evaluation of a medication, and is often reflected in clinical guidelines or recommendations. For example, the National Institute for Health and Care Excellence in the UK provides “advice on effective, good value healthcare” [75]. For such a widespread condition as diabetes, defining optimal cost-effective approaches to care is essential [20]. In general, insulin, SGLT2i, DPP4i and GLP-1RA medications are more costly than the relatively inexpensive metformin and sulfonylureas [20]. Glimepiride and gliclazide daily treatment costs are 7 and 8 Indian rupees (Rp), respectively, compared with 44 Rp for the DPP4i vildagliptin [76]. Also of note, in India, approximately 80% of people pay ‘out of pocket’ for their type 2 diabetes management, posing a significant economic burden.

In Thailand, the cost of treatment was reported to be approximately US$465/year for DPP4i, US$15.05 for metformin and US$4.52 for sulfonylureas [77]. These examples from developing countries indicate that although healthcare systems may differ from country to country, large relative differences are observed between sulfonylureas and other agents in terms of treatment costs.

This price difference is also seen in developed countries. In the UK, metformin and sulfonylureas are generally available at low cost (£17–50 and £34–173, respectively, for 1 year of treatment), while the other agents are markedly more expensive (£391–482, £414–434 and £830–1432 for thiazolidinediones, DPP4i and GLP-1RA, respectively) [78].

In 2017, an independent Canadian group updated a systematic review, network meta-analysis and cost-effectiveness analysis of second-line therapies for type 2 diabetes [79, 80]. The review considered the comparative efficacy and safety of using second-line drugs for adults with type 2 diabetes with inadequate glycaemic control on metformin monotherapy. The therapies considered included sulfonylureas, SGLT2i, DPP4i and GLP-1RA. The analysis concluded that the addition of a sulfonylurea remains the most cost-effective second-line therapy for patients. Threshold analyses indicated that the costs of the newer agents SGLT2i, DPP4i and GLP-1RA would have to be reduced by 60–70% in order to match the cost-effectiveness of sulfonylureas as second-line treatment [79]. A similar report was published by a WHO expert group, recommending only metformin, short-acting sulfonylureas and regular human insulin in all low- and middle-income countries, unless there is a compelling need to use the newer agents [81].

However, numerous cost-effectiveness analyses are emerging, suggesting that newer oral agents may be cost-effective compared with sulfonylurea. Such analyses have been considered in the WHO guidelines, which highlight that industry-funded cost-effectiveness analyses tend to report cost-effectiveness of newer treatments [82‐86], while independent studies favour sulfonylureas [26, 62]. A specific example of the disparity in these cost-effectiveness trials is shown by a systematic review of DPP4i versus sulfonylureas in which DPP4i appeared to be more cost-effective [87]. However, this was based on a limited number of industry-funded studies and did not take into account low-resource settings and associated access issues. Another trial in this type of setting in Thailand found that DPP4i did not, in fact, appear to be more cost-effective when compared with sulfonylureas [88].

The WHO has developed a clinical guideline on treatment intensification in low-resource settings, which applies to both low- and high-income countries [81]. The drug classes under consideration included sulfonylureas, SGLT2i, DPP4i, thiazolidinediones and insulin. The first recommendation is to “give a sulfonylurea to patients with type 2 diabetes who do not achieve glycaemic control with metformin alone or who have contraindications to metformin (strong recommendation, moderate-quality evidence)”. These agents produce similar and statistically significant improvements in HbA1c. Taking into account the higher cost of newer agents, the panel decided that recommending the new agents for universal use as second- or third-line treatment in resource-limited settings would be premature.

The International Diabetes Federation Access to Medicines and Supplies for People with Diabetes report in 2017 analysed the main barriers to access of diabetes medicine from the perspective of patients and healthcare professionals. Despite some low-income regions, such as Brazil, having free distribution of metformin, sulfonylureas and insulin in all of their pharmacies, in this analysis, availability of the range of diabetes medicines was much lower in low- and middle-income countries compared with high-income countries (Table 2) [16]. Similarly, the PURE [Prospective Urban Rural Epidemiology] study examined the availability and affordability of metformin, sulfonylureas and insulin across multiple regions of the world [15]. Availability was defined as the presence of medication in the pharmacy on the day of audit and medicines were defined as affordable if the cost was less than 20% of the capacity to pay (household income minus food expenditure). The authors concluded that availability and affordability of essential diabetes medicines were poor in low- and middle-income countries. With these two reports combined, it is clear that access remains a major issue with diabetes management and treatment decisions should be made with this in mind.

In its 2018 guidelines on pharmacological agents for managing diabetes in low-resource settings, the WHO noted that sulfonylureas are currently more affordable than newer oral anti-hyperglycaemic agents for people who pay ‘out of pocket’ [1]. Consequently, they are likely to be more accessible. This supports the South Asia consensus on diabetes management, which highlighted that cost is an important consideration in this region of the world, as a majority of patients are not covered under medical insurance [32]. As a result, sulfonylureas could be the oral glucose-lowering agent of choice in these countries. Furthermore, oral administration and daily dosing should benefit adherence to medication. Single-pill combinations of two or more diabetic drugs are known to increase patient adherence compared with two-pill therapy [32]. A scored, breakable, extended release, once-daily, single-pill combination of a second-generation sulfonylurea and metformin was found to be effective in controlling blood glucose in a large proportion of patients with type 2 diabetes in India, and risk of hypoglycaemia was low [89, 90]. The findings of this trial are important to note, as they give rise to a potential synergy between the pharmacodynamic profiles of metformin and sulfonylureas. Specifically, the respective weight loss and gain may counteract each other, although this requires further investigation.

The relationship between medication cost and adherence is well established, and there is a wide variation in adherence to diabetic medication worldwide, with reported non-adherence rates of approximately 40% in India and 50% in Malaysia [91]. This issue is also important in countries such as Nigeria and India, where the majority of patients pay ‘out of pocket’. In a study of patients with type 2 diabetes attending a tertiary hospital clinic in Nigeria, oral anti-hyperglycaemic agents (metformin alone or in combination) were the most prescribed drugs. According to study participants, common factors that may affect adherence to medications included cost of treatment (20.2%) and non-availability of prescribed medications (10%) [91]. Even in higher-income countries, patients may be deterred from initiating essential medications because of cost, undermining adherence and risk factor control, as reported in an observational, new-prescription cohort study that evaluated the effect of out-of-pocket cost on medication initiation and adherence in patients with diabetes in California, USA [92].

Essential medicines are defined by the WHO as “those that satisfy the priority healthcare needs of the population” and, as such, it lists five diabetes-related medicines on its Model List of Essential Medicines (short-acting insulin, intermediate insulin, metformin, glucagon and sulfonylurea, and gliclazide) [93].