A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes

Abstract

In 2020, the Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a ‘JDS Committee on Consensus Statement Development’. These consensus statements are intended to present the committee's take on diabetes management in Japan based on evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will never fail to consult these statements to provide the best available practice in their respective clinical settings. Of note, while as many as one-third of all people with diabetes in the world are shown to be concentrated in the Asian region, diabetes mellitus varies in its pathology, including the extent of obesity involved in affected patients, between the East and West. Again, given that timely consensus statements to come out of Japan are thus expected to have enormous implications for clinical practice, it is also planned to make each consensus statement available in English. Following publication in 2020 of the committee's first consensus statement on ‘Medical Nutrition Therapy and Dietary Counseling for People with Diabetes’ (Tonyobyou 2020; 63: 91–109) in Japanese, the committee has taken this opportunity to propose a consensus ‘algorithm for pharmacotherapy in people with diabetes’, in this statement. There are three reasons that prompted the committee to address this issue. First, there are characteristic differences in diabetes pathology between Westerners and the Japanese, where individuals with insulin resistance account primarily for all people with diabetes among the former, while obese and non-obese individuals account equally for all people with diabetes among the latter, with the severity of insulin insufficiency and insulin resistance varying from one individual to the next. Second, there are differences in treatment strategy adopted for diabetes between the West and Japan. Indeed, up until 2021, metformin was recommended as first-line therapy for Western patients, with those shown to be effective against relevant comorbidities, e.g., atherosclerotic cardiovascular disease, renal dysfunction, and heart failure (HF), particularly recommended. In contrast, prompted by the results of the Kumamoto study (Diabetes Res Clin Pract. 1995; 28: 103–117) and the J-DOIT3 study (Lancet Diabetes Endocrinol. 2017; 5: 951–964), multifactorial intervention including glycemic control has been recommended in Japanese people with diabetes to reduce diabetic complications, with the choice of one medication class over the others for each patient remaining an issue to be determined in light of his/her current condition. Third, an analysis of the National Database of Health Insurance Claims and Specific Health Check-ups in Japan brought a disparity in initial antidiabetic medication prescribing patterns between Western countries and Japan (J Diabetes Investig. 2022; 13: 280–291), with the judicious use of biguanides in elderly patients likely to be widespread as per the JDS warning message, leading to the preferential use of DPP-4 inhibitors over biguanides in these patients. Again, of note, none of the biguanides were shown to be used as medications of first choice in as many as 38.2% of all non-JDS-certified facilities, suggesting the need for the committee to develop a standard algorithm for diabetes pharmacotherapy. In developing the algorithm for diabetes pharmacotherapy in patients with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient, while at the same time weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. Specifically, the proposed algorithm would involve choosing medications according to diabetes pathology in each patient in step 1; ensuring their safety in step 2; weighing their additional benefits for comorbidities in step 3; and choosing medications with relevant patient background characteristics of interest in mind in step 4. It is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan but continue to evolve into a better one over time, reflecting new evidence as it becomes available. Type 2 diabetes mellitus is a metabolic disease in which insulin insufficiency or decreased insulin sensitivity (insulin resistance), combined with relative decreased insulin action to varying degrees, accounts for such a lack of insulin action as to cause chronic hyperglycemia1. Again, multiple genetic factors responsible for insulin insufficiency or insulin resistance and environmental factors (e.g., overeating or lack of physical activity and resultant obesity) combine to lead to such a lack of insulin action as to cause type 2 diabetes mellitus. A comparison of the insulin-secretory capacity and insulin resistance between Westerners and the Japanese as stratified by glucose tolerance shows that the Japanese have less insulin-secretory capacity than the Westerners, even while their glucose tolerance is shown to be normal and that while Westerners exhibit acutely increased insulin resistance as they move from normal glucose tolerance to diabetes, Japanese tend to exhibit lower insulin-secretory capacity than that usually associated with increased insulin resistance2, 3. Again, a study comparing insulin sensitivity and initial insulin response between East Asians, Caucasians, and Blacks shows that these races vary in the balance between their insulin-secretory capacity and insulin resistance and that East Asians and Blacks are more susceptible to diabetes than Caucasians4. Again, the pathology of type 2 diabetes mellitus in Japanese is also shown to be characterized as a decreased initial insulin response, regardless of the presence of obesity5. On the other hand, a recent study in Hisayama-cho investigated the correlation between pancreatic β-cell failure (i.e., low insulinogenic index/HOMA-IR) or insulin resistance and the onset of type 2 diabetes mellitus and found that while pancreatic β-cell failure and insulin resistance are both associated with the risk of type 2 diabetes mellitus, they are associated with a markedly increased risk of type 2 diabetes mellitus when they are found together in obese individuals6. In addition, histological studies of the pancreas have shown that, among non-diabetic Westerners, obese individuals have a significantly greater islet mass than non-obese individuals and that, among Westerners with type 2 diabetes, both obese and non-obese individuals have an islet mass about 50% lower than that in non-diabetic individuals and that no increase in pancreatic β-cell mass is noted even in obese Japanese7, 8. Research also shows that, among individuals with type 2 diabetes, amyloid deposition is noted in more than 80% of Westerners but only in 30% of Japanese9, 10. Thus, it is suggested that histological findings in the pancreas differ greatly between different races, suggesting that these differences may account in part for differences in their diabetes pathology. Also of note, advances in genetic analysis of type 2 diabetes mellitus have also led to the identification of numerous type 2 diabetes mellitus susceptibility loci including KCNQ111-13. A meta-analysis of genome-wide association studies (GWAS) in type 2 diabetes mellitus has recently shown that many Japanese individuals but very few Westerners, had the R131Q mutation in the GLP-1 receptor gene (GLP-1R), which is known to be involved in inducing a 2-fold increase in insulin secretion. Furthermore, a cross-racial molecular biological pathway analysis has shown that the pathways involved in the onset of maturity-onset diabetes of the young (MODY) are most strongly associated with type 2 diabetes mellitus in both races evaluated and that the pathways involved in the regulation of insulin secretion are significantly associated with type 2 diabetes mellitus in Japanese alone14. Thus, taken together, the pathology of type 2 diabetes mellitus clearly differs between Japanese and Westerners, not only functionally but histologically and genetically, and a decreased insulin-secretory capacity has a greater role to play in the onset of type 2 diabetes mellitus in Japanese than in Westerners. As detailed above, type 2 diabetes mellitus can be primarily characterized as having, as an underlying core pathology in most Japanese, insulin resistance and insulin insufficiency, whose respective contribution is shown to vary from individual to individual, in contrast to that in Westerners which can be characterized as having obesity and insulin resistance as a core pathology. For its ability to reduce the risk of microangiopathy, macroangiopathy and death, as well as for its beneficial impact on body weight, low hypoglycemia risk, and low cost15, 16, metformin has long been recommended as first-line therapy in Western countries17, 18. However, the Standards of Medical Care in Diabetes by the American Diabetes Association (ADA) have been extensively revised in 2022 to address compelling issues in diabetes management, such as diabetic comorbidities (e.g., atherosclerotic cardiovascular disease), patient-related factors in diabetes treatment, and therapeutic needs of affected individuals19. In contrast, the treatment strategy for type 2 diabetes mellitus in Japan is characterized as allowing for the choice of medications from all classes to address the diabetes pathology in each affected individual, while taking into account the extent of their metabolic derangement, but also on their age, extent of their obesity, status of their insulin secretion/insulin resistance, severity of their chronic complications, status of their liver/renal function20. The rationale for this approach has indeed been provided through the accumulation of relevant evidence, including that from the Kumamoto study21 and the Japan Diabetes Outcome Interventional Trial 3 (J-DOIT3)22, which corroborated the importance of multifactorial intervention, including glycemic control, in reducing complications in Japanese patients with diabetes. It is not difficult to imagine how significantly such differences in treatment strategy for type 2 diabetes mellitus might impact on the choice of medications or their prescribing patterns. In this regard, while there are studies on antidiabetic medication prescribing patterns in Japan23, 24, they each suffered from a small sample size and lack of data from elderly patients and a nationwide survey has been awaited to provide a full picture of the prescribing patterns in clinical practice. Thus, the Japan Diabetes Society (JDS) conducted a nationwide survey to clarify the prescribing patterns in clinical practice as a step to developing an algorithm for diabetes pharmacotherapy25. The survey demonstrated that, among the more than 1 million people with type 2 diabetes registered with the National Database of Health Insurance Claims and Specific Health Check-ups from the latter half of the fiscal year 2014 to the fiscal year 2017, the most frequently prescribed of all antidiabetic medications was, unlike those in Western countries26, dipeptidyl peptidase-4 (DPP-4) inhibitors, followed by biguanides and sodium-glucose cotransporter 2 (SGLT2) inhibitors, with age shown to the factor most strongly influencing this prescribing pattern; and that the older the patients were, the more likely they were to have been prescribed DPP-4 inhibitors and the markedly less likely they were to have been prescribed biguanides and SGLT2 inhibitors. An analysis of the initial prescribing pattern by prefecture also showed that the biguanide and DPP-4 inhibitor prescriptions varied from one prefecture to the next, while an analysis of the initial prescribing pattern by facility (JDS-certified vs non-JDS-certified) showed that no patients receiving initial medication therapy had been initially prescribed biguanides at 38.2% of non-JDS-certified facilities and that the DPP-4 inhibitor prescribing pattern varied greatly between JDS- certified and non-JDS-certified facilities (i.e., there were not a few non-JDS- certified facilities where almost 100% of patients had been initially prescribed DPP-4 inhibitors alone). Thus, while the survey results suggested that antidiabetic medications were being chosen to address the characteristics of diabetes in each individual patient and that the JDS recommendations on the use of metformin and SGLT2 inhibitors27, 28 were widely adhered to by primary care physicians, the disparity in DPP-4 inhibitor and biguanide prescribing patterns between regions and facilities, nevertheless, pointed to the need to renew awareness of the JDS-proposed principle of medication choice for each patient based not only on the extent of their metabolic derangement, but also on their age, extent of their obesity, severity of their chronic complications, status of their liver/renal function, and status of their insulin secretion/insulin resistance, thus a need to formulate an algorithm as a tool to promote the proper use of antidiabetic medications. Given that type 2 diabetes mellitus differs in pathology between Asians including Japanese and Westerners, the Japan Diabetes Society has long advanced a different treatment strategy for Japanese from that for Westerners (Figure 1). By the same token, it became clear from the survey results that the initial diabetes medication prescribing patterns differ greatly between Japan and Western countries25, suggesting that the JDS-proposed treatment strategy for diabetes has become widespread among diabetologists and general practitioners alike. It is also likely that the initial diabetes medication prescribing patterns reflected the informed use of antidiabetic medications, except imeglimin, on the part of many physicians, based on their glucose-lowering efficacy and safety profiles that became known after a certain lapse of time since their approval. Furthermore, it became also clear that the disparity in the prescribing patterns of DPP-4 inhibitors and biguanides between facilities and regions needed to be resolved to ensure the proper use of these medications. Of note, given that evidence has recently been accumulated, mostly overseas, that demonstrates the efficacy of GLP-1 receptor agonists and SGLT2 inhibitors against diabetic comorbidities (i.e., atherosclerotic cardiovascular disease, heart failure and chronic kidney disease [CKD]), suggesting that these additional benefits (i.e., cardio/reno-protective and mortality-reducing effects) are worth considering in medication selection for patients with type 2 diabetes mellitus. Thus, overall, based on the basic concept that (1) medications can be selected to address the diabetes pathology in Japanese and Asians; (2) the medication selection should reflect the prescribing patterns in clinical practice in Japan; and (3) medications can be selected for their additional benefits in patients with comorbidities that call for medical attention, an algorithm for diabetes pharmacotherapy was developed to allow for such choice of medications as to address each patient's pathology/condition, with the priority in medication selection determined, with consideration also given to current prescribing patterns and other relevant factors. The overriding premise behind diabetes pharmacotherapy was defined as ensuring safety (Figure 2). Thus, medication selection was first assumed to involve assessing whether there were any absolute or relative indications for insulin therapy in each patient. Then, as individuals 65 years old or older account for more than half of all people with diabetes in Japan, the HbA1c control goal was determined, based on those proposed in the Kumamoto Declaration 2013 and the JDS-proposed ‘Glycemic targets (HbA1c values) for elderly patients with diabetes’20, 29. It was also assumed that while the HbA1c control goal of <7% remained valid for prevention of complications in people with diabetes, the HbA1c control goal could also be determined with consideration given to other factors such as their age or comorbidities. While the insulinogenic index (II) or C-peptide index remain useful as measures of insulin-secretory capacity, as does Homeostatic Model Assessment – Insulin Resistance (HOMA-IR) to evaluate insulin resistance in assessing people with diabetes for insulin deficiency or insulin resistance as part of the core pathology, type 2 diabetes mellitus is such a common disease that assessing all affected individuals using these indices is hardly feasible in clinical practice. Given that one of the important aims of the proposed algorithm is to promote the proper use of antidiabetic medications among non-experts, the presence or absence of obesity was adopted as the single most important clinical measure to allow the core pathology of diabetes to be detected to some extent. Thus, it is recommended that patients are assessed for obesity using the definition of obesity in Japan, body mass index (BMI) 25 kg/m2 or more30, in choosing medications for type 2 diabetes mellitus. Given that the extent of obesity (BMI) and insulin resistance are shown to be positively correlated, insulin resistance is assumed to have a greater contribution to type 2 diabetes mellitus in highly obese patients, thus prompting the choice of medications to address the pathology in question. The caveat is that visceral fat accumulation is often noted in Japanese and Asian individuals with a BMI lower than that in obese Westerners and that insulin resistance may be implicated due to visceral fat accumulation in some of these patients, they are usually categorized by BMI as being non-obese4, 31, 32. Despite this caveat, however, it is assumed that patients can be accurately assessed for excessive visceral fat accumulation by assessing them for BMI and waist circumference at the same time. Note here that excessive visceral fat accumulation may be suspected in men with a waist circumference of 85 cm or greater as well as in women with a waist circumference of 90 cm or greater. Now, candidate medications for patients with obesity include non-insulin secretagogues, e.g., biguanides, SGLT2 inhibitors, and thiazolidinediones, as well as insulin secretagogues, e.g., GLP-1 receptor agonists with potential for weight-reducing effects and imeglimin, for which obesity/insulin resistance is a good indication, given its insulin-sensitizing properties. In most non-obese individuals with type 2 diabetes mellitus in whom insulin insufficiency is assumed to constitute the core pathology, consideration should be given in medication selection to insulin secretagogues as the mainstay of treatment. Of these, DPP-4 inhibitors remain the most frequently prescribed for people with type 2 diabetes in Japan, particularly most frequently in elderly patients, probably reflecting the high expectations for their safety in the elderly25. DPP-4 inhibitors are also shown in some reports to exert far greater glucose-lowering efficacy in Asians than in other races33, 34, suggesting that non-obese patients with type 2 diabetes likely represent a good indication for this medication class, given its safety and efficacy. Again, while numerous studies conducted to date consistently suggest a low cardiovascular risk with DPP-4 inhibitors as a class35-37, some of these medications are also reported to be associated with an increased risk of heart failure, thus calling for their judicious use in patients at high risk of heart failure38. Of the insulin secretagogues, sulfonylureas (SUs) are also of interest, in that they are non-glucose-dependent insulin secretagogues and are associated with a high risk of hypoglycemia39, while glinides and α-glucosidase inhibitors also represent good medication candidates for patients exhibiting marked postprandial hyperglycemia. Metformin is shown to exert comparable HbA1c-lowering efficacy in both non-obese and obese Japanese patients with type 2 diabetes mellitus and thus represents an option for non-obese people with type 2 diabetes40, 41. Note here that non-obese patients include lean patients (BMI <18.5 kg/m2) who are mainly elderly; thus, caution should be exercised in using antidiabetic medications with weight-reducing properties, i.e., GLP-1 receptor agonists and SGLT2 inhibitors, in lean patients16, as it may be associated with an increased risk of geriatric syndrome, e.g., sarcopenia and frailty. Note that the most desirable attribute required of antidiabetic medications is their ability to ‘lower blood glucose safely’. Thus, the proposed algorithm has included a summary of their glucose-lowering potency relative to their efficacy and safety and risk of hypoglycemia, as well as precautions (particularly contraindications) for their use in patients with organ derangement (e.g., renal impairment, hepatic disorder [particularly cirrhosis], cardiovascular disorder, and heart failure) in Table 1, with running commentary on areas where caution should be exercised in their use: (1) the use in elderly patients of sulfonylureas and glinides, both of which are associated with a high risk of hypoglycemia; (2) safety precautions in medication selection in patients with renal impairment, a highly common comorbidity in people with type 2 diabetes; and (3) medications contraindicated in patients with heart failure. According to a network meta-analysis of the HbA1c-lowering efficacy of antidiabetic medications, GLP-1 receptor agonists are shown to be the most potent of all medications in lowering HbA1c, followed by metformin, pioglitazone, and sulfonylureas42. It is also shown that metformin lowers glucose dose-dependently and exerts highly potent glucose-lowering effects at its high doses and that the thiazolidinedione lowers glucose through its insulin-sensitizing effects on adipose tissue and skeletal muscle and thus is shown to be more effective in obese patients. Safety against hypoglycemia risk remains the most relevant of all safety requirements for antidiabetic medications. As single agents, antidiabetic medications other than the non-glucose dependent sulfonylureas and glinides are generally associated with a low risk of hypoglycemia, while sulfonylureas are among the agents associated with a high risk of hypoglycemia. Indeed, according to a report from the JDS Committee on Survey of Severe Hypoglycemia Associated with Diabetes Treatment, patients treated with sulfonylureas accounted for about 30% of all patients treated with any antidiabetic medications (or about 85% of all patients treated with medications other than insulin therapy) who required emergency transportation for severe hypoglycemia39. A finding of particular interest from this survey is that elderly patients accounted for a large proportion of those thus transported for severe hypoglycemia, suggesting that caution should be exercised in the use of sulfonylureas in elderly patients. The impact of antidiabetic medications on body weight is also particularly relevant to the correction of obesity and the prevention of geriatric syndrome, two major issues referred to above. In this regard, SGLT2 inhibitors are shown to be associated with a weight reduction of 2 kg with suggesting their for use in obese people with type 2 diabetes. GLP-1 receptor agonists are also shown to have weight-reducing effects and are thus for use in obese people with type 2 diabetes, with the reduction in body weight reported to be 2 kg on in patients treated with these medications with those treated with Of these, was evaluated for its efficacy in Japanese patients with type 2 diabetes mellitus in a recently reported which demonstrated that the medication was associated with a reduction in body weight from 2 to 3 at high Again, α-glucosidase inhibitors are shown to be associated with a greater weight reduction in obese Japanese people with type 2 diabetes than many studies reported a weight of about 2 kg in patients treated with sulfonylureas than that in patients treated with while was shown to be associated with a weight of and likely as needs to be exercised in the use of multiple antidiabetic medications in patients with diabetes by renal Given that most non-glucose-dependent insulin secretagogues (e.g., sulfonylureas and are their use is likely to be associated with increased risk of hypoglycemia, and sulfonylureas and are both contraindicated for use in those with renal as a with is shown to be for use in patients with renal than other Metformin is shown to be associated with an increased risk of in patients with renal and is thus contraindicated in those with but is recommended for use at a of and in those with and is available for use even in patients but is contraindicated for use in patients in Japan. As their glucose-lowering efficacy is shown to be in patients, SGLT2 inhibitors over their failure to glucose lowering in patients. Severe hepatic disorder a for biguanides, and being a relative indication for insulin Of all patients with cardiovascular disease those with disease and heart failure are a for biguanides, while metformin is no contraindicated in patients with heart failure contraindicated in patients with heart failure) in Western reports of in the need for due to heart failure and in risk with While patients with or heart failure are a and those with A and an indication, for thiazolidinediones, consideration should be given in the latter to their and use of for associated While not in Table 1, it is important that patients receiving SGLT2 inhibitors be for diabetic SGLT2 inhibitors are expected to increase glucose and to lower blood glucose and leading to an increased and an increased hepatic in adipose thus in increased of for SGLT2 inhibitors are associated with the risk of even in patients with due to an increase in on the of insulin insufficiency or their Given that numerous clinical conducted mainly have shown the efficacy of SGLT2 inhibitors and GLP-1 receptor agonists against chronic kidney (particularly cardiovascular disease, and heart failure, the proposed algorithm included cardiovascular disease, heart failure, and chronic kidney disease (particularly as of interest for which antidiabetic medications may be to additional While it should be noted that, the algorithm mainly on the evidence available from due to the of data from Japan on this these comorbidities to be a valid indication for the use of SGLT2 inhibitors and GLP-1 receptor with the caveat that the reduction in cardiovascular in these may be accounted for in part by that in HbA1c with these suggesting that their effects may not be of their glucose-lowering effects and that studies are awaited to the clinical of SGLT2 inhibitors (i.e., and have been conducted in people with type 2 diabetes having cardiovascular disease or patients with type 2 diabetes with major cardiovascular of cardiovascular death, and as the primary and demonstrated a reduction in with these with this finding also by of these of the GLP-1 receptor agonists those of have been shown in clinical (i.e., and to a reduction in with this also in a Thus, while it should be noted that there is a of data from in Japanese patients and that Japanese people with diabetes are at lower risk of cardiovascular disease than their Western the evidence available is numerous and of such high that SGLT2 inhibitors and GLP-1 receptor agonists were included as highly recommended in the for their additional for cardiovascular disease in the proposed and people with type 2 diabetes mellitus for heart failure is of given that even people with type 2 diabetes mellitus are to be in a

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