Improving Type 2 Diabetes Treatment by Identifying Different Subtypes

There is full consensus in recognizing that the pathophysiology of T2D is related to two processes: the ineffective action of insulin and its deficient secretion, in which multiple signaling pathways from different organs interact (15). Both processes contribute to the development of the disease, resulting in inadequate uptake, storage, and disposal of ingested glucose, along with excessive hepatic glucose production, which culminates in chronic hyperglycemia (16) (Figure 1).

Adipose tissue stores fatty acids and maintains energy homeostasis through its communication with organs such as the brain, muscles, liver, and pancreas. When the function of this tissue is modified, there is an alteration in the secretion of cellular signaling molecules, known as adipokines, among which leptin and resistin stand out (17). An increase in leptin levels can induce damage to pancreatic β-cells because it inhibits insulin synthesis, induces inflammatory processes, and generates oxidative stress. On the other hand, resistin, another adipokine secreted by adipose tissue, promotes the release of cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor (TNF), through the activation of nuclear factor kappa B (NF-κB) (18). In contrast, adiponectin, an anti-inflammatory agent that inactivates NF-κB, is elevated in the blood after weight loss in obese individuals, which improves insulin sensitivity (19). The imbalance in the concentration of cytokines and elements that protect the function of pancreatic β-cells can generate functional damage and cell apoptosis (18).

Insulin resistance (IR) is defined as an alteration in the biological response of target cells to insulin, which translates into a reduction in glucose uptake by muscle and adipose tissues. Among the most common causes of IR are the reduction in the number of insulin receptors (IR) and their catalytic activity, as well as the increase in phosphorylation of serine/threonine (Ser/Thr) residues of the IR and the insulin receptor substrate (IRS). In addition, the decrease in the activity of phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (Akt), the increase in the activation of tyrosine residue phosphatases (Tyr), and alterations in the expression and function of glucose transporters type 4 (GLUT4) contribute directly to resistance (20).

In patients with obesity, adipose tissue cells release high amounts of IL-6, resistin, and TNF-alpha, cytokines that will alter the phosphorylation of Tyr residues of IRS-1 and the genetic expression of GLUT-4. In addition, these substances activate lipolysis, releasing free fatty acids from the adipocyte, which, when accumulated in the muscle and liver, cause lipotoxicity. In this sense, diacylglycerol (DAG), formed from long-chain acyl-CoA, plays a fundamental role in this process by activating protein kinase C isoforms. This activation alters the phosphorylation of IRS-1 and PI3K, blocking the translocation of GLUT4 and, therefore, reducing glucose uptake (21).

In Europe and the United States, T2D has been described mainly as a model of processes linked to obesity. As mentioned, ectopic fat accumulation in both skeletal muscle and the liver increases insulin resistance (IR) (22) and impairs insulin action (23). However, the considerable heterogeneity of this pathology represents a challenge for its prevention. This is because, although obesity constitutes an important risk factor, most people with a high body mass index (BMI) do not develop T2D. However, a certain proportion of people with normal weight also develop it (14). In this sense, in relation to ethnic differences, it has been observed that the Indo-Asian population, due to its greater predisposition to the accumulation of visceral fat, has a greater IR despite having a lower BMI. This can probably be related to the lower capacity of subcutaneous fat storage. However, adiposity alone does not fully explain the excessive risk of T2D in these populations (24).

In fact, several studies suggest that this population has a slightly different pathophysiology with an earlier and faster dysfunction of pancreatic β-cells, which positions severe insulin deficiency as the main pathophysiological defect in the development of the disease (10). Because IR and secretory insufficiency are two well-established characteristics of T2D, the working group led by Tanabe et al., suggests that, despite this variability among individuals, the onset and development of diabetes in Asian and non-Asian populations can be divided into two main subtypes: obese insulin-resistant and lean insulin-sensitive (14, 25). This classification reflects the pathophysiological diversity of T2D and suggests the need for personalized approaches in clinical management.

T2D is a disease associated with subclinical systemic inflammation, which acts as a pathogenic link between the disease and its complications, such as kidney disease, cardiovascular disease, depression, cognitive impairment, and dementia (Figure 2).

The immune response and inflammatory modulators are strongly related to pancreatic β-cell dysfunction and IR in patients with T2D. For example, pro-inflammatory cytokines such as interleukin-1β (IL-1β) inhibit insulin secretion and the proliferation of pancreatic β-cells by inducing the transcription and secretion of chemokines (26). Therefore, the inhibition of these inflammatory factors could protect pancreatic β-cells and delay the progression of hyperglycemia (27).

Inflammation and oxidative stress, exacerbated by the imbalance between the production of reactive oxygen species and hyperglycemia, are essential in the progression of diseases such as diabetic nephropathy (DN) (28). Evidence indicates that, despite being a multifactorial disease, the immune response and inflammation are relevant factors. Currently, among the factors related to inflammation, the following stand out: ultra-sensitive C-reactive protein (hs-CRP), toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), IAP-1, IL-1β, IL-6, IL-18, TNF-α, NFkB, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. All of them are linked to signaling pathways of oxidative stress, hyperglycemia and its complications (29).

On the other hand, inflammatory biomarkers, when dysregulated, contribute to states of hypercoagulability and hypofibrinolysis, a fact observed in patients with T2D. The study conducted by Randeria et al., identified elevated levels of anti-inflammatory cytokines (IFN-α, IL-10, Il-4, IL-13, IL-1β, IL-6, IL-8 and sP-selectin, among others) in patients with T2D, a novel finding in the context of this disease (30). These pro-inflammatory signaling pathways and their triggering products appear to be promising biomarkers and therapeutic targets. Currently, anti-inflammatory therapy based on a healthy diet has proven effective by increasing plasma levels of antioxidants, reducing C-reactive protein and mitigating the effect of acute hyperglycemia on inflammation, oxidative stress and endothelial function (31).

Hyperglycemia, dyslipidemia, and hypertension, combined with the duration and type of diabetes, contribute to the distinctive pathophysiology of chronic complications such as diabetic kidney disease, diabetic neuropathy, and retinopathy. Elevated levels of plasma free fatty acids (FFAs) trigger a marked inhibition of insulin mRNA expression, decreasing both glucose-stimulated insulin secretion and insulin content of pancreatic islets (32).

As will be seen later, although there are no drugs specifically approved to treat IR, metformin and thiazolidinediones (TZDs) are sensitizers and increase peripheral glucose utilization (33).

Increased fatty acid metabolism in adipose tissue and lipogenesis in response to elevated glycemia and IR contribute to dyslipidemia in diabetes. Therefore, increased IR leads to overproduction of very low-density lipoprotein cholesterol (VLDL-C) and increased concentration of very low-density lipoproteins (VLDL), which clinically manifests as hypertriglyceridemia. In addition, VLDL-C could stimulate the exchange of triglycerides to cholesterol esters of high-density lipoproteins (HDL) and low-density lipoproteins (LDL), which causes a higher catabolic rate of HDL and the conversion of LDL to small and dense LDL, which are highly atherogenic (34).

These processes also lead to an overproduction of ApoB-containing lipoproteins in the liver, which manifests as hepatic overproduction of VLDL. The atherogenic dyslipidemia associated with these changes is a significant risk factor for the development of cardiovascular disease in patients with T2D. Therefore, it is important to establish interventions to reduce future macrovascular events (35).

These findings reinforce the multifactorial nature of type 2 diabetes, summarized in Figure 3, which integrates the role of adipokines, inflammation, and lipid metabolism in metabolic dysfunction.

Numerous studies confirm the proposal made by Ahlqvist et al., which suggests the possibility of grouping patients into different subgroups and that belonging to a subgroup is more strongly linked to the predisposition of certain complications (9, 11).

The identification of homogeneous groups is carried out through a K-means cluster analysis (CA). Patients with adult-onset diabetes are stratified by applying a data-driven approach, using clinical variables such as the level of glutamate decarboxylase antibodies (GADA), age at diagnosis, BMI, glycated hemoglobin (HbA1c), measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA2-IR). The reviewed studies used homeostasis model assessment indices based on C-peptide (HOMA, or its updated variant, HOMA 2) (41). The analysis, differentiated by sex, carried out by Ahlqvist et al., was performed, for the first time, in a Swedish cohort (n=8980), All New Diabetics in Scania (ANDIS), with prospective data from patient records on the development of complications and the prescription of medication. Five replicable subgroups were identified with significantly different clinical characteristics, disease progression and outcomes. The groups were named severe autoimmune diabetes (SAID), due to the presence of GADA antibodies, severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and the fifth group, mild age-related diabetes (MARD) (9).

Due to possible differences between ethnicities, genetic backgrounds and lifestyles, the CA has been replicated in different populations confirming the identification of the non-autoimmune diabetes subtypes of the ANDIS cohort (42). To refine this classification, other clinical parameters that contribute to the progression of diabetes have been included in the analyses, among which are triglycerides (TG), high- and low-density lipoproteins (HDL and LDL), uric acid (UA), waist circumference, estimated glomerular filtration rate (eGFR) and fasting and stimulated C-peptide (10, 28). The result has been the identification of new subgroups. Unlike genetic tests, the use of clinical parameters at the time of diagnosis is an easily applicable method in routine clinical practice to classify diabetes and establish a more individualized treatment plan.

The mild or absent symptoms present among the subjects of this group make this type of diabetes go unnoticed, especially in the Asian population who have an innate deficiency in insulin secretion. Despite the apparent lack of symptomatology, at the time of MIDD diagnosis, the function of pancreatic islets is usually significantly compromised. The finding of this subgroup is of great clinical importance to establish optimal interventions and avoid further deterioration in pancreatic β-cells (43).

Lifestyle modification (healthy diet, regular physical exercise, smoking, stress management, among others) remains the cornerstone of care for people with prediabetes or diabetes at any stage, with the aim of delaying the progression of the disease and future complications. When these measures fail to control glycemia in the initial 3–6 months, it is necessary to prescribe pharmacological therapy. Metformin is currently the most widely recommended first-line pharmacological therapy due to its efficacy, safety profile, and good tolerability. This recommendation is supported by international guidelines (ADA, EASD), which consistently demonstrate reductions in diabetes progression and improvements in glycemic control (37, 64, 65).

In fact, the administration of metformin along with a healthy lifestyle shows additional benefits to prevent disease progression. However, it is important to adjust the dose of metformin according to the patient's renal function to minimize the risk of lactic acidosis, a rare but serious complication associated with treatment.

The suboptimal glycemic control presented by both groups makes it necessary to intensify treatment compared to the MIDD group.

Considering that the abnormal function of pancreatic β-cells is associated with poor glycemic control, preserving and recovering their function by reducing the excessive workload, seems to be the most effective strategy (66). Initial intensive insulin therapy, defined as the use of this hormone as a first-line hypoglycemic treatment for two or more weeks in patients with newly diagnosed T2D, has been shown to be effective in preserving pancreatic β-cell function. In this sense, the insulinization through multiple daily injections of insulin, for a period of 2 to 3 weeks, not only achieves glycemic control, but also induces glycemic remission, restoring β-cell function (67). Additionally, it improves biomarkers related to inflammation, endothelial function and decreases the risk of ketoacidosis. Furthermore, the observational study by Luo et al., indicates that early insulin therapy may confer cardiovascular benefits, including a reduction in the risk of major events such as stroke and heart failure (68).

Therefore, in view of the characteristics present in EOIDD and LOIDD, this review proposes to initiate treatment with (rapid) insulin for 2 weeks in combination with diet and exercise. If after this time the glycemia values normalize, healthy lifestyle habits should be continued and assess whether treatment with metformin is necessary. Otherwise, and following the guidelines of the American Diabetes Association (ADA) for newly diagnosed patients, with clinical and HbA1c > 10%, we recommend administering basal (slow) insulin along with additional agents or without them (69). Subsequently, as a response is obtained, treatment should be simplified to avoid weight gain and the risk of cardiovascular and microvascular complications (RD) involved in insulin therapy (70).

The EOIDD group showed a high prevalence of RD. This condition is one of the main causes of vision loss developed in response to prolonged hyperglycemia. Therefore, early retinal examinations are recommended to identify lesions of various degrees, such as microaneurysm, hemorrhage and the formation of new vessels, which eventually transform into retinal thickening. A personalized therapy adjusted to the degree of the lesion should be established. Among the treatment modalities are glucocorticoids (dexamethasone, triamcinolone acetonide), intravitreal angiostatic therapy with growth factor inhibitors (bevacizumab), retinal laser therapy and vitrectomy, in the diagnosis of proliferative RD and in diabetic macular edema (42, 71).

In this group, insulin treatment would accentuate HOMA2-IR values; therefore, glycemic control with metformin is recommended initially, reserving possible intensification with secretagogues, glinides, or sulfonylureas (SU) for patients who do not achieve an adequate response. If SU therapy is initiated, close monitoring is advised to prevent β-cell function loss. This approach is supported by Saisho et al., who emphasizes the critical importance of preserving functional β-cell mass in the prevention and management of type 2 diabetes. Metformin improves insulin sensitivity and reduces β-cell workload, whereas SU use should be carefully managed to avoid accelerated deterioration of β-cell function (66).

In relation to retinopathy, it is advised to follow the same control and treatment guidelines applied to the EOIDD group, together with incorporation into a physical training program to reduce neuropathic pain. The prescription of exercises in a structured way can delay the incorporation of drugs indicated in ND, among which are tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors or antiepileptics such as gabapentin and pregabalin (40).

The management of the EOIRD group should focus on reducing BMI to improve insulin sensitivity. Papakonstantinou et al., indicated that lifestyle interventions through moderate weight reduction (7-10%), 150 minutes of moderate intensity exercise per week and approaches to behavioral therapy are effective in treating insulin resistance that causes obesity and preventing the progression of T2D (72). Based on the ADA/EASD consensus guidelines, the indicated line of treatment would be the reduction of body weight and the administration of metformin. This drug, a biguanide, in addition to inhibiting hepatic gluconeogenesis, increases insulin sensitivity and reduces glycemia (73).

In case of not reaching therapeutic objectives, treatment should be intensified with glucagon-like peptide-1 receptor agonists (GLP-1 RA). These drugs (semaglutide, dulaglutide, liraglutide) present a glucose-dependent mechanism of action, stimulating insulin secretion and reducing glucagon secretion in situations of hyperglycemia. In addition, they slow gastric emptying in the early postprandial phase, thus reducing caloric intake and promoting a reduction in body weight and fat mass. In this way, they reduce body weight and body fat mass by reducing caloric intake, which implies an overall reduction in appetite.

GLP-1 receptors are also expressed in organs such as the heart, vascular system, immune system and kidneys. In fact, they exert a beneficial effect on plasma lipids, systolic blood pressure, attenuate the development of atherosclerosis by preventing the progression of the aortic plaque and reducing inflammation in the plaque. The available evidence, according to the meta-analysis conducted by Evans et al., indicates that GLP-1 receptor agonists provide significant cardiovascular and renal benefits compared with DPP-4 inhibitors and basal insulin in patients with type 2 diabetes. Moreover, these agents appear to be a particularly suitable therapeutic option for patients with a BMI > 30 kg/m², as they may confer even greater cardiorenal benefits than basal insulin or DPP-4 inhibitors (74).

Patients included in this group present more impaired renal function than in EOIRD. In this context, the incorporation of sodium-glucose cotransporter inhibitors (SGLT2i), such as empagliflozin, is especially relevant. These drugs increase urinary glucose excretion, reduce HbA1c, body weight, blood pressure and decrease cardiovascular events through an improvement in the content of circulating regenerative cells and the lipid profile (66, 75). These properties make these drugs a useful therapeutic option in the management of patients in LOIRD.

Therapy aimed at reducing AU levels could be useful for the prevention and treatment of vascular complications in this population (76).

The systematic review carried out by Bletsa et al., provides evidence that allopurinol, a xanthine oxidase inhibitor, can reduce the risk of CVD in patients with T2D by lowering uric acid levels. However, as the authors point out, it is necessary to carry out randomized and placebo-controlled trials to confirm these findings and evaluate their clinical applicability in the patients included in this group (77).

The better glycemic control of this group over EOIRD and LOIRD leads to less intense hypoglycemic treatment, so we suggest allopurinol together with metformin and weight control strategies as therapy to reduce the progression of diabetes.

The therapeutic approach for this group focuses on glycemic control guided by the severity of the factors associated with these patients, with special attention to improving insulin sensitivity. Metformin is the first-line drug for SIRD, which is characterized by obesity and severe insulin resistance (14, 37). In addition, intensification of therapy with active interventions is required to reduce hepatic fat, a goal influenced by BMI. According to the Semergen 25 guidelines from the Spanish Society of Primary Care Physicians, pioglitazone is recommended for patients with a BMI< 30 kg/m² (78). In fact, the data-driven subgroup analysis of clinical trial data by Dennis et al., provides robust observational evidence that thiazolidinedione therapy produces greater glycemic benefits in the SIRD group. These drugs enhance insulin sensitivity in skeletal muscle and adipose tissue by increasing the number of GLUT4 transporters in the cell membrane, leading to improved glucose uptake and utilization in tissues, similarly to metformin. However, thiazolidinedione use requires careful cardiovascular monitoring, as it has been associated with an increased risk of heart failure in patients with type 2 diabetes (79).

For patients with a BMI > 30 kg/m2 SGLT2 inhibitors or GLP-1 RA are recommended. SGLT inhibitors are effective in reducing visceral fat (80), ectopic fat (81), improve insulin sensitivity, reduce CKD progression and can reduce obesity-related complications (14). In turn, GLP-1 drugs provide good results in weight reduction, hepatic fat and stroke, so this treatment option is also very beneficial for SIRD (63).

Therefore, according to ADA recommendations, the choice between GLP-1 RA, SGLT2i or combined treatment will depend on the individual characteristics of each patient (associated risk in patients over 55 years of age, atherosclerotic disease, heart failure or kidney disease) (82).

In patients with a high risk of renal and cardiovascular deterioration, the treatment approach is more complex, with the need to combine the aforementioned antidiabetics with non-hypoglycemic drugs, if the patient has not had them indicated. The reduction of albuminuria with inhibitors of the renin-angiotensin-aldosterone system (RAASi) is key to improving renal outcomes and constitutes, together with blood pressure control, the cornerstone of diabetic nephropathy treatment (83). However, sometimes, it is necessary to further intensify treatment. In this sense, sulodexide, a purified mixture of sulfated glycosaminoglycans of low molecular weight heparin, provides a renoprotective benefit through its ability to reduce urinary albumin excretion rates, so it occupies an important place in the treatment for the prevention of end-stage renal disease (84).

The more aggressive phenotype of this group characterized by difficult-to-control hyperglycemia, a product of the combination of insulin deficiency and resistance, together with overweight, dyslipidemia and markedly significant risks of cardiovascular, renal and retinopathy disease, makes it necessary to intensify treatment compared to SIDD and SIRD. Among the therapies considered for patients with high cardiovascular risk, metformin together with SGLT-2i and/or GLP1 RA stands out. In case glycemic control is not sufficient, treatment should be intensified with the incorporation of another oral drug or with basal insulin (78).

Regarding lipid control, SGLT2i improve diabetic dyslipidemia by reducing triglycerides and increasing HDL cholesterol (85). The American Diabetes Association (ADA) indications for the treatment of blood cholesterol in diabetes suggest considering the administration of moderate doses of statins to patients with diabetes mellitus between 40 and 75 years, even without associated cardiovascular risk factors. Therefore, if therapeutic and lifestyle measures do not work, it should be considered to prescribe moderate doses of statins 10–20 mg of atorvastatin, 5–10 mg of rosuvastatin, 20–40 mg of simvastatin or 40–80 mg of pravastatin (64).

It is recommended to follow the same guidelines for control and treatment of retinopathy as the EOIDD and SIDD groups, ensuring regular evaluation and implementation of timely interventions when necessary.

In this group, metformin continues to be the treatment of choice together with SGLT2i to reduce cardiorenal risk and glycemia. According to ADA recommendations, insulin therapy should be initiated if HbA1c is ≥ 10% or glycemia ≥ 300 mg/dL. In this context, the early use of basal insulin degludec or insulin glargine-300 is proposed, prioritizing them over glargine-100 due to their ability to reduce the risk of hypoglycemia, both general and nocturnal (86). In turn, it is recommended to prescribe RAASi treatment in cases of elevated blood pressure to prevent the risk of deterioration at the associated renal level. The possibility of incorporating sulodexide and statins should also be evaluated.

In relation to the risk of hepatic fibrosis, in addition to lifestyle modifications, such as weight loss, adherence to the Mediterranean diet and regular physical activity, current international guidelines suggest pharmacological treatment with vitamin E and pioglitazone for NAFLD (87).

Weight loss along with lifestyle changes can significantly improve glucose homeostasis and cardiometabolic risk factors in patients with T2D, although these strategies are not effective in the long term (88). In patients with high BMI, novel antidiabetic agents, particularly tirzepatide, a dual GIP/GLP-1 receptor agonist, as well as GLP-1 receptor agonists (semaglutide, dulaglutide, liraglutide), represent the most effective pharmacological strategy for managing type 2 diabetes and obesity insufficiently controlled by lifestyle interventions, as recommended by the Semergen 25 guidelines and supported by evidence from meta-analysis of randomized controlled trials conducted by Karagiannis et al. (78, 89). These agents not only promote significant weight loss but also improve insulin resistance, blood pressure, and plasma lipid profiles, including LDL, HDL, and triglycerides (90).

In case of needing an intensification in treatment, dipeptidyl peptidase 4 inhibitors (DPP4i) are recommended, which act by inhibiting the enzyme that blocks glucagon-like peptide type 1 (GLP1), which allows it to accumulate and remain longer in the body. This, in turn, stimulates insulin secretion after ingestion (the so-called incretinic effect), while at the same time reducing the counter-regulatory hormone, glucagon, and thus decreases glucose production by the liver. DPP4i are characterized by a neutral effect on weight, in the risk of hypoglycemia and in cardiovascular risk, so their indications are postulated to be wider than SU (91, 92).

The characteristics shared with MOD suggest that patients in the IROD 1 group would benefit from the same established treatment mentioned above. Regarding the IROD 2 group, the study conducted by Fedotkina et al., indicates that treatment may be more flexible, with a smaller number of patients in treatment with insulin, SU and a higher percentage of patients without pharmacological treatment, compared to IROD 1 (57). However, due to the high BMI (> 30 kg/m2) we advise, following the recommendations of Semergen 25, therapy with metformin, SGLT2i/GLP RA or the combination of both (78).

The features of this group lead to a therapy focused on decreasing BMI and improving insulin sensitivity. Therefore, the indicated drugs would be the combination of metformin and pioglitazone. In case of not achieving the proposed objectives and/or presence of metabolic liver disease, the recommended treatment is GLP1 RA/tirzepatide together with SGLT2i (37, 78).

In the case of patients with advanced age and frailty, predominant characteristics of this group, the treatment of choice continues to be metformin. However, it should be taken into account that this drug can intensify side effects over time. In addition, the deterioration of renal function, common in these patients, could lead to toxic levels of metformin. Also, congestive heart failure and liver failure are relative contraindications for treatment with this biguanide due to the increased risk of lactic acidosis (93).

The ADOPT and RECORD trials, on the benefits of differential treatment in subgroups, found a better response when MARD received a sulfonylurea. Despite these results and due to the associated risk of hypoglycemia, these secretagogues are discouraged in frail patients (94).

DPP-4 inhibitors belong to the group of incretin derivatives and have specific advantages for use in association and in special situations. Their low risk of hypoglycemia and weight gain together with the antioxidant and anti-inflammatory effects, which attenuate the cardiovascular complications of diabetes, constitute an effective therapeutic option in frail patients (92, 95). In the event of needing intensification of treatment, the indicated drugs are SGLT2 inhibitors (78).

In this group, as in others, metformin is the drug of choice. However, the atypical characteristics cited in the description of the group induce research into prospective strategies, such as genome association studies, to identify patients more accurately and quickly. This would allow for a more personalized therapy tailored to individual needs (37).

Insulin treatment is essential to prevent life-threatening complications in GADA+ patients. In most cases, multiple daily injections are required to achieve and maintain strict glycemic control, reflecting the progressive decline in β-cell function characteristic of this condition (96).

, provides a comprehensive summary of the main diabetes subgroups analyzed in this review, highlighting their clinical characteristics, associated risks for disease progression, and recommended therapeutic strategies. This synthesis offers a concise reference tool to facilitate comparison and evaluation across the different subtypes. 1