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      Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study

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          Abstract

          Background

          In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus.

          Methods

          The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA 1c at week 24.

          Results

          Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA 1c at week 24 was −0.028% (−0.192 to 0.137) in the placebo group, compared with −0.797% (−0.960 to −0.634) in the tofogliflozin 10 mg group, −1.017% (−1.178 to −0.856) in the tofogliflozin 20 mg group, and −0.870% (−1.031 to −0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity.

          Conclusions

          Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA 1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study.

          Trial registration

          This study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).

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          Most cited references 16

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          Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach

          Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits. These recommendations should be considered within the context of the needs, preferences, and tolerances of each patient; individualization of treatment is the cornerstone of success. Our recommendations are less prescriptive than and not as algorithmic as prior guidelines. This follows from the general lack of comparative-effectiveness research in this area. Our intent is therefore to encourage an appreciation of the variable and progressive nature of type 2 diabetes, the specific role of each drug, the patient and disease factors that drive clinical decision making (20–23), and the constraints imposed by age and comorbidity (4,6). The implementation of these guidelines will require thoughtful clinicians to integrate current evidence with other constraints and imperatives in the context of patient-specific factors. PATIENT-CENTERED APPROACH Evidence-based advice depends on the existence of primary source evidence. This emerges only from clinical trial results in highly selected patients, using limited strategies. It does not address the range of choices available, or the order of use of additional therapies. Even if such evidence were available, the data would show median responses and not address the vital question of who responded to which therapy and why (24). Patient-centered care is defined as an approach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions” (25). This should be the organizing principle underlying health care for individuals with any chronic disease, but given our uncertainties in terms of choice or sequence of therapy, it is particularly appropriate in type 2 diabetes. Ultimately, it is patients who make the final decisions regarding their lifestyle choices and, to some degree, the pharmaceutical interventions they use; their implementation occurs in the context of the patients’ real lives and relies on the consumption of resources (both public and private). Patient involvement in the medical decision making constitutes one of the core principles of evidence-based medicine, which mandates the synthesis of best available evidence from the literature with the clinician's expertise and patient's own inclinations (26). During the clinical encounter, the patient's preferred level of involvement should be gauged and therapeutic choices explored, potentially with the utilization of decision aids (21). In a shared decision-making approach, clinician and patient act as partners, mutually exchanging information and deliberating on options, in order to reach a consensus on the therapeutic course of action (27). There is good evidence supporting the effectiveness of this approach (28). Importantly, engaging patients in health care decisions may enhance adherence to therapy. BACKGROUND Epidemiology and health care impact Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and westernization of lifestyle. The attendant economic burden for health care systems is skyrocketing, owing to the costs associated with treatment and diabetes complications. Type 2 diabetes remains a leading cause of cardiovascular disorders, blindness, end-stage renal failure, amputations, and hospitalizations. It is also associated with increased risk of cancer, serious psychiatric illness, cognitive decline, chronic liver disease, accelerated arthritis, and other disabling or deadly conditions. Effective management strategies are of obvious importance. Relationship of glycemic control to outcomes It is well established that the risk of microvascular and macrovascular complications is related to glycemia, as measured by HbA1c; this remains a major focus of therapy (29). Prospective randomized trials have documented reduced rates of microvascular complications in type 2 diabetic patients treated to lower glycemic targets. In the UK Prospective Diabetes Study (UKPDS) (30,31), patients with newly diagnosed type 2 diabetes were randomized to two treatment policies. In the standard group, lifestyle intervention was the mainstay with pharmacological therapy used only if hyperglycemia became severe. In the more intensive treatment arm, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomized to metformin. The overall HbA1c achieved was 0.9% lower in the intensive policy group compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference in glycemic control was a reduction in the risk of microvascular complications (retinopathy, nephropathy, neuropathy) with intensive therapy. A trend toward reduced rates of myocardial infarction in this group did not reach statistical significance (30). By contrast, substantially fewer metformin-treated patients experienced myocardial infarction, diabetes-related and all-cause mortality (32), despite a mean HbA1c only 0.6% lower than the conventional policy group. The UKPDS 10-year follow-up demonstrated that the relative benefit of having been in the intensive management policy group was maintained over a decade, resulting in the emergence of statistically significant benefits on cardiovascular disease (CVD) end points and total mortality in those initially assigned to sulfonylurea/insulin, and persistence of CVD benefits with metformin (33), in spite of the fact that the mean HbA1c levels between the groups converged soon after the randomized component of the trial had concluded. In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD) (34), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) (35), Veterans Affairs Diabetes Trial (VADT) (36)] reported the effects of two levels of glycemic control on cardiovascular end points in middle-aged and older individuals with well-established type 2 diabetes at high risk for cardiovascular events. ACCORD and VADT aimed for an HbA1c 16.7–19.4 mmol/L [>300–350 mg/dL]) or HbA1c (e.g., ≥10.0–12.0%), insulin therapy should be strongly considered from the outset. Such treatment is mandatory when catabolic features are exhibited or, of course, if ketonuria is demonstrated, the latter reflecting profound insulin deficiency. Importantly, unless there is evidence of type 1 diabetes, once symptoms are relieved, glucotoxicity resolved, and the metabolic state stabilized, it may be possible to taper insulin partially or entirely, transferring to noninsulin antihyperglycemic agents, perhaps in combination. Figure 2 Antihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential sequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA1c target is not achieved after ∼3 months, consider one of the five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g., ≥9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c ≥10.0–12.0%). DPP-4-i, DPP-4 inhibitor; Fx's, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this stage in patients with very high HbA1c (e.g., ≥9%). b Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c See Table 1 for additional potential adverse effects and risks, under “Disadvantages.” d Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. e Certain noninsulin agents may be continued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia (≥16.7–19.4 mmol/L [≥300–350 mg/dL]; HbA1c ≥10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.). If metformin cannot be used, another oral agent could be chosen, such as a sulfonylurea/glinide, pioglitazone, or a DPP-4 inhibitor; in occasional cases where weight loss is seen as an essential aspect of therapy, initial treatment with a GLP-1 receptor agonist might be useful. Where available, less commonly used drugs (AGIs, colesevelam, bromocriptine) might also be considered in selected patients, but their modest glycemic effects and side-effect profiles make them less attractive candidates. Specific patient preferences, characteristics, susceptibilities to side effects, potential for weight gain and hypoglycemia should play a major role in drug selection (20,21). (See Supplementary Figs. for adaptations of Fig. 2 that address specific patient scenarios.) Advancing to dual combination therapy. Figure 2 (and Supplementary Figs.) also depicts potential sequences of escalating glucose-lowering therapy beyond metformin. If monotherapy alone does not achieve/maintain an HbA1c target over ∼3 months, the next step would be to add a second oral agent, a GLP-1 receptor agonist, or basal insulin (5,10). Notably, the higher the HbA1c, the more likely insulin will be required. On average, any second agent is typically associated with an approximate further reduction in HbA1c of ∼1% (70,79). If no clinically meaningful glycemic reduction (i.e., “nonresponder”) is demonstrated, then, adherence having been investigated, that agent should be discontinued, and another with a different mechanism of action substituted. With a distinct paucity of long-term comparative-effectiveness trials available, uniform recommendations on the best agent to be combined with metformin cannot be made (80). Thus, advantages and disadvantages of specific drugs for each patient should be considered (Table 1). Some antihyperglycemic medications lead to weight gain. This may be associated with worsening markers of insulin resistance and cardiovascular risk. One exception may be TZDs (57); weight gain associated with this class occurs in association with decreased insulin resistance. Although there is no uniform evidence that increases in weight in the range observed with certain therapies translate into a substantially increased cardiovascular risk, it remains important to avoid unnecessary weight gain by optimal medication selection and dose titration. For all medications, consideration should also be given to overall tolerability. Even occasional hypoglycemia may be devastating, if severe, or merely irritating, if mild (81). Gastrointestinal side effects may be tolerated by some, but not others. Fluid retention may pose a clinical or merely an aesthetic problem (82). The risk of bone fractures may be a specific concern in postmenopausal women (57). It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering agents in many environments. For resource-limited settings, less expensive agents should be chosen. However, due consideration should be also given to side effects and any necessary monitoring, with their own cost implications. Moreover, prevention of morbid long-term complications will likely reduce long-term expenses attributed to the disease. Advancing to triple combination therapy. Some studies have shown advantages of adding a third noninsulin agent to a two-drug combination that is not yet or no longer achieving the glycemic target (83–86). Not surprisingly, however, at this juncture, the most robust response will usually be with insulin. Indeed, since diabetes is associated with progressive β-cell loss, many patients, especially those with long-standing disease, will eventually need to be transitioned to insulin, which should be favored in circumstances where the degree of hyperglycemia (e.g., ≥8.5%) makes it unlikely that another drug will be of sufficient benefit (87). If triple combination therapy exclusive of insulin is tried, the patient should be monitored closely, with the approach promptly reconsidered if it proves to be unsuccessful. Many months of uncontrolled hyperglycemia should specifically be avoided. In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action (Fig. 2 and Supplementary Figs.). Increasing the number of drugs heightens the potential for side effects and drug–drug interactions, raises costs, and negatively impacts patient adherence. The rationale, benefits, and side effects of each new medication should be discussed with the patient. The clinical characteristics of patients more or less likely to respond to specific combinations are, unfortunately, not well defined. Transitions to and titrations of insulin. Most patients express reluctance to beginning injectable therapy, but, if the practitioner feels that such a transition is important, encouragement and education can usually overcome such reticence. Insulin is typically begun at a low dose (e.g., 0.1–0.2 U kg−1 day−1), although larger amounts (0.3–0.4 U kg−1 day−1) are reasonable in the more severely hyperglycemic. The most convenient strategy is with a single injection of a basal insulin, with the timing of administration dependent on the patient's schedule and overall glucose profile (Fig. 3). Figure 3 Sequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In patients willing to take more than one injection and who have higher HbA1c levels (≥9.0%), twice-daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime insulin, consisting of one to three injections of rapid-acting analogs (see text for details). A less studied alternative—progression from basal insulin to a twice-daily premixed insulin—could be also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Mod., moderate. Although extensive dosing instructions for insulin are beyond the scope of this statement, most patients can be taught to uptitrate their own insulin dose based on several algorithms, each essentially involving the addition of a small dose increase if hyperglycemia persists (74,76,88). For example, the addition of 1–2 units (or, in those already on higher doses, increments of 5–10%) to the daily dose once or twice weekly if the fasting glucose levels are above the preagreed target is a reasonable approach (89). As the target is neared, dosage adjustments should be more modest and occur less frequently. Downward adjustment is advisable if any hypoglycemia occurs. During self-titration, frequent contact (telephone, e-mail) with the clinician may be necessary. Practitioners themselves can, of course, also titrate basal insulin, but this would involve more intensive contact with the patient than typically available in routine clinical practice. Daily self-monitoring of blood glucose is of obvious importance during this phase. After the insulin dose is stabilized, the frequency of monitoring should be reviewed (90). Consideration should be given to the addition of prandial or mealtime insulin coverage when significant postprandial glucose excursions (e.g., to >10.0 mmol/L [>180 mg/dL]) occur. This is suggested when the fasting glucose is at target but the HbA1c remains above goal after 3–6 months of basal insulin titration (91). The same would apply if large drops in glucose occur during overnight hours or in between meals, as the basal insulin dose is increased. In this scenario, the basal insulin dose would obviously need to be simultaneously decreased as prandial insulin is initiated. Although basal insulin is titrated primarily against the fasting glucose, generally irrespective of the total dose, practitioners should be aware that the need for prandial insulin therapy will become likely the more the daily dose exceeds 0.5 U kg−1 day−1, especially as it approaches 1 U kg−1 day−1. The aim with mealtime insulin is to blunt postprandial glycemic excursions, which can be extreme in some individuals, resulting in poor control during the day. Such coverage may be provided by one of two methods. The most precise and flexible prandial coverage is possible with “basal-bolus” therapy, involving the addition of premeal rapid-acting insulin analog to ongoing basal insulin. One graduated approach is to add prandial insulin before the meal responsible for the largest glucose excursion—typically that with the greatest carbohydrate content, often, but not always, the evening meal (92). Subsequently, a second injection can be administered before the meal with the next largest excursion (often breakfast). Ultimately, a third injection may be added before the smallest meal (often lunch) (93). The actual glycemic benefits of these more advanced regimens after basal insulin are generally modest in typical patients (92). So, again, individualization of therapy is key, incorporating the degree of hyperglycemia needing to be addressed and the overall capacities of the patient. Importantly, data trends from self-monitoring may be particularly helpful in titrating insulins and their doses within these more advanced regimens to optimize control. A second, perhaps more convenient but less adaptable method involves “premixed” insulin, consisting of a fixed combination of an intermediate insulin with regular insulin or a rapid analog. Traditionally, this is administered twice daily, before morning and evening meals. In general, when compared with basal insulin alone, premixed regimens tend to lower HbA1c to a larger degree, but often at the expense of slightly more hypoglycemia and weight gain (94). Disadvantages include the inability to titrate the shorter- from the longer-acting component of these formulations. Therefore, this strategy is somewhat inflexible but may be appropriate for certain patients who eat regularly and may be in need of a simplified approach beyond basal insulin (92,93). (An older and less commonly used variation of this two-injection strategy is known as “split-mixed,” involving a fixed amount of intermediate insulin mixed by the patient with a variable amount of regular insulin or a rapid analog. This allows for greater flexibility in dosing.) The key messages from dozens of comparative insulin trials in type 2 diabetes include the following: 1. Any insulin will lower glucose and HbA1c. 2. All insulins are associated with some weight gain and some risk of hypoglycemia. 3. The larger the doses and the more aggressive the titration, the lower the HbA1c, but often with a greater likelihood of adverse effects. 4. Generally, long-acting insulin analogs reduce the incidence of overnight hypoglycemia, and rapid-acting insulin analogs reduce postprandial glucose excursions as compared with corresponding human insulins (NPH, Regular), but they generally do not result in clinically significantly lower HbA1c. Metformin is often continued when basal insulin is added, with studies demonstrating less weight gain when the two are used together (95). Insulin secretagogues do not seem to provide for additional HbA1c reduction or prevention of hypoglycemia or weight gain after insulin is started, especially after the dose is titrated and stabilized. When basal insulin is used, continuing the secretagogue may minimize initial deterioration of glycemic control. However, secretagogues should be avoided once prandial insulin regimens are employed. TZDs should be reduced in dose (or stopped) to avoid edema and excessive weight gain, although in certain individuals with large insulin requirements from severe insulin resistance, these insulin sensitizers may be very helpful in lowering HbA1c and minimizing the required insulin dose (96). Data concerning the glycemic benefits of incretin-based therapy combined with basal insulin are accumulating; combination with GLP-1 receptor agonists may be helpful in some patients (97,98). Once again, the costs of these more elaborate combined regimens must be carefully considered. OTHER CONSIDERATIONS Age Older adults (>65–70 years) often have a higher atherosclerotic disease burden, reduced renal function, and more comorbidities (99,100). Many are at risk for adverse events from polypharmacy and may be both socially and economically disadvantaged. Life expectancy is reduced, especially in the presence of long-term complications. They are also more likely to be compromised by hypoglycemia; for example, unsteadiness may result in falls and fractures (101), and a tenuous cardiac status may deteriorate into catastrophic events. It follows that glycemic targets for elderly with long-standing or more complicated disease should be less ambitious than for the younger, healthier individuals (20). If lower targets cannot be achieved with simple interventions, an HbA1c of <7.5–8.0% may be acceptable, transitioning upward as age increases and capacity for self-care, cognitive, psychological and economic status, and support systems decline. While lifestyle modification can be successfully implemented across all age-groups, in the aged, the choice of antihyperglycemic agent should focus on drug safety, especially protecting against hypoglycemia, heart failure, renal dysfunction, bone fractures, and drug–drug interactions. Strategies specifically minimizing the risk of low blood glucose may be preferred. In contrast, healthier patients with long life expectancy accrue risk for vascular complications over time. Therefore, lower glycemic targets (e.g., an HbA1c <6.5–7.0%) and tighter control of body weight, blood pressure, and circulating lipids should be achieved to prevent or delay such complications. This usually requires combination therapy, the early institution of which may have the best chance of modifying the disease process and preserving quality of life. Weight The majority of individuals with type 2 diabetes are overweight or obese (∼80%) (102). In these, intensive lifestyle intervention can improve fitness, glycemic control, and cardiovascular risk factors for relatively small changes in body weight (103). Although insulin resistance is thought of as the predominate driver of diabetes in obese patients, they actually have a similar degree of islet dysfunction to leaner patients (37). Perhaps as a result, the obese may be more likely to require combination drug therapy (20,104). While common practice has favored metformin in heavier patients, because of weight loss/weight neutrality, this drug is as efficacious in lean individuals (75). TZDs, on the other hand, appear to be more effective in those with higher BMIs, although their associated weight gain makes them, paradoxically, a less attractive option here. GLP-1 receptor agonists are associated with weight reduction (38), which in some patients may be substantial. Bariatric surgery is an increasingly popular option in severe obesity. Type 2 diabetes frequently resolves rapidly after these procedures. The majority of patients are able to stop some, or even all, of their antihyperglycemic medications, although the durability of this effect is not known (105). In lean patients, consideration should be given to the possibility of latent autoimmune diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. These individuals, while presenting with mild hyperglycemia, often responsive to oral agents, eventually develop more severe hyperglycemia and require intensive insulin regimens (106). Measuring titres of islet-associated autoantibodies (e.g., anti-GAD) may aid their identification, encouraging a more rapid transition to insulin therapy. Sex/racial/ethnic/genetic differences While certain racial/ethnic features that increase the risk of diabetes are well recognized [greater insulin resistance in Latinos (107), more β-cell dysfunction in East Asians (108)], using this information to craft optimal therapeutic strategies is in its infancy. This is not surprising given the polygenic inheritance pattern of the disease. Indeed, while matching a drug's mechanism of action to the underlying causes of hyperglycemia in a specific patient seems logical, there are few data that compare strategies based on this approach (109). There are few exceptions, mainly involving diabetes monogenic variants often confused with type 2 diabetes, such as maturity-onset diabetes of the young (MODY), several forms of which respond preferentially to sulfonylureas (110). While there are no prominent sex differences in the response to various antihyperglycemic drugs, certain side effects (e.g., bone loss with TZDs) may be of greater concern in women. Comorbidities Coronary artery disease. Given the frequency with which type 2 diabetic patients develop atherosclerosis, optimal management strategies for those with or at high risk for coronary artery disease (CAD) are important. Since hypoglycemia may exacerbate myocardial ischemia and may cause dysrhythmias (111), it follows that medications that predispose patients to this adverse effect should be avoided, if possible. If they are required, however, to achieve glycemic targets, patients should be educated to minimize risk. Because of possible effects on potassium channels in the heart, certain sulfonylureas have been proposed to aggravate myocardial ischemia through effects on ischemic preconditioning (112), but the actual clinical relevance of this remains unproven. Metformin may have some cardiovascular benefits and would appear to be a useful drug in the setting of CAD, barring prevalent contraindications (32). In a single study, pioglitazone was shown to reduce modestly major adverse cardiovascular events in patients with established macrovascular disease. It may therefore also be considered, unless heart failure is present (60). In very preliminary reports, therapy with GLP-1 receptor agonists and DPP-4 inhibitors has been associated with improvement in either cardiovascular risk or risk factors, but there are no long-term data regarding clinical outcomes (113). There are very limited data suggesting that AGIs (114) and bromocriptine (115) may reduce cardiovascular events. Heart failure. With an aging population and recent decreases in mortality after myocardial infarction, the diabetic patient with progressive heart failure is an increasingly common scenario (116). This population presents unique challenges given their polypharmacy, frequent hospitalizations, and contraindications to various agents. TZDs should be avoided (117,118). Metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patient's cardiovascular status is stable, and if renal function is normal (119). As mentioned, cardiovascular effects of incretin-based therapies, including those on ventricular function, are currently under investigation (120). Chronic kidney disease. Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal functional impairment (eGFR <60 mL/min) occurs in approximately 20–30% of patients (121,122). The individual with progressive renal dysfunction is at increased risk for hypoglycemia, which is multifactorial. Insulin and, to some degree, the incretin hormones are eliminated more slowly, as are antihyperglycemic drugs with renal excretion. Thus, dose reduction may be necessary, contraindications need to be observed, and consequences (hypoglycemia, fluid retention, etc.) require careful evaluation. Current U.S. prescribing guidelines warn against the use of metformin in patients with a serum creatinine ≥133 mmol/L (≥1.5 mg/dL) in men or 124 mmol/L (≥1.4 mg/dL) in women. Metformin is eliminated renally, and cases of lactic acidosis have been described in patients with renal failure (123). There is an ongoing debate, however, as to whether these thresholds are too restrictive and that those with mild–moderate renal impairment would gain more benefit than harm from using metformin (124,125). In the U.K., the National Institute for Health and Clinical Excellence (NICE) guidelines are less proscriptive and more evidence-based than those in the U.S., generally allowing use down to a GFR of 30 mL/min, with dose reduction advised at 45 mL/min (14). Given the current widespread reporting of estimated GFR, these guidelines appear very reasonable. Most insulin secretagogues undergo significant renal clearance (exceptions include repaglinide and nateglinide) and the risk of hypoglycemia is therefore higher in patients with chronic kidney disease (CKD). For most of these agents, extreme caution is imperative at more severe degrees of renal dysfunction. Glyburide (known as glibenclamide in Europe), which has a prolonged duration of action and active metabolites, should be specifically avoided in this group. Pioglitazone is not eliminated renally, and therefore there are no restrictions for use in CKD. Fluid retention may be a concern, however. Among the DPP-4 inhibitors, sitagliptin, vildagliptin, and saxagliptin share prominent renal elimination. In the face of advanced CKD, dose reduction is necessary. One exception is linagliptin, which is predominantly eliminated enterohepatically. For the GLP-1 receptor agonists exenatide is contraindicated in stage 4–5 CKD (GFR <30 mL/min) as it is renally eliminated; the safety of liraglutide is not established in CKD though pharmacokinetic studies suggest that drug levels are unaffected as it does not require renal function for clearance. More severe renal functional impairment is associated with slower elimination of all insulins. Thus doses need to be titrated carefully, with some awareness for the potential for more prolonged activity profiles. Liver dysfunction. Individuals with type 2 diabetes frequently have hepatosteatosis as well as other types of liver disease (126). There is preliminary evidence that patients with fatty liver may benefit from treatment with pioglitazone (45,127,128). It should not be used in an individual with active liver disease or an alanine transaminase level above 2.5 times the upper limit of normal. In those with steatosis but milder liver test abnormalities, this insulin sensitizer may be advantageous. Sulfonylureas can rarely cause abnormalities in liver tests but are not specifically contraindicated; meglitinides can also be used. If hepatic disease is severe, secretagogues should be avoided because of the increased risk of hypoglycemia. In patients with mild hepatic disease, incretin-based drugs can be prescribed, except if there is a coexisting history of pancreatitis. Insulin has no restrictions for use in patients with liver impairment and is indeed the preferred choice in those with advanced disease. Hypoglycemia. Hypoglycemia in type 2 diabetes was long thought to be a trivial issue, as it occurs less commonly than in type 1 diabetes. However, there is emerging concern based mainly on the results of recent clinical trials and some cross-sectional evidence of increased risk of brain dysfunction in those with repeated episodes. In the ACCORD trial, the frequency of both minor and major hypoglycemia was high in intensively managed patients—threefold that associated with conventional therapy (129). It remains unknown whether hypoglycemia was the cause of the increased mortality in the intensive group (130,131). Clearly, however, hypoglycemia is more dangerous in the elderly and occurs consistently more often as glycemic targets are lowered. Hypoglycemia may lead to dysrhythmias, but can also lead to accidents and falls (which are more likely to be dangerous in the elderly) (132), dizziness (leading to falls), confusion (so other therapies may not be taken or taken incorrectly), or infection (such as aspiration during sleep, leading to pneumonia). Hypoglycemia may be systematically under-reported as a cause of death, so the true incidence may not be fully appreciated. Perhaps just as importantly, additional consequences of frequent hypoglycemia include work disability and erosion of the confidence of the patient (and that of family or caregivers) to live independently. Accordingly, in at-risk individuals, drug selection should favor agents that do not precipitate such events and, in general, blood glucose targets may need to be moderated. FUTURE DIRECTIONS/RESEARCH NEEDS For antihyperglycemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metformin monotherapy (70). There is a significant need for high-quality comparative-effectiveness research, not only regarding glycemic control, but also costs and those outcomes that matter most to patients—quality of life and the avoidance of morbid and life-limiting complications, especially CVD (19,23,70). Another issue about which more data are needed is the concept of durability of effectiveness (often ascribed to β-cell preservation), which would serve to stabilize metabolic control and decrease the future treatment burden for patients. Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects. We need more clinical data on how phenotype and other patient/disease characteristics should drive drug choices. As new medications are introduced to the type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in studies versus best current treatment, substantial enough both in size and duration to provide meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head comparisons of all combinations and permutations would be impossibly large (133). Informed judgment and the expertise of experienced clinicians will therefore always be necessary.
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            Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis.

            Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs. To assess the efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities' reports; and gray literature. Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes. Three reviewers extracted or checked data for study characteristics, outcomes of interest, and risk of bias, and 3 reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Sodium-glucose cotransporter 2 inhibitors were compared with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175). They had a favorable effect on hemoglobin A1c level (mean difference vs. placebo, -0.66% [95% CI, -0.73% to -0.58%]; mean difference vs. active comparators, -0.06% [CI, -0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, -1.80 kg [CI, -3.50 to -0.11 kg]) and systolic blood pressure (mean difference, -4.45 mm Hg [CI, -5.73 to -3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06 to 1.90] and 5.06 [CI, 3.44 to 7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control. Most trials were rated as high risk of bias because of missing data and last-observation-carried-forward methods. Sodium-glucose cotransporter 2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear. None.
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              Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

              Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.
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                Author and article information

                Contributors
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central
                1475-2840
                2014
                28 March 2014
                : 13
                : 65
                Affiliations
                [1 ]Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
                [2 ]Department of Endocrinology & Metabolism, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
                [3 ]Tokyo Women's Medical University School of Medicine, 8-1, Kawada, Shinjuku-ku, Tokyo 162-8666, Japan
                [4 ]Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
                [5 ]Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
                [6 ]The First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
                [7 ]Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
                [8 ]Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan
                [9 ]Clinical Research Planning Department, Chugai, 1-1 Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo 103-8324, Japan
                [10 ]Clinical Data Science Department, Biostatistics Section, Kowa, 3-4-14, Nihonbashi-honcho, Chuo-ku, Tokyo 103-0023, Japan
                [11 ]Research & Development, Clinical Sciences & Operations, Biostatistics & Programming, Biostatistics, Sanofi, Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan
                Author notes
                for The Tofogliflozin 003 Study Group
                Article
                1475-2840-13-65
                10.1186/1475-2840-13-65
                4021346
                24678906
                Copyright © 2014 Kaku et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Original Investigation

                Endocrinology & Diabetes

                body weight, hba1c, rg7201, csg452, tofogliflozin, sglt2 inhibitor

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