Blog
About

65
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pathophysiologic Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes

      , MD, , MD, PHD, , MD, PHD

      Diabetes Care

      American Diabetes Association

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Two general approaches to the treatment of type 2 diabetes mellitus (T2DM) have been advocated. 1) A “guideline” approach that advocates sequential addition of antidiabetes agents with “more established use” (1); this approach more appropriately should be called the “treat to failure” approach, and deficiencies with this approach have been discussed (2). And 2) a “pathophysiologic” approach using initial combination therapy with agents known to correct established pathophysiologic defects in T2DM (3). Within the pathophysiologic approach, choice of antidiabetes agents should take into account the patient’s general health status and associated medical disorders. This individualized approach, which we refer to as the ABCD(E) of diabetes treatment (4), has been incorporated into the updated American Diabetes Association (ADA) guidelines (5). A = Age B = Body weight C = Complications (microvascular and macrovascular) D = Duration of diabetes E = Life Expectancy E = Expense Even though physicians must be cognizant of these associated conditions (ABCDE) when initiating therapy in newly diagnosed T2DM patients, we believe that the most important consideration is to select antidiabetes agents that correct specific pathophysiologic disturbances present in T2DM and that have complementary mechanisms of action. Although it has been argued that the pathogenesis of T2DM differs in different ethnic groups (6), evidence to support this is weak. Although the relative contributions of β-cell failure and insulin resistance to development of glucose intolerance may differ in different ethnic groups (6), the core defects of insulin resistance in muscle/liver/adipocytes and progressive β-cell failure (3) are present in virtually all T2DM patients and must be treated aggressively to prevent the relentless rise in HbA1c that is characteristic of T2DM. In subsequent sections, we provide a review of the natural history of T2DM, specific pathophysiologic abnormalities responsible for T2DM, currently available antidiabetes agents and their mechanism of action, recommended glycemic goals, and use of combination therapy based upon reversal of pathophysiologic defects present in T2DM. We will not address expense but recognize that this is an important consideration in choosing any antidiabetes regimen. Overview of T2DM: pathophysiology and general therapeutic approach T2DM is a complex metabolic/cardiovascular disorder with multiple pathophysiologic abnormalities. Insulin resistance in muscle/liver and β-cell failure represent the core defects (7,8). β-Cell failure occurs much earlier in the natural history of T2DM and is more severe than previously thought (9–12). Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost >80% of their β-cell function. In addition to muscle, liver, and β-cells (“triumvirate”) (7), adipocytes (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cells (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance and neurotransmitter dysregulation) play important roles in development of glucose intolerance in T2DM individuals (3). Collectively, these eight players comprise the “ominous octet” (Fig. 1) and dictate that 1) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing HbA1c, and 3) therapy must be started early to prevent/slow progressive β-cell failure that is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with agents that correct known pathogenic defects in T2DM and produce durable reduction in HbA1c rather than just focusing on the glucose-lowering ability of the drug. Figure 1 The ominous octet (3) depicting the mechanism and site of action of antidiabetes medications based upon the pathophysiologic disturbances present in T2DM. Natural history of T2DM Individuals destined to develop T2DM inherit genes that make their tissues resistant to insulin (2,8,13–15). In liver, insulin resistance is manifested by glucose overproduction during the basal state despite fasting hyperinsulinemia (16) and impaired suppression of hepatic glucose production (HGP) by insulin (17), as occurs following a meal (18). In muscle (17,19,20), insulin resistance is manifest by impaired glucose uptake after carbohydrate ingestion, resulting in postprandial hyperglycemia (18). Although the origins of insulin resistance can be traced to their genetic background (8,14,15), the current diabetes epidemic is related to the epidemic of obesity and physical inactivity (21), which are insulin-resistant states (22) and place stress on pancreatic β-cells to augment insulin secretion to offset insulin resistance (2,3,8). As long as β-cells augment insulin secretion sufficiently to offset the insulin resistance, glucose tolerance remains normal (2,3,8,23–29). However, with time β-cells begin to fail, and initially postprandial plasma glucose levels and subsequently fasting plasma glucose begin to rise, leading to overt diabetes (2,3,8). Thus, it is progressive β-cell failure that determines the rate of disease progression. The natural history of T2DM described above (2,3) is depicted by a prospective study carried out by DeFronzo (3); Jallut, Golay, and Munger (30); and Felber et al. (31) (Fig. 2). Figure 2 Natural history of T2DM. The plasma insulin response depicts the classic Starling’s Curve of the Pancreas. See text for a detailed explanation (7). Upper panel: Insulin-mediated glucose disposal (insulin clamp technique) and mean plasma insulin concentration during OGTT. Lower panel: Mean plasma glucose concentration during OGTT. DIAB, T2DM; Hi, high; Lo, low; OB, obese. β-Cell function Although the plasma insulin response to insulin resistance is increased early in the natural history of T2DM (Fig. 2), this does not mean that β-cells are functioning normally (3). Simply measuring the plasma insulin response to a glucose challenge does not provide a valid index of β-cell function (32). β-Cells respond to an increment in glucose (ΔG) with an increment in insulin (ΔI). Thus, a better measure of β-cell function is ΔI/ΔG. However, β-cells also increase insulin section to offset insulin resistance and maintain normoglycemia (9,10,12,23,32,33). Thus, the gold standard measure of β-cell function in vivo in man is the insulin secretion/insulin resistance (disposition) index (ΔI/ΔG ÷ IR). Figure 3 depicts the insulin secretion/insulin resistance index in normal glucose tolerant (NGT), IGT, and T2DM subjects as a function of 2-h plasma glucose during oral glucose tolerance test (OGTT) (2,9,10,12). Subjects in the upper tertile of NGT (2-h plasma glucose 120–139 mg/dL) have lost >50% of β-cell function, while subjects in upper tertile of IGT (2-h plasma glucose 180–199 mg/dL) have lost ∼80% of β-cell function (Fig. 3). Similar conclusions are evident from other publications (24,27,34,35). The therapeutic implications of these findings are obvious. When the diagnosis of diabetes is made, the patient has lost ∼80% of their β-cell function, and it is essential that physicians intervene with therapies known to correct established pathophysiological disturbances in β-cell function. Even more ominous are observations of Butler et al. (36), who demonstrated that as individuals progress from NGT to IFG, there is significant loss of β-cell mass that continues with progression to diabetes. Similar results have been published by others (37,38) and indicate that significant loss of β-cells occurs long before onset of T2DM, according to current diagnostic criteria (1). Figure 3 Insulin secretion/insulin resistance (disposition) index (ΔI/ΔG ÷ IR) during OGTT in individuals with NGT, IGT, and T2DM as a function of the 2-h plasma glucose (PG) concentration in lean and obese subjects (9–12). In summary, although insulin resistance in liver/muscle is well established early in the natural history of T2DM, overt diabetes does not occur in the absence of progressive β-cell failure. Insulin resistance The liver and muscle are severely resistant to insulin in T2DM (rev. in 2,3,8). Liver. After an overnight fast, the liver produces glucose at ∼2 mg/kg/min (2,16). In T2DM, the rate of basal HGP is increased, averaging ∼2.5 mg/kg/min (2,16). This amounts to addition of an extra 25–30 g glucose to the systemic circulation nightly and is responsible for the increased fasting plasma glucose concentration. This hepatic overproduction of glucose occurs despite fasting insulin levels that are increased two- to threefold, indicating severe hepatic insulin resistance. Muscle. With use of the euglycemic insulin clamp with limb catheterization (2,3,17,19,20,39,40), it has conclusively been demonstrated that lean, as well as obese, T2DM individuals are severely resistant to insulin and that the primary site of insulin resistance resides in muscle. Multiple intramyocellular defects in insulin action have been documented in T2DM (rev. in 2,3,8,40), including impaired glucose transport/phosphorylation (17), reduced glycogen synthesis (39), and decreased glucose oxidation (17). However, more proximal insulin signaling defects play a paramount role in muscle insulin resistance (3,40–42). Ominous octet In addition to the triumvirate (β-cell failure and insulin resistance in muscle and liver), at least five other pathophysiologic abnormalities contribute to glucose intolerance in T2DM (3) (Fig. 1): 1) adipocyte resistance to insulin’s antilipolytic effect, leading to increased plasma FFA concentration and elevated intracellular levels of toxic lipid metabolites in liver/muscle and β-cells that cause insulin resistance and β-cell failure/apoptosis (17); 2) decreased incretin (glucagon-like peptide [GLP]-1/glucose-dependent insulinotropic polypeptide [GIP]) effect resulting from impaired GLP-1 secretion (43) but, more importantly, severe β-cell resistance to the stimulatory effect of GLP-1 and GIP (44,45); 3) increased glucagon secretion by α-cells and enhanced hepatic sensitivity to glucagon, leading to increased basal HGP and impaired HGP suppression by insulin (46,47); 4) enhanced renal glucose reabsorption contributing to maintenance of elevated plasma glucose levels (48,49); and 5) central nervous system resistance to the anorectic effect of insulin and altered neurosynaptic hormone secretion contributing to appetite dysregulation, weight gain, and insulin resistance in muscle/liver (50–52). Implications for therapy The preceding review of pathophysiology has important therapeutic implications: 1) effective treatment will require multiple drugs in combination to correct the multiple pathophysiological defects, 2) treatment should be based upon established pathogenic abnormalities and not simply on HbA1c reduction, and 3) therapy must be started early in the natural history of T2DM to prevent progressive β-cell failure. Figure 1 displays therapeutic options as they relate to key pathophysiological derangements in T2DM (Fig. 1). In liver, both metformin (53–55) and thiazolidinediones (TZDs) (56–62) are potent insulin sensitizers and inhibit the increased rate of HGP. In muscle, TZDs are potent insulin sensitizers (56–58,61,63), whereas metformin is, at best, a weak insulin sensitizer (53,55,64). Since TZDs work through the insulin signaling pathway (65), whereas metformin works through the AMP kinase pathway (66), combination TZD/metformin therapy gives a completely additive effect to reduce HbA1c (67–72). Further, hypoglycemia is not encountered because these drugs are insulin sensitizers and do not augment insulin secretion. In adipocytes, TZDs are excellent insulin sensitizers and potent inhibitors of lipolysis (73). TZDs also mobilize fat out of muscle, liver, and β-cells, thereby ameliorating lipotoxicity (57,62,63,74–76). Although weight loss has the potential to improve both the defects in insulin sensitivity and insulin secretion (77), two meta-analyses involving 46 published studies demonstrated that the ability to maintain the initial weight loss is difficult (78,79). In the following sections, we will focus on pharmacologic agents—as monotherapy and combination therapy—that have been proven to reverse pathophysiologic abnormalities in T2DM. In the β-cell, sulfonylureas and glinides augment insulin secretion (80), but only TZDs (81–83) and GLP-1 analogs (84–86) improve and preserve β-cell function and demonstrate durability of glycemic control (70,82–85,87–93). Importantly, TZDs and GLP-1 analogs cause durable HbA1c reduction for up to 5 and 3.5 years, respectively (82,93). Although dipeptidyl peptidase inhibitors (DPP4i) augment insulin secretion (94), their β-cell effect is weak compared with GLP1 analogs and they begin to lose efficacy (manifested by rising HbA1c) within 2 years after initiation of therapy (95,96). Despite the potent effects of TZDs and GLP-1 agonists on β-cells, the two most commonly prescribed drugs in the U.S. and worldwide are sulfonylureas and metformin, neither of which exerts any β-cell protective effect. This is a major concern, since progressive β-cell failure is the primary pathogenic abnormality responsible for development of T2DM and progressive HbA1c rise (Fig. 3). GLP-1 analogs augment and preserve β-cell function for at least 3 years (84). This protective effect has its onset within 24 h (86) and persists as long as GLP-1 therapy is continued (84,85,93). Further, both exenatide and liraglutide promote weight loss, inhibit glucagon secretion, and delay gastric emptying, reducing postprandial hyperglycemia (45,93,97–99). Weight loss depletes lipid from muscle and liver, improving muscle and hepatic insulin sensitivity (84,85). GLP-1 analogs also correct multiple cardiovascular risk factors (rev. in 100) and, thus, have the potential to reduce cardiovascular events (101,102). Although DPP4i share some characteristics with GLP-1 analogs, they do not raise plasma GLP-1 levels sufficiently to offset β-cell resistance to GLP-1 (103). Not surprisingly, their ability to augment insulin secretion and reduce HbA1c is considerably less than GLP-1 analogs (94,104,105), and they do not promote weight loss (94). In a 1-year study involving 665 metformin-treated T2DM patients, HbA1c reduction with sitagliptin (0.9%) was significantly less than liraglutide dosed at 1.2 mg/day (ΔHbA1c = 1.2%) or 1.8 mg/day (ΔHbA1c = 1.8%) (105). In a short-term, mechanism-of-action, crossover study, exenatide was far superior to sitagliptin in reducing glucose area under the curve and 2-h glucose after a meal, increasing insulin secretion, inhibiting glucagon secretion, and promoting weight loss (104). Metformin increases GLP-1 secretion by intestinal L-cells (106–108), and the combination of metformin plus DPP4i may exert a more durable effect on β-cell function. The major mechanism of action of DPP4i to improve glycemic control is mediated via inhibition of glucagon secretion with subsequent decline in HGP (109) Although not yet approved by U.S. regulatory agencies, sodium glucose transporter 2 inhibitors (approved in Europe) demonstrate modest efficacy in reducing HbA1c, promote weight loss, reduce blood pressure, and can be added to any antidiabetes agent (48,110). Instituting therapy in newly diagnosed T2DM patients When initiating therapy in newly diagnosed T2DM patients, the following considerations are of paramount importance: Therapy should have the ability to achieve the desired level of glycemic control, based upon starting HbA1c. According to the ADA, European Association for the Study of Diabetes (EASD), and American Association of Clinical Endocrinologists (AACE), the desired HbA1c is 6.5% (EASD and AACE) or 7.0% (ADA) (5,111). However, we believe that in newly diagnosed diabetic patients without cardiovascular disease, the optimal HbA1c should be ≤6.0%, while avoiding adverse events, primarily hypoglycemia. This is consistent with the expanded ADA/EASD statement (5). In most newly diagnosed diabetic patients, monotherapy will not reduce HbA1c <6.5–7.0% or, most optimally, <6.0%, and combination therapy will be required. Importantly, medications used in combination therapy should have an additive effect, and individual drugs should correct established pathophysiologic disturbances in T2DM. If antidiabetes medications do not correct underlying pathogenic abnormalities, long-term durable glycemic control cannot be achieved. Progressive β-cell failure is responsible for progressive HbA1c rise in T2DM (3). Therefore, medications used to treat T2DM should preserve or improve β-cell function to ensure durable glycemic control. Because insulin resistance is a core defect in T2DM and exacerbates the decline in β-cell function, medications also should ameliorate insulin resistance in muscle/liver. T2DM is associated with an increased incidence of atherosclerotic cardiovascular complications. Therefore, it is desirable that drugs exert beneficial effects on cardiovascular risk factors and decrease cardiovascular events. Since obesity is a major problem in diabetic individuals, combination therapy should be weight neutral and, if possible, promote weight loss. Combination therapy should be safe and not exacerbate underlying medical conditions. No single antidiabetes agent can correct all of the pathophysiologic disturbances present in T2DM, and multiple agents, used in combination, will be required for optimal glycemic control. Further, the HbA1c decrease produced by a single antidiabetes agent, e.g., metformin, sulfonylurea, TZD, GLP-1 analog, is in the range of 1.0–1.5% depending upon the starting HbA1c (5). Thus, in newly diagnosed T2DM with HbA1c >8.0–8.5%, a single agent is unlikely to achieve HbA1c goal <6.5–7.0%, and virtually no one will achieve HbA1c <6.0%. When maximal-dose metformin, sulfonylurea, or TZD is initiated as monotherapy, <40% of newly diagnosed T2DM subjects can be expected to achieve HbA1c <6.5–7.0%. Thus, most patients with HbA1c >8.0–8.5% will require initial combination therapy to reach HbA1c <6.5–7.0%. Moreover, because different agents lower plasma glucose via different mechanisms, combination therapy will have an additive effect to reduce HbA1c compared with each agent alone. Simultaneous correction of the β-cell defect and insulin resistance is more likely to cause durable HbA1c reduction. Lastly, combination therapy allows use of submaximal doses of each antidiabetes agent, resulting in fewer side effects (112). In summary, initiating therapy with multiple antidiabetes agents in newly diagnosed T2DM patients, especially those with HbA1c >8.0–8.5%, represents a rational approach to achieve the target HbA1c level while minimizing side effects. Indeed, AACE recommends starting newly diagnosed diabetic subjects with HbA1c >7.5% on multiple antidiabetes agents (111). “Treat to fail” algorithm The 2009 ADA/EASD algorithm (1) recommended initiation of therapy with metformin to achieve HbA1c <7.0%, followed by, importantly, sequential addition of a sulfonylurea. If sulfonylurea addition failed to reduce HbA1c <7.0%, addition of basal insulin was recommended. Although the revised 2012 ADA/EASD algorithm (5) includes newer antidiabetes agents (GLP-1 receptor agonists, DPP4i, and TZDs) as potential choices if metformin fails, the initial box in the treatment algorithm still depicts sequential addition of sulfonylurea and then insulin to maintain HbA1c <7.0%. This algorithm has little basis in pathophysiology and more appropriately should be called the treat to fail algorithm. Moreover, it does not consider the starting HbA1c or need for initial combination therapy in most newly diagnosed T2DM patients, especially if HbA1c goal <6.0–6.5% is desired, as suggested by us (4) and by the 2012 ADA/EASD consensus statement (5). Because β-cell failure is progressive (9–12,24–30,34,35,113,114) and results in loss of β-cell mass (36–38), it is essential to intervene with agents that normalize HbA1c and halt the progressive β-cell demise (Fig. 3). Failure to do so will result in the majority of T2DM patients progressing to insulin therapy, as demonstrated in the UK Prospective Diabetes Study (UKPDS) (113,114). Sulfonylureas/glinides: the treat to fail approach. Until recently (5), sulfonylureas have been considered the drug of choice for add-on therapy to metformin (1). In large part, this is attributed to their low cost and rapid onset of hypoglycemic effect. However, they lack “glycemic durability” and within 1–2 years lose their efficacy, resulting in steady HbA1c rise to or above pretreatment levels (107,108) (Figs. 4 and 5). Although long-term studies examining glycemic durability with glinides (nateglinide, repaglinide) in T2DM are not available, nateglinide failed to prevent prediabetic (IGT) patients from progressing to T2DM (115). In a 2-year study in newly diagnosed T2DM subjects, durability of netaglinide plus metformin was comparable with glyburide plus metformin (116) and both groups experienced a small but progressive HbA1c rise after the first year. Since deterioration in glycemic control is largely accounted for by progressive β-cell failure (3), it is clear that both sulfonylureas and glinides fail to prevent the progressive decline in β-cell function characteristic of T2DM. Consistent with this, in vitro studies have demonstrated a proapoptotic β-cell effect of sulfonylureas and glinides (117–120). Figure 4 The effect of sulfonylurea (glibenclamide = glyburide) and metformin therapy on the plasma HbA1c concentration in newly diagnosed T2DM subjects in UKPDS. Conventionally treated diabetic subjects received diet plus exercise therapy (113,114). Figure 5 Durability of glycemic control with sulfonylureas. Summary of studies examining the effect of sulfonylurea treatment versus placebo or versus active comparator on HbA1c in T2DM. See text for a more detailed discussion (70,82,87–92,113,114,124–127,131,132). UKPDS conclusively demonstrated that sulfonylureas exerted no β-cell protective effect in newly diagnosed T2DM patients (starting HbA1c = 7.0%) over a 15-year follow-up (113,114). After an initial HbA1c drop, sulfonylurea-treated patients experienced progressive deterioration in glycemic control that paralleled HbA1c rise in conventionally treated individuals (Fig. 4). Moreover, some studies have suggested that sulfonylureas may accelerate atherogenesis (121,122). Similarly, metformin-treated patients in UKPDS, after initial HbA1c decline (secondary to inhibition of HGP), also experienced progressive deterioration in glycemic control (123) (Fig. 4). With use of homeostasis model assessment of β-cell function, it was shown that the relentless HbA1c rise observed with sulfonylureas and metformin resulted from progressive decline in β-cell function and that within 3–5 years, ∼50% of diabetic patients required an additional pharmacologic agent to maintain HbA1c <7.0% (114,124–127). Although there is in vitro evidence that metformin may improve β-cell function (128,129), in vivo data from UKPDS and other studies (130) fail to support any role for metformin in preservation of β-cell function in humans. Metformin did reduce macrovascular events in UKPDS (123), although by today’s standards the number of metformin-treated subjects (n = 342) would be considered inadequate to justify any conclusions about cardiovascular protection. Other than its effect to reduce the elevated rate of basal and postprandial HGP (53,55,64), metformin does not correct any other component of the ominous octet (Fig. 1), and even its muscle insulin-sensitizing effect is difficult to demonstrate in absence of weight loss (53,55,64). UKPDS was designed as a monotherapy study. However, after 3 years it became evident that monotherapy with neither metformin nor sulfonylureas could prevent progressive β-cell failure and stabilize HbA1c at its starting level (113,114,123–127). Therefore, study protocol was altered to allow metformin addition to sulfonylurea and sulfonylurea addition to metformin. Although addition of a second antidiabetes agent initially improved glycemic control, progressive β-cell failure continued and HbA1c rose progressively. Numerous long-term (>1.5 years) active-comparator or placebo-controlled studies have demonstrated inability of sulfonylureas to produce durable HbA1c reduction in T2DM patients. These studies (70,83,87–92,113,131–133) showed that after initial HbA1c decline, sulfonylureas (glyburide, glimepiride, and gliclazide) were associated with progressive decline in β-cell function with accompanying loss of glycemic control (Fig. 5). There are no exceptions to this consistent loss of glycemic control with sulfonylureas after the initial 18 months of therapy. Thus, evidence-based medicine demonstrates that the glucose-lowering effect of sulfonylureas is not durable and that loss of glycemic control is associated with progressive β-cell failure. Sulfonylurea treatment does not correct any pathophysiologic component of the ominous octet (3) (Fig. 1) and is associated with significant weight gain and hypoglycemia (89,90). Although no study has clearly implicated sulfonylureas with an increased incidence of cardiovascular events, a deleterious effect of glibenclamide (glyburide) on the cardioprotective process of ischemic preconditioning has been demonstrated (134), while some (121,122,135–142) but not all (143,144) studies have suggested a possible association between sulfonylureas and adverse cardiovascular outcomes. Since metformin was the comparator in many of these studies (121,122,137,138,140–142), it is difficult to determine whether sulfonylureas increased or metformin decreased cardiovascular morbidity/mortality. In the study by Sillars et al. (143) the increased cardiovascular mortality/morbidity disappeared after adjusting for confounding variables, and failure to do so in other sulfonylurea studies may have clouded their interpretation. Among the sulfonylurea studies, the older sulfonylureas (i.e., glibenclamide) more commonly have been associated with increased adverse cardiovascular outcomes than the newer sulfonylurea agents (i.e., gliclazide and glimeperide) (139,144–146). In summary, we believe that currently available insulin secretagogues (sulfonylureas and glinides) represent a poor option as add-on therapy to metformin. However, in many countries newer antidiabetes agents are not available or are expensive (ABCDE) (4). In such circumstances, sulfonylureas may be the only option. Antidiabetes agents known to reverse pathophysiologic defects Pioglitazone: unique benefits, unique side effects. Rosiglitazone has been removed from the market or its use severely restricted because of cardiovascular safety concerns (147). Therefore, pioglitazone is the only representative TZD. Pioglitazone is unique in that it both exerts β-cell protective effects (81) and is a powerful insulin sensitizer in muscle and liver (56–61,65,74–76) Thus, it is the only antidiabetes agent that corrects the core defects of insulin resistance and β-cell failure in T2DM. Not surprisingly, it has a durable effect to reduce HbA1c with low risk of hypoglycemia. Eight long-term (>1.5 years) studies with TZDs (70,82,81–92) (Fig. 6) have demonstrated that, after initial decline in HbA1c, durability of glycemic control is maintained because of preservation of β-cell function in T2DM patients. Further, five studies demonstrate that TZDs prevent progression of IGT to T2DM (148–152). All five studies showed that, in addition to their insulin-sensitizing effect, TZDs had a major action to preserve β-cell function. In Actos Now for Prevention of Diabetes (ACT NOW), improved insulin secretion/insulin resistance (disposition) index was shown both with OGTT and frequently sampled intravenous glucose tolerance test. Similar results were documented in Troglitazone in Prevention of Diabetes (TRIPOD) and Pioglitazone in Prevention of Diabetes (PIPOD) (148,151). Many in vivo and in vitro studies with human and rodent islets have demonstrated that TZDs exert a β-cell–protective effect (153–157). Figure 6 Durability of glycemic control with TZDs. Summary of studies examining the effect of TZDs versus placebo or versus active comparator on HbA1c in T2DM subjects. See text for a more detailed discussion (70,82,87–92). Pio, pioglitazone; Rosi, rosiglitazone. Pioglitazone has additional beneficial pleiotropic properties, including increased HDL cholesterol, reduced plasma triglyceride, decreased blood pressure, improved endothelial dysfunction, anti-inflammatory effects (76,158–161), and amelioration of nonalcoholic steatohepatitis (75). In addition to reduced cardiovascular events in PROactive and U.S. phase 3 trials (162,163), pioglitazone slows progression of carotid intimal-media thickness (87,152) and reduces coronary atheroma volume (88). Physicians must be cognizant of side effects associated with TZDs including weight gain (81,164), fluid retention (162,165), bone fractures (166), and possibly bladder cancer (162,167,168) (see article on peroxisome proliferator–activated receptors in this supplement [169]). The preferred starting dose of pioglitazone is 15 mg/day titrated to 30 mg/day, which provides 70–80% of the glycemic efficacy with minimal side effects (170–174); titrating to 45 mg/day is not recommended. HbA1c lowering has been observed with a pioglitazone dose of 7.5 mg/day with minimal side effects. In a 26-week study (172) involving a Caucasian population, 7.5 mg/day pioglitazone reduced the HbA1c by 0.9% compared with placebo (P = 0.14), while 15 mg/day reduced the HbA1c by 1.3% vs. placebo (P < 0.05). Similar HbA1c reduction with pioglitazone, 7.5 mg/day, has been observed in an Asian population (173,174). In combination with metformin (inhibits hepatic gluconeogenesis), pioglitazone (improves insulin sensitivity in liver/muscle and preserves β-cell function) offers an effective, durable, and additive therapy that retards progressive β-cell failure with little risk of hypoglycemia. In a 6-month trial comparing fixed-dose combination with pioglitazone (30 mg)/metformin (1,700 mg) in 600 drug-naïve T2DM patients, HbA1c declined by 1.8% (from baseline HbA1c 8.6%) and was significantly greater than the 1.0% reduction observed with metformin alone or pioglitazone alone (175). Similar results were reported by Rosenstock et al. (176) using initial combination therapy with rosiglitazone (8 mg)/metformin (2,000 mg). Combining pioglitazone with GLP-1 analog curbs weight gain associated with the TZD (177). Further, the natriuretic effect of GLP-1 analogs (178) mitigates against fluid retention observed with TZDs. Therefore, we advocate combined GLP-1 analog/pioglitazone therapy with or without metformin in newly diagnosed T2DM patients (3). Intensive therapy with insulin plus metformin: reversal of metabolic decompensation. Newly diagnosed T2DM patients who present in poor metabolic control are markedly resistant to insulin and have severely impaired β-cell function. Glucotoxicity (8), lipotoxicity (8,42,62), and multiple metabolic abnormalities (3) play an important role in the insulin resistance and β-cell dysfunction. Institution of intensive insulin therapy with or without other antidiabetes agents to correct these many metabolic abnormalities, therefore, represents a rational approach to therapy based upon pathophysiology. After a period of sustained metabolic control, the insulin therapy can be continued or the patient can be switched to a noninsulin therapeutic regimen. This approach has recently been examined by Harrison et al. (179). Fifty-eight newly diagnosed T2DM patients in poor metabolic control (HbA1c 10.8%) initially were treated for 3 months with metformin plus insulin to reduce the HbA1c to 5.9%. Subjects then were randomized to continued therapy with insulin-metformin combination therapy with pioglitazone/metformin/glyburide. During 3 years of follow-up, both groups maintained the reduction in HbA1c, but the insulin dose had to be increased, indicating that, despite excellent glycemic control, β-cell failure continued in this group. Further, glycemic control in both groups was achieved at the expense of a relatively high rate of hypoglycemia and weight gain in the insulin/metformin group, consistent with multiple studies demonstrating a high incidence of hypoglycemia in sulfonylurea-treated and insulin-treated subjects. Metformin plus GLP-1 analog plus pioglitazone: a pathophysiologic option that offers robust glycemic control and weight loss. The combination of biguanide (metformin), TZD (pioglitazone), and GLP-1 analog offers a rational treatment choice, targeting multiple pathophysiologic abnormalities in T2DM: muscle insulin resistance (pioglitazone), adipocyte insulin resistance (pioglitazone), pancreatic β-cell failure (GLP-1 analog, pioglitazone), hepatic insulin resistance (metformin, pioglitazone, and GLP-1 analog), and excessive glucagon secretion (GLP-1 analog) (3) with weight loss (GLP-1 analog) and low risk of hypoglycemia (93,97). Studies with exenatide have demonstrated durable glycemic control for 3 years (84,93). β-Cells in T2DM are blind to glucose, and GLP-1 analogs have the unique ability to restore β-cell glucose sensitivity (84–86) (Fig. 7) by augmenting glucose transport, activating glucokinase, increasing Pdx, and replenishing β-cell insulin stores (180,181). Because pharmacologic GLP-1 levels (∼80–90 pmol/L) are achieved with GLP-1 analogs, they overcome β-cell incretin resistance and augment insulin secretion. Increased insulin and inhibited glucagon secretion reduce basal HGP, reducing fasting plasma glucose concentration and enhancing HGP suppression after a meal (98,99). Although GLP-1 analogs do not have a direct insulin-sensitizing effect, they augment insulin-mediated glucose disposal secondary to weight loss (97). The combination of pioglitazone plus exenatide reduces hepatic fat content and markers of liver damage in T2DM (182). In T2DM patients treated with rosiglitazone, exenatide, or both (as add-on to metformin), improved β-cell function and insulin sensitivity were noted, with weight loss in all exenatide-treated groups (177). Similar results have been reported by others (182–185) with combined GLP-1 analog/TZD therapy. Figure 7 A single dose of liraglutide (Lira) (7.5 μg/kg or 0.75 mg for 100-kg person) administered acutely completely restores β-cell sensitivity to glucose using the graded glucose infusion technique to evaluate β-cell function (86). In an ongoing study, we compared triple combination therapy with pioglitazone/metformin/exenatide with the standard ADA approach (metformin followed by sequential addition of sulfonylurea and then basal insulin) in 134 newly diagnosed T2DM patients with starting HbA1c 8.7% (186). After 2 years, HbA1c reduction was greater in the triple therapy versus sequential ADA group (2.7 vs. 2.2%, P < 0.01), triple therapy subjects lost 1.5 vs. 4.1 kg weight gain with the ADA approach, and hypoglycemia incidence was 13.5-fold higher in the sequential ADA group. These preliminary results indicate that a triple combination approach focused on reversing underlying insulin resistance and β-cell dysfunction is superior to sequential therapy (metformin, add sulfonylurea, add basal insulin) with agents that do not correct core pathophysiologic defects in T2DM. DPP4i: weak but easy alternative to GLP-1 analogs. DPP4i have gained widespread use in combination with metformin because of their weight neutrality, modest efficacy, and safety (187,188). Metformin has a modest effect to increase GLP-1 secretion (107,189). Thus, combination metformin/DPP4i therapy may result in increased GLP-1 levels (190) and an additive glucose-lowering effect (191,192). When used in triple combination with metformin plus pioglitazone (30 mg/day), alogliptin resulted in better glycemic control and fewer pioglitazone dose-dependent side effects (edema, weight gain) compared with metformin with a higher pioglitazone dose (45 mg/day) (172). Because they correct multiple components of the ominous octet, have superior glucose-lowering efficacy, promote weight loss, and preserve β-cell function, we favor GLP-1 analogs over DPP4i in the triple therapy approach. Nonetheless, because of their ease of administration and safety, DPP4i represent a reasonable alternative. Conclusions and recommendations T2DM is a multifactorial, multiorgan disease, and antidiabetes medications should address underlying pathogenic mechanisms rather than solely reducing the blood glucose concentration. Emphasis should be placed on medications that ameliorate insulin resistance and prevent β-cell failure if durable HbA1c reduction is to be achieved. Further, the long-practiced glucocentric paradigm has become antiquated. Diabetic patients are at high risk for cardiovascular events, and comprehensive evaluation/treatment of all cardiovascular risk factors is essential. Simply focusing on glycemic control will not have a major impact to reduce cardiovascular risk (113,123). Therefore, we favor a therapeutic approach based not only on the drug’s glucose-lowering efficacy/durability but also on its effect on weight, blood pressure, lipids, cardiovascular protection, and side effect profile, especially hypoglycemia. Initial therapy in newly diagnosed T2DM patients without cardiovascular disease should be capable of achieving the desired glycemic goal, which should be as close to normal as possible: HbA1c ≤6.0%. This will require combination therapy in the majority of T2DM patients (3) (Fig. 1). While we favor the pathophysiologic approach, physicians must be cognizant of the ABCDE of diabetes management (4). An approach that emphasizes pathophysiology but allows for individualized therapy will provide optimal results. Evidence-based medicine (UPKDS) has taught us that sequential therapy with metformin followed by sulfonylurea addition with subsequent insulin addition represents the treat to fail approach, and we do not recommend this approach unless cost is the overriding concern.

          Related collections

          Most cited references 184

          • Record: found
          • Abstract: found
          • Article: not found

          Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

           R Turner,  C Fox,  DR Matthews (1998)
          Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            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.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.

              Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes. Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes. Copyright 2007 Massachusetts Medical Society.
                Bookmark

                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                August 2013
                17 July 2013
                : 36
                : Suppl 2
                : S127-S138
                Affiliations
                Diabetes Division, University of Texas Health Science Center, San Antonio, Texas
                Author notes
                Corresponding author: Ralph A. DeFronzo, albarado@ 123456uthscsa.edu .
                Article
                2011
                10.2337/dcS13-2011
                3920797
                23882037
                © 2013 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                Counts
                Pages: 12
                Product
                Categories
                Diabetes Pathophysiology

                Endocrinology & Diabetes

                Comments

                Comment on this article