Vivian Fonseca

Nonhypoglycemic Effects of Thiazolidinediones

The thiazolidinediones are a new class of compounds for treatment of type 2 diabetes mellitus. The efficacy of these drugs in decreasing plasma glucose levels is well established (1-6). Troglitazone, a member of this class, became available for clinical use in the United States in 1997 but was withdrawn in March 2000 because of reports of severe hepatic injury. Rosiglitazone and pioglitazone became available in 1999 and are approved as monotherapy and in combination with other oral hypoglycemic agents; pioglitazone is also approved in combination with insulin. The glucose-lowering effects of the thiazolidinediones are mediated primarily by decreasing insulin resistance at the level of the muscle and thereby increasing glucose uptake. To a lesser extent, they decrease insulin resistance in the liver and thereby decrease hepatic glucose production (1). The mechanisms of action of the thiazolidinediones are still being investigated; however, some of their actions are mediated through binding and activation of the peroxisome proliferatoractivated receptor- (PPAR-), a nuclear receptor that has a regulatory role in differentiation of cells, particularly adipocytes (7). This receptor is also expressed in several other tissues, including vascular tissue (7). The thiazolidinediones also decrease plasma concentrations of free fatty acids and in doing so may indirectly improve insulin sensitivity (8). Thiazolidinediones may also activate other members of the PPAR family of receptors (such as PPAR- and PPAR-), which along with PPAR serve as gene transcription factors (9). These receptors are present in many tissues, and although their functions are still being elucidated, the data suggest that they have many important effects. Thus, the thiazolidinediones may affect many organ systems and disease processes (9). Substantial evidence indicates that insulin resistance, along with compensatory hyperinsulinemia, not only contributes to hyperglycemia in type 2 diabetes but also may play a pathophysiologic role in other metabolic abnormalities. These include high levels of plasma triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, abnormal fibrinolysis, and coronary heart disease (10-13). This cluster of abnormalities is called the insulin resistance syndrome, syndrome X, or the metabolic syndrome (14). Since thiazolidinediones directly improve insulin resistance (2), it has been proposed that they may correct other abnormalities of the insulin resistance syndrome, as well as improve hyperglycemia. Thus, use of these agents to treat patients with type 2 diabetes may confer benefits beyond decreases in glucose level. Because of the effects of thiazolidinediones on hyperinsulinemia and insulin resistance, their vascular effect is a subject of considerable research interest (Table 1). Table 1. Effects of the Thiazolidinediones on Cardiovascular Risk Factors We discuss the nonhypoglycemic effects of the thiazolidinediones that have been described in the literature. We emphasize their potential to improve other components of the insulin resistance syndrome, such as dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. We discuss their effects in other insulin-resistant states, such as the polycystic ovary syndrome; examine their effects on body weight and composition; and draw attention to other potential effects currently being investigated. Much of the data presented relates to troglitazone (the most extensively studied thiazolidinedione) but may be relevant to the other thiazolidinediones. In vitro data support the possibility of a class effect, although proof from currently ongoing clinical trials (Freed M, SmithKline Beecham; Wishner W, Takeda Pharmaceuticals. Personal communication) is needed. Long-term clinical trials are also needed to determine whether such reduction in risk factors will prevent cardiovascular disease. Cardiovascular Effects Epidemiologic studies have demonstrated that hyperinsulinemia, a marker for insulin resistance, is an independent risk factor for cardiovascular disease (47). Correction of insulin resistance may be clinically important in type 2 diabetes and may decrease risk for cardiovascular disease. In the United Kingdom Prospective Diabetes Study, treatment with metformin (another drug that decreases hyperinsulinemia and insulin resistance) was shown to produce greater reduction in cardiovascular disease events and mortality than sulfonylureas and insulin (48). The latter drugs decreased blood glucose level to a similar degree as metformin but did not decrease plasma insulin concentrations. This effect may have been mediated through a decrease in insulin resistance, although other effects of metformin, such as improvement in lipid profile, improved fibrinolysis, and prevention of weight gain, may be important (48). Further clinical trials are needed to determine whether treatment of diabetes with agents that reduce insulin resistance (such as the thiazolidinediones and metformin) is superior to use of agents that stimulate insulin secretion (such as sulfonylureas). The National Institutes of Health recently initiated such a clinical trial (49). Cardiac Output and Left Ventricular Mass Initial studies of cardiac function with thiazolidinedione therapy were performed because of reported cardiac enlargement in animals treated with drugs of this class (3). Ghazzi and colleagues (3) investigated whether patients with type 2 diabetes treated with troglitazone, 800 mg/d (a dosage higher than that used in clinical practice), or glyburide experienced an increase in cardiac mass or functional impairment. Two-dimensional echocardiography and pulsed Doppler ultrasonography demonstrated that neither troglitazone nor glyburide changed left ventricular mass index significantly over 48 weeks. However, substantial increases in stroke volume index and cardiac index and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients but not glyburide-treated patients, who experienced no change (3). These findings are reassuring and contrast with those of animal studies. Similar studies of rosiglitazone and pioglitazone have also demonstrated no adverse effect on cardiac mass or function (4, 5, 50). Nevertheless, thiazolidinediones are currently contraindicated in patients with advanced heart failure because of their effect on plasma volume (43). Lipid Metabolism and Oxidation Insulin resistance and type 2 diabetes are associated with a characteristic pattern of lipid abnormalities, including an elevated plasma triglyceride level and a low plasma high-density lipoprotein (HDL) cholesterol level. Plasma levels of low-density lipoprotein (LDL) cholesterol do not differ from those in nondiabetic persons, but qualitative changes in LDL cholesterol, with an increase in small, dense LDL cholesterol, are common (15, 51-55). In several clinical trials, troglitazone therapy significantly lowered triglyceride levels (3, 16, 17) and increased HDL cholesterol levels in persons with type 2 diabetes (3, 16). A modest increase in LDL cholesterol level was observed, but the ratio of LDL cholesterol to HDL cholesterol and apolipoprotein B levels did not change. Data published to date indicate that all of the thiazolidinediones increase HDL cholesterol levels and that troglitazone and pioglitazone decrease triglyceride levels (3-5, 16-18). A recent small study (19) demonstrated a possible difference in the lipid-lowering effects of thiazolidinediones: Compared with rosiglitazone, pioglitazone seemed to produce a greater decrease in the triglyceride level and a lesser increase in the LDL cholesterol level. However, the study was neither randomized nor double-blind. Further studies on such possible differences are therefore needed. Similar changes in lipid levels have been observed in nondiabetic persons with insulin resistance. Like troglitazone, pioglitazone significantly reduced fasting serum levels of triglycerides and increased fasting levels of HDL cholesterol in 20 patients with type 2 diabetes (56). The effects of the thiazolidinediones on LDL cholesterol are more complex. Persons with insulin resistance or type 2 diabetes are more likely than nondiabetic persons to have small, dense, triglyceride-rich LDL cholesterol particles (51). These characteristics may make LDL cholesterol susceptible to oxidation. Oxidative modification confers atherogenic properties on LDL cholesterol particles; this may be a key initial event in the progression of atherosclerosis (15) and is a measurable risk factor (52-55). Evidence suggests that PPAR- may be an important regulator of foam-cell gene expression and that oxidized LDL cholesterol regulates macrophage gene expression through activation of PPAR- (57). Furthermore, PPAR- promotes uptake of oxidized LDL cholesterol by macrophages (58). Thus, an interaction between PPAR- and oxidized LDL cholesterol may be important in the development of atherosclerosis in diabetes. Thiazolidinediones have been shown to substantially increase levels of total cholesterol and LDL cholesterol (4, 5). However, the increase is predominantly in the larger buoyant particles of LDL cholesterol, which may be less atherogenic than small, dense LDL cholesterol particles. Levels of the latter have been shown to decrease with troglitazone therapy (20). These data were confirmed in other studies demonstrating that troglitazone increased the resistance of LDL cholesterol to oxidation (20-24). Whether these effects are produced by the other thiazolidinediones or were related to vitamin E moiety in the troglitazone molecule is unclear and warrants further study. Although the effects of the thiazolidinediones on LDL cholesterol oxidation are in theory appealing, their role in preventing cardiovascular events is unclear. Of note, vitamin E, which also has antioxidant and free radicalscavenging prope

Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial

BACKGROUNDnIn people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin.nnnMETHODSnIn this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35-70 years with glycated haemoglobin A(1c) (HbA(1c)) of 7-11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25-45 kg/m(2) were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0-5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA(1c) from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT00751114.nnnFINDINGSn732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA(1c) was greater for patients on insulin glargine (n=227; -1·72%, SE 0·06) than for those on sitagliptin (n=253; -1·13%, SE 0·06) with a mean difference of -0·59% (95% CI -0·77 to -0·42, p<0·0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4·21 [SE 0·54] vs 0·50 [SE 0·09] events per patient-year; p<0·0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event.nnnINTERPRETATIONnOur results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease.nnnFUNDINGnSanofi.

An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia

Aim: To evaluate the benefits of initiating insulin at an earlier versus later treatment stage, and regimens with/without sulfonylurea (SU).

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes

AIMSnTo assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500 mg/day) and pioglitazone (≥30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5% and ≤11%).nnnMETHODSnThis placebo-controlled, double-blind study included 313 patients, mean baseline HbA1c=8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks.nnnRESULTSnThe addition of sitagliptin led to significant (P<.001) mean changes from baseline relative to placebo in HbA1c (-0.7%), fasting plasma glucose (-1.0 mmol/L), and 2-h post-meal glucose (-2.2 mmol/L). In patients with baseline HbA1c ≥9.0%, mean changes from baseline in HbA1c were -1.6% and -0.8% for the sitagliptin and placebo groups, respectively (between-group difference -0.8%; P<.001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P=.786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance.nnnCONCLUSIONSnIn this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.

From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy

Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, affecting, by some estimates, up to one quarter of diabetic patients. Since 2010, no fewer than 5 major international treatment guidelines for painful DPN have been issued, and there are meaningful differences among them. Duloxetine, pregabalin, gabapentin, and tricyclic antidepressants are the mainstays of treatment, but the choice of which class or agent to use in any given patient should be informed by patient characteristics. This review seeks to describe the differences among the recently issued guidelines, to assess the evidence on which they are based, and to offer insight into the most appropriate treatment choices based on patient characteristics.

Emerging concepts in the pathophysiology of type 2 diabetes mellitus

Type 2 diabetes mellitus is a multifactorial metabolic disorder. It is characterized by chronic hyperglycemia, insulin resistance, and a relative insulin secretion defect. The prevalence of type 2 diabetes mellitus has risen worldwide in large part because of an increase in obesity and sedentary lifestyles. The underlying pathophysiology and complications of type 2 diabetes mellitus are still being elucidated. Recent advances in diabetes research have helped us to gain a better understanding about insulin resistance and insulin secretion defects. The evolving understanding about the influence of the incretin effect, insulin signal transduction, adipose tissue, intra-islet cell communication, and inflammation is changing the way in which we view type 2 diabetes mellitus. This new understanding will eventually provide us with new treatment approaches to help patients who have type 2 diabetes mellitus. This article gives a review of the current and emerging concepts of the pathophysiology of type 2 diabetes mellitus.

New developments in diabetes management: medications of the 21st century.

BACKGROUNDnSuboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches.nnnOBJECTIVEnThe purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes.nnnMETHODSnPublished evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed.nnnRESULTSnSeveral new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia.nnnCONCLUSIONSnAdvances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients use of them as directed. Long-term effectiveness and safety trials are ongoing.

Plasma Homocysteine Concentrations in Type II Diabetic Patients in India: Relationship to Body Weight

Hyperhomocysteinemia has been established as a risk factor for cardiovascular disease and occurs with a high prevalence in patients with type II diabetes and microvascular disease. In order to determine whether plasma homocysteine concentrations vary with body-mass index in patients with type II diabetes, we measured plasma homocysteine in lean, normal weight, and overweight subjects living in India. Plasma homocysteine concentrations were significantly lower in the lean persons with diabetes when compared to those who were obese and compared to control subjects (p < 0.02). We conclude that plasma homocysteine concentrations are lower in lean persons with type II diabetes and that this efficiency in homocysteine metabolism may contribute towards protection from cardiovascular disease in this population.

Beta-blockers have a beneficial effect upon endothelial function and microalbuminuria in African-American subjects with diabetes and hypertension

BACKGROUNDnType 2 diabetes mellitus (T2DM) with microalbuminuria (MA) is associated with increased risk of cardiovascular events (CVE) that may be attenuated by angiotensin-converting enzyme inhibitors (ACEIs), unless microalbuminuria persists (PMA). African-Americans (AA) have a higher prevalence of nephropathy with suboptimal response to ACEIs. We studied the effects of beta-blockers addition and comparative effects of carvedilol with metoprolol on 24-h urinary-albumin excretion (UAE) and endothelial function (EF) in AA with PMA.nnnMETHODSnThirty-four AA 30-70 years of age with T2DM and PMA despite ACEI therapy were randomized to receive carvedilol or metoprolol in addition to ACEI and any other concurrent therapy. Carvedilol/metoprolol dose was titrated to achieve blood pressure (BP) <130/80 mm Hg. UAE and brachial-artery reactivity were studied at baseline and 12 weeks. We analyzed the effects of addition of beta-blockers and whether there was any difference in response between the two beta-blockers.nnnRESULTSnThirty-three subjects completed the study; BP decreased to <135/80 mm Hg. After 12 weeks, beta-blocker treatment resulted in significant increase in flow-mediated dilatation (FMD) from 3.5+/-1% to 8.5+/-1% (P=.004) and significant reduction in mean log-transformed UAE from 2.655 g/g Cr+/-0.087 to 2.533 g/g Cr+/-0.093 (P=.028). FMD increased by 240% (P=.033) with carvedilol and by 110% (P=.096; NS) with metoprolol. UAE decreased with carvedilol by 0.35 g/g Cr (P=.023) and with metoprolol by 0.23 g/g Cr (P=.298; NS).nnnCONCLUSIONnOur results clearly indicate that addition of beta-blockers to ACEI improves EF and reduces UAE in high-risk AA T2DM patients with PMA. Carvedilol but not metoprolol improves EF and reduces UAE in AA with identical BP control. Larger trials are needed to further elucidate the differential effects of carvedilol/metoprolol on EF and UAE and its impact on CVE in such patients.

Insulin Resistance, Diabetes, Hypertension, and Renin—Angiotensin System Inhibition: Reducing Risk for Cardiovascular Disease

Insulin resistance, diabetes mellitus, and hypertension are associated with significant cardiovascula: morbidity and mortality. Lifestyle modifications effectively decrease the risk of progression to diabetes in high‐risk patients, but intensive interventions can be costly and difficult for patients to maintain. The addition of pharmacotherapy is often necessary to treat hyperglycemia and hypertension and lower the risk of cardiovascular complications. Clinical trial data suggest the use of insulin‐sensitizing and antihyperglycemic agents to delay the progression to diabetes. Similarly, analysis of data from clinical trials of angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers indicate that the use of these agents results in fewer cases of new‐onset diabetes among patients with hypertension, when compared with other antihypertensive agents. Angiotensin II has direct and indirect effects on insulin and its signaling pathways, providing support for the biologic mechanism underlying the benefits of renin‐angiotensin system inhibition in preventing diabetes and cardiovascular events. Clinical trials now under way will further evaluate the role of renin‐angiotensin system inhibition in preventing diabetes and its microvascular and macrovascular complications.