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Papers by Jaime Davidson

Endocrine Practice, 2016

Objective: To compare two methods of delivering intensified insulin therapy (IIT) in patients wit... more Objective: To compare two methods of delivering intensified insulin therapy (IIT) in patients with type 2 diabetes inadequately controlled on basal insulin ± concomitant antihyperglycemic agents in a real-world clinical setting. Methods: Data for this retrospective study were obtained using electronic medical records from a large multicenter diabetes system. Records were queried to identify patients transitioned to V-Go ® disposable insulin delivery device (V-Go) or multiple daily injections (MDI) using an insulin pen to add prandial insulin when A1C was >7% on basal insulin therapy. The primary endpoint was the difference in A1C change using follow-up A1C results. Results: A total of 116 patients were evaluated (56 V-Go, 60 MDI). Both groups experienced significant glycemic improvement from similar mean baselines. By 27 weeks, A1C least squares mean change from baseline was −1.98% (−21.6 mmol/mol) with V-Go and −1.34% (−14.6 mmol/mol) with MDI, for a treatment difference of −0.64% (−7.0 mmol/mol; P = .020). Patients using V-Go administered less mean ± SD insulin compared to patients using MDI, 56 ± 17 units/day versus 78 ± 40 units/day

Endocrine Practice, 2016

The aim of this post hoc analysis was to assess the efficacy and safety of once-weekly dulaglutid... more The aim of this post hoc analysis was to assess the efficacy and safety of once-weekly dulaglutide in Hispanic/Latino patients with type 2 diabetes (T2D) in phase 3 AWARD trials 1 to 6. Hispanic/Latino data at Week 26 were pooled across studies for each dulaglutide dose to analyze the change from baseline in glycosylated hemoglobin (HbA1c), percent to HbA1c goal, and adverse events (AEs). Change from baseline in HbA1c, change from baseline in weight and hypoglycemia were analyzed by Hispanic/Latino and non-Hispanic/Latino subgroups for each study. Of the 3,136 patients randomized to dulaglutide 1.5 or 0.75 mg, 949 were reported as having Hispanic/Latino ethnicity. Baseline characteristics were similar for Hispanic/Latino and overall populations, except there were slightly more Hispanic/Latino females and weight was slightly lower for Hispanic/Latino patients. Hispanic/Latino patients receiving dulaglutide 1.5 mg had a reduction in HbA1c of 1.25% (95% confidence interval [CI]: -1.35, -1.15); dulaglutide 0.75 mg had a reduction of 1.07% (95% CI: -1.18, -0.96). Reductions in HbA1c and percent to goal HbA1c <7% and ≤6.5% were similar between Hispanic/Latino patients and the overall population. Weight change and hypoglycemia were similar between Hispanic/Latino and non-Hispanic/Latino subgroups for all studies. Treatment-emergent AEs were consistent with the overall population. Dulaglutide improved glycemic control with the potential for weight loss in Hispanic/Latino patients with T2D. Dulaglutide was well tolerated and had a low risk of hypoglycemia when used without insulin secretagogues or insulin. In the Hispanic/Latino population, dulaglutide efficacy and safety was consistent with that of the overall population. AE = adverse event AWARD = Assessment of Weekly AdministRation of dulaglutide in Diabetes BID = twice daily CARMELA = The Cardiovascular Risk Factor Multiple Evaluation of Latin America CI = confidence interval GLP-1 RA = glucagon-like peptide-1 receptor agonist HbA1c = glycosylated hemoglobin T2D = type 2 diabetes.

Metformin may play in important role in the future in helping to prevent the development of diabe... more Metformin may play in important role in the future in helping to prevent the development of diabetes: it is a strong candidate therapy for delaying the onset of the disease and potentially as part of a treatment programme to correct features of the metabolic syndrome. This book celebrates 50 years of research into metformin and its use in the treatment of diabetes. Metformin is still the drug of choice for managing patients with type 2 diabetes and all new drugs are tested in comparison with this, the gold standard. Comprising seven sections, addressing different aspects of research on metformin and its applications, this book is edited by a world class team of expert diabetologists and beautifully presented in two colour throughout. It also includes a bibliography of all papers published on metformin and a complete list of all authors on those papers.

touchendocrinology.com

The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and p... more The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and pioglitazone-are insulin-sensitising oral antidiabetic agents that are an effective treatment for type 2 diabetes. The primary pharmacological actions of these drugs are to increase adipose and muscle insulin sensitivity and to inhibit gluconeogenesis in the liver. In type 2 diabetes patients, rosiglitazone reduces plasma levels of fasting glucose, glycated haemoglobin (HbA 1c) and insulin. 1 It may also improve β-cell function. 2 However, emerging evidence regarding the relationship between the use of TZDs and bone loss in type 2 diabetes patients gives cause for concern. 3 There is an increased risk of bone fractures in patients with type 2 diabetes. Some-although not all-studies have shown higher rates of fracture in people with type 2 diabetes compared with normal individuals. The Health, Aging and Body Composition (Health ABC) Study showed that elderly white women with type 2 diabetes (but not elderly men or black women) had more rapid bone loss at the femoral neck and total hip than those with normal glucose homeostasis. 4 This was despite having higher bone mineral density (BMD) at baseline. These data suggest that elderly white women with type 2 diabetes are at a greater risk of hip fracture than the normal population, and more so than men or black women with the disease. There is already a higher prevalence of fracture risk in the elderly population as a whole and bone loss could put older patients with type 2 diabetes at an even higher risk of fracture. Data from the Study of Osteoporotic Fractures (SOF) reported by Taylor et al. 5 showed that although hip BMD is strongly related to hip-fracture risk in elderly white women, there are a number of other clinical risk factors that are independent predictors of long-term risk (e.g. more frequent falls, poor balance, diabetes complications, etc.). This is an important consideration when assessing risk in diabetes patients, and suggests that a wider viewpoint should be embraced.

touchendocrinology.com

The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and p... more The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and pioglitazone-are insulin-sensitising oral antidiabetic agents that are an effective treatment for type 2 diabetes. The primary pharmacological actions of these drugs are to increase adipose and muscle insulin sensitivity and to inhibit gluconeogenesis in the liver. In type 2 diabetes patients, rosiglitazone reduces plasma levels of fasting glucose, glycated haemoglobin (HbA 1c) and insulin. 1 It may also improve β-cell function. 2 However, emerging evidence regarding the relationship between the use of TZDs and bone loss in type 2 diabetes patients gives cause for concern. 3 There is an increased risk of bone fractures in patients with type 2 diabetes. Some-although not all-studies have shown higher rates of fracture in people with type 2 diabetes compared with normal individuals. The Health, Aging and Body Composition (Health ABC) Study showed that elderly white women with type 2 diabetes (but not elderly men or black women) had more rapid bone loss at the femoral neck and total hip than those with normal glucose homeostasis. 4 This was despite having higher bone mineral density (BMD) at baseline. These data suggest that elderly white women with type 2 diabetes are at a greater risk of hip fracture than the normal population, and more so than men or black women with the disease. There is already a higher prevalence of fracture risk in the elderly population as a whole and bone loss could put older patients with type 2 diabetes at an even higher risk of fracture. Data from the Study of Osteoporotic Fractures (SOF) reported by Taylor et al. 5 showed that although hip BMD is strongly related to hip-fracture risk in elderly white women, there are a number of other clinical risk factors that are independent predictors of long-term risk (e.g. more frequent falls, poor balance, diabetes complications, etc.). This is an important consideration when assessing risk in diabetes patients, and suggests that a wider viewpoint should be embraced.

Clinical Diabetes and Endocrinology

Postgraduate Medicine

Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is... more Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is associated with poor clinical outcomes, including an increased risk of all-cause and cardiovascular mortality, as well as adverse economic and social effects. Slowing the development and progression of CKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering that include cardiovascular benefits and potential renoprotective effects. Although the glucose-lowering efficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m 2. Clinical evidence has indicated that these agents can reduce the risk of development or worsening of albuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressure lowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory processes, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressurelowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute to reduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies in these patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding to the growing evidence of the potential renoprotective effects of these agents in patients with T2DM. Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinical role of SGLT2 inhibitors in slowing the development and progression of renal impairment in individuals with T2DM.

Postgraduate medicine, 2017

to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators f... more to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. At baseline in the Latino/Hispa...

Proceedings of the National Academy of Sciences of the United States of America, Jun 5, 2017

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the t... more Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose. In these type 1 diabetic rats, glucose stimulated glucagon secretion by alpha cells; this was prevented by dapagliflozin. Two models of type 2 diabetes, severely diabetic Zucker rats and db/db mice fed dapagliflozin, showed significant improvement of blood glucose levels and glucose disposal, with reduced evidence of glucagon signaling in the liver, as exemplified by reduced phosphorylation of hepatic cAMP-responsive element binding protein, reduced expression of phosphoeno...

Diabetes & metabolic syndrome, Jan 13, 2016

Excess body weight is a leading cause of metabolic complications such as hypertension and dyslipi... more Excess body weight is a leading cause of metabolic complications such as hypertension and dyslipidemia in T2DM patients. Available antihyperglycemic agents have minimal or no impact on these complications and a majority are known to trigger weight gain, thereby exerting a paradoxical effect on overall metabolic status. This review introduces the concept of 'KgA1c paradox' and underscores the significance of resolving this paradox for comprehensive T2DM management. It provides a therapeutic rationale for inclusion of sodium glucose cotransporter 2 inhibitors in the T2DM treatment algorithm as these agents have demonstrated favorable glycemic effects along with reduction in body weight.

Advances in therapy, Jan 16, 2016

Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM... more Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with...

Diabetes, Obesity and Metabolism, 2016

Postgraduate Medicine, 2016

To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions ... more To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks. Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c <0% and body weight <0 kg, and attainment of HbA1c <7.0% and body weight reduction ≥5% at Week 52 were evaluated. Safety was assessed based on adverse event reports. Canagliflozin provided reductions in HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c <7.0% and body weight reduction ≥5% with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (18.9%, 18.3%, and 5.7%, respectively). Canagliflozin was generally well tolerated. A greater proportion of patients with T2DM achieved reductions in both HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks. www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

Endocrine Practice Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Mar 1, 2011

are systematically developed statements to assist health care professionals in medical decision-m... more are systematically developed statements to assist health care professionals in medical decision-making for specific clinical conditions, but are in no way a substitute for a medical professional's independent judgment and should not be considered medical advice. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with, and not as a replacement for, their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Clinical Therapeutics, 2016

The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs and hormo... more The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs and hormones, suggesting that successful treatment may require therapies that target multiple mechanisms. Exenatide, a glucagon-like peptide 1 receptor agonist, has a multifaceted mechanism of action involving pancreatic α and β cells, hepatic glucose production, gastric motility, and satiety. Exenatide once weekly (a twice-daily formulation is also available) utilizes continuous release from biodegradable microspheres. This review discusses relevant efficacy and tolerability outcomes with exenatide once weekly in the context of its pharmacology. The medical literature was searched to identify relevant data on the pharmacology and clinical effects of exenatide once weekly. Exenatide once weekly, like the twice-daily formulation, has been shown to improve glycemic parameters, promote weight loss, result in beneficial changes in cardiovascular risk factors, and is well-tolerated. The characteristics of exenatide once weekly make it a treatment option for patients with type 2 diabetes.

Endocr Pract, 2010

To explore the impact of race/ethnicity on efficacy and safety of twice-daily insulin lispro mix ... more To explore the impact of race/ethnicity on efficacy and safety of twice-daily insulin lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% insulin lispro) and once daily insulin glargine (GL). More than 2,000 Patients with type 2 diabetes enrolled in the 24-week initiation phase of the DURABLE Trial. Efficacy and safety variables at endpoint, including hemoglobin A1c (HbA1c), self-monitored plasma glucose (SMPG), and hypoglycemia, in each racial/ethnic group were compared to Caucasians within treatment groups. Asian patients had less (LM75/25: -1.46%, P < .01; GL: -1.25%, P < .01) and Hispanic patients had greater (LM75/25: -2.17%) HbA1c reduction from baseline vs Caucasian patients (LM75/25: -1.84%; GL: -1.78%). Fewer Asian (LM75/25: 20%, P < .001; GL: 22%, P < .001) and Hispanic patients (LM75/25: 40%, P < .01) reached HbA1c target (< 7%) vs Caucasian patients (LM75/25: 53%; GL: 44%). Fasting plasma glucose was similar among groups, postprandial glucose (PPG) with GL was lower for African patients post-breakfast and post-dinner and higher for Asian patients post-lunch. Only PPG with LM75/25 was lower for Hispanic patients post-breakfast. Weight gain was lower in Asian patients (LM75/ 25). Insulin dose was higher for Asian (LM75/25 and GL) and lower for African patients (GL). Hypoglycemia rate was lower for Asian (LM75/25 and GL) and Hispanic patients (LM75/25). There were significant efficacy and safety differences among racial/ethnic groups in the DURABLE trial. These differences may be important in designing insulin based treatment plans.

Circulation, Nov 26, 2013

Endocrine Practice, 2016

Objective: To compare two methods of delivering intensified insulin therapy (IIT) in patients wit... more Objective: To compare two methods of delivering intensified insulin therapy (IIT) in patients with type 2 diabetes inadequately controlled on basal insulin ± concomitant antihyperglycemic agents in a real-world clinical setting. Methods: Data for this retrospective study were obtained using electronic medical records from a large multicenter diabetes system. Records were queried to identify patients transitioned to V-Go ® disposable insulin delivery device (V-Go) or multiple daily injections (MDI) using an insulin pen to add prandial insulin when A1C was >7% on basal insulin therapy. The primary endpoint was the difference in A1C change using follow-up A1C results. Results: A total of 116 patients were evaluated (56 V-Go, 60 MDI). Both groups experienced significant glycemic improvement from similar mean baselines. By 27 weeks, A1C least squares mean change from baseline was −1.98% (−21.6 mmol/mol) with V-Go and −1.34% (−14.6 mmol/mol) with MDI, for a treatment difference of −0.64% (−7.0 mmol/mol; P = .020). Patients using V-Go administered less mean ± SD insulin compared to patients using MDI, 56 ± 17 units/day versus 78 ± 40 units/day

Endocrine Practice, 2016

The aim of this post hoc analysis was to assess the efficacy and safety of once-weekly dulaglutid... more The aim of this post hoc analysis was to assess the efficacy and safety of once-weekly dulaglutide in Hispanic/Latino patients with type 2 diabetes (T2D) in phase 3 AWARD trials 1 to 6. Hispanic/Latino data at Week 26 were pooled across studies for each dulaglutide dose to analyze the change from baseline in glycosylated hemoglobin (HbA1c), percent to HbA1c goal, and adverse events (AEs). Change from baseline in HbA1c, change from baseline in weight and hypoglycemia were analyzed by Hispanic/Latino and non-Hispanic/Latino subgroups for each study. Of the 3,136 patients randomized to dulaglutide 1.5 or 0.75 mg, 949 were reported as having Hispanic/Latino ethnicity. Baseline characteristics were similar for Hispanic/Latino and overall populations, except there were slightly more Hispanic/Latino females and weight was slightly lower for Hispanic/Latino patients. Hispanic/Latino patients receiving dulaglutide 1.5 mg had a reduction in HbA1c of 1.25% (95% confidence interval [CI]: -1.35, -1.15); dulaglutide 0.75 mg had a reduction of 1.07% (95% CI: -1.18, -0.96). Reductions in HbA1c and percent to goal HbA1c <7% and ≤6.5% were similar between Hispanic/Latino patients and the overall population. Weight change and hypoglycemia were similar between Hispanic/Latino and non-Hispanic/Latino subgroups for all studies. Treatment-emergent AEs were consistent with the overall population. Dulaglutide improved glycemic control with the potential for weight loss in Hispanic/Latino patients with T2D. Dulaglutide was well tolerated and had a low risk of hypoglycemia when used without insulin secretagogues or insulin. In the Hispanic/Latino population, dulaglutide efficacy and safety was consistent with that of the overall population. AE = adverse event AWARD = Assessment of Weekly AdministRation of dulaglutide in Diabetes BID = twice daily CARMELA = The Cardiovascular Risk Factor Multiple Evaluation of Latin America CI = confidence interval GLP-1 RA = glucagon-like peptide-1 receptor agonist HbA1c = glycosylated hemoglobin T2D = type 2 diabetes.

Metformin may play in important role in the future in helping to prevent the development of diabe... more Metformin may play in important role in the future in helping to prevent the development of diabetes: it is a strong candidate therapy for delaying the onset of the disease and potentially as part of a treatment programme to correct features of the metabolic syndrome. This book celebrates 50 years of research into metformin and its use in the treatment of diabetes. Metformin is still the drug of choice for managing patients with type 2 diabetes and all new drugs are tested in comparison with this, the gold standard. Comprising seven sections, addressing different aspects of research on metformin and its applications, this book is edited by a world class team of expert diabetologists and beautifully presented in two colour throughout. It also includes a bibliography of all papers published on metformin and a complete list of all authors on those papers.

touchendocrinology.com

The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and p... more The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and pioglitazone-are insulin-sensitising oral antidiabetic agents that are an effective treatment for type 2 diabetes. The primary pharmacological actions of these drugs are to increase adipose and muscle insulin sensitivity and to inhibit gluconeogenesis in the liver. In type 2 diabetes patients, rosiglitazone reduces plasma levels of fasting glucose, glycated haemoglobin (HbA 1c) and insulin. 1 It may also improve β-cell function. 2 However, emerging evidence regarding the relationship between the use of TZDs and bone loss in type 2 diabetes patients gives cause for concern. 3 There is an increased risk of bone fractures in patients with type 2 diabetes. Some-although not all-studies have shown higher rates of fracture in people with type 2 diabetes compared with normal individuals. The Health, Aging and Body Composition (Health ABC) Study showed that elderly white women with type 2 diabetes (but not elderly men or black women) had more rapid bone loss at the femoral neck and total hip than those with normal glucose homeostasis. 4 This was despite having higher bone mineral density (BMD) at baseline. These data suggest that elderly white women with type 2 diabetes are at a greater risk of hip fracture than the normal population, and more so than men or black women with the disease. There is already a higher prevalence of fracture risk in the elderly population as a whole and bone loss could put older patients with type 2 diabetes at an even higher risk of fracture. Data from the Study of Osteoporotic Fractures (SOF) reported by Taylor et al. 5 showed that although hip BMD is strongly related to hip-fracture risk in elderly white women, there are a number of other clinical risk factors that are independent predictors of long-term risk (e.g. more frequent falls, poor balance, diabetes complications, etc.). This is an important consideration when assessing risk in diabetes patients, and suggests that a wider viewpoint should be embraced.

touchendocrinology.com

The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and p... more The thiazolidinediones (TZDs)-of which the two most frequently prescribed are rosiglitazone and pioglitazone-are insulin-sensitising oral antidiabetic agents that are an effective treatment for type 2 diabetes. The primary pharmacological actions of these drugs are to increase adipose and muscle insulin sensitivity and to inhibit gluconeogenesis in the liver. In type 2 diabetes patients, rosiglitazone reduces plasma levels of fasting glucose, glycated haemoglobin (HbA 1c) and insulin. 1 It may also improve β-cell function. 2 However, emerging evidence regarding the relationship between the use of TZDs and bone loss in type 2 diabetes patients gives cause for concern. 3 There is an increased risk of bone fractures in patients with type 2 diabetes. Some-although not all-studies have shown higher rates of fracture in people with type 2 diabetes compared with normal individuals. The Health, Aging and Body Composition (Health ABC) Study showed that elderly white women with type 2 diabetes (but not elderly men or black women) had more rapid bone loss at the femoral neck and total hip than those with normal glucose homeostasis. 4 This was despite having higher bone mineral density (BMD) at baseline. These data suggest that elderly white women with type 2 diabetes are at a greater risk of hip fracture than the normal population, and more so than men or black women with the disease. There is already a higher prevalence of fracture risk in the elderly population as a whole and bone loss could put older patients with type 2 diabetes at an even higher risk of fracture. Data from the Study of Osteoporotic Fractures (SOF) reported by Taylor et al. 5 showed that although hip BMD is strongly related to hip-fracture risk in elderly white women, there are a number of other clinical risk factors that are independent predictors of long-term risk (e.g. more frequent falls, poor balance, diabetes complications, etc.). This is an important consideration when assessing risk in diabetes patients, and suggests that a wider viewpoint should be embraced.

Clinical Diabetes and Endocrinology

Postgraduate Medicine

Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is... more Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is associated with poor clinical outcomes, including an increased risk of all-cause and cardiovascular mortality, as well as adverse economic and social effects. Slowing the development and progression of CKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering that include cardiovascular benefits and potential renoprotective effects. Although the glucose-lowering efficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m 2. Clinical evidence has indicated that these agents can reduce the risk of development or worsening of albuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressure lowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory processes, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressurelowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute to reduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies in these patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding to the growing evidence of the potential renoprotective effects of these agents in patients with T2DM. Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinical role of SGLT2 inhibitors in slowing the development and progression of renal impairment in individuals with T2DM.

Postgraduate medicine, 2017

to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators f... more to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. At baseline in the Latino/Hispa...

Proceedings of the National Academy of Sciences of the United States of America, Jun 5, 2017

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the t... more Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose. In these type 1 diabetic rats, glucose stimulated glucagon secretion by alpha cells; this was prevented by dapagliflozin. Two models of type 2 diabetes, severely diabetic Zucker rats and db/db mice fed dapagliflozin, showed significant improvement of blood glucose levels and glucose disposal, with reduced evidence of glucagon signaling in the liver, as exemplified by reduced phosphorylation of hepatic cAMP-responsive element binding protein, reduced expression of phosphoeno...

Diabetes & metabolic syndrome, Jan 13, 2016

Excess body weight is a leading cause of metabolic complications such as hypertension and dyslipi... more Excess body weight is a leading cause of metabolic complications such as hypertension and dyslipidemia in T2DM patients. Available antihyperglycemic agents have minimal or no impact on these complications and a majority are known to trigger weight gain, thereby exerting a paradoxical effect on overall metabolic status. This review introduces the concept of 'KgA1c paradox' and underscores the significance of resolving this paradox for comprehensive T2DM management. It provides a therapeutic rationale for inclusion of sodium glucose cotransporter 2 inhibitors in the T2DM treatment algorithm as these agents have demonstrated favorable glycemic effects along with reduction in body weight.

Advances in therapy, Jan 16, 2016

Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM... more Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with...

Diabetes, Obesity and Metabolism, 2016

Postgraduate Medicine, 2016

To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions ... more To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks. Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c <0% and body weight <0 kg, and attainment of HbA1c <7.0% and body weight reduction ≥5% at Week 52 were evaluated. Safety was assessed based on adverse event reports. Canagliflozin provided reductions in HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c <7.0% and body weight reduction ≥5% with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (18.9%, 18.3%, and 5.7%, respectively). Canagliflozin was generally well tolerated. A greater proportion of patients with T2DM achieved reductions in both HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks. www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

Endocrine Practice Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Mar 1, 2011

are systematically developed statements to assist health care professionals in medical decision-m... more are systematically developed statements to assist health care professionals in medical decision-making for specific clinical conditions, but are in no way a substitute for a medical professional's independent judgment and should not be considered medical advice. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with, and not as a replacement for, their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Clinical Therapeutics, 2016

The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs and hormo... more The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs and hormones, suggesting that successful treatment may require therapies that target multiple mechanisms. Exenatide, a glucagon-like peptide 1 receptor agonist, has a multifaceted mechanism of action involving pancreatic α and β cells, hepatic glucose production, gastric motility, and satiety. Exenatide once weekly (a twice-daily formulation is also available) utilizes continuous release from biodegradable microspheres. This review discusses relevant efficacy and tolerability outcomes with exenatide once weekly in the context of its pharmacology. The medical literature was searched to identify relevant data on the pharmacology and clinical effects of exenatide once weekly. Exenatide once weekly, like the twice-daily formulation, has been shown to improve glycemic parameters, promote weight loss, result in beneficial changes in cardiovascular risk factors, and is well-tolerated. The characteristics of exenatide once weekly make it a treatment option for patients with type 2 diabetes.

Endocr Pract, 2010

To explore the impact of race/ethnicity on efficacy and safety of twice-daily insulin lispro mix ... more To explore the impact of race/ethnicity on efficacy and safety of twice-daily insulin lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% insulin lispro) and once daily insulin glargine (GL). More than 2,000 Patients with type 2 diabetes enrolled in the 24-week initiation phase of the DURABLE Trial. Efficacy and safety variables at endpoint, including hemoglobin A1c (HbA1c), self-monitored plasma glucose (SMPG), and hypoglycemia, in each racial/ethnic group were compared to Caucasians within treatment groups. Asian patients had less (LM75/25: -1.46%, P < .01; GL: -1.25%, P < .01) and Hispanic patients had greater (LM75/25: -2.17%) HbA1c reduction from baseline vs Caucasian patients (LM75/25: -1.84%; GL: -1.78%). Fewer Asian (LM75/25: 20%, P < .001; GL: 22%, P < .001) and Hispanic patients (LM75/25: 40%, P < .01) reached HbA1c target (< 7%) vs Caucasian patients (LM75/25: 53%; GL: 44%). Fasting plasma glucose was similar among groups, postprandial glucose (PPG) with GL was lower for African patients post-breakfast and post-dinner and higher for Asian patients post-lunch. Only PPG with LM75/25 was lower for Hispanic patients post-breakfast. Weight gain was lower in Asian patients (LM75/ 25). Insulin dose was higher for Asian (LM75/25 and GL) and lower for African patients (GL). Hypoglycemia rate was lower for Asian (LM75/25 and GL) and Hispanic patients (LM75/25). There were significant efficacy and safety differences among racial/ethnic groups in the DURABLE trial. These differences may be important in designing insulin based treatment plans.

Circulation, Nov 26, 2013