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Showing papers in "Diabetes Care in 2015"


Journal ArticleDOI
TL;DR: This briefer article should be read as an addendum to the previous full account on the management of hyperglycemia, which described the need to individualize both treatment targets and treatment strategies with an emphasis on patient-centered care and shared decision making.
Abstract: In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2). Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

2,553 citations


Journal ArticleDOI
TL;DR: There remains considerable room for improving outcomes of treatment of type 1 diabetes across all age-groups and barriers to more effective use of current treatments need to be addressed and new therapies are needed to achieve optimal metabolic control in people with type 1 Diabetes.
Abstract: To examine the overall state of metabolic control and current use of advanced diabetes technologies in the U.S., we report recent data collected on individuals with type 1 diabetes participating in the T1D Exchange clinic registry. Data from 16,061 participants updated between 1 September 2013 and 1 December 2014 were compared with registry enrollment data collected from 1 September 2010 to 1 August 2012. Mean hemoglobin A1c (HbA1c) was assessed by year of age from 75 years. The overall average HbA1c was 8.2% (66 mmol/mol) at enrollment and 8.4% (68 mmol/mol) at the most recent update. During childhood, mean HbA1c decreased from 8.3% (67 mmol/mol) in 2–4-year-olds to 8.1% (65 mmol/mol) at 7 years of age, followed by an increase to 9.2% (77 mmol/mol) in 19-year-olds. Subsequently, mean HbA1c values decline gradually until ∼30 years of age, plateauing at 7.5–7.8% (58–62 mmol/mol) beyond age 30 until a modest drop in HbA1c below 7.5% (58 mmol/mol) in those 65 years of age. Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) remain all too common complications of treatment, especially in older (SH) and younger patients (DKA). Insulin pump use increased slightly from enrollment (58–62%), and use of continuous glucose monitoring (CGM) did not change (7%). Although the T1D Exchange registry findings are not population based and could be biased, it is clear that there remains considerable room for improving outcomes of treatment of type 1 diabetes across all age-groups. Barriers to more effective use of current treatments need to be addressed and new therapies are needed to achieve optimal metabolic control in people with type 1 diabetes.

1,033 citations


Journal ArticleDOI
TL;DR: Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio.
Abstract: Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.

634 citations


Journal ArticleDOI
TL;DR: SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion.
Abstract: OBJECTIVE Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (DKA) in hopes that it will enhance recognition of this potentially life-threatening complication. RESEARCH DESIGN AND METHODS Cases identified incidentally are described. RESULTS We identified 13 episodes of SGLT-2 inhibitor-associated euglycemic DKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers. CONCLUSIONS SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise, or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy, should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.

626 citations


Journal ArticleDOI
TL;DR: A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7–8 h per day.
Abstract: OBJECTIVE It remains unclear how many hours of sleep are associated with the lowest risk of type 2 diabetes. This meta-analysis was performed to assess the dose-response relationship between sleep duration and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS PubMed and Embase were searched up to 20 March 2014 for prospective observational studies that assessed the relationship of sleep duration and risk of type 2 diabetes. Both semiparametric and parametric methods were used. RESULTS Ten articles with 11 reports were eligible for inclusion in the meta-analysis. A total of 18,443 incident cases of type 2 diabetes were ascertained among 482,502 participants with follow-up periods ranging from 2.5 to 16 years. A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7–8 h per day. Compared with 7-h sleep duration per day, the pooled relative risks for type 2 diabetes were 1.09 (95% CI 1.04–1.15) for each 1-h shorter sleep duration among individuals who slept CONCLUSIONS Our dose-response meta-analysis of prospective studies shows a U-shaped relationship between sleep duration and risk of type 2 diabetes, with the lowest type 2 diabetes risk at 7–8 h per day of sleep duration. Both short and long sleep duration are associated with a significantly increased risk of type 2 diabetes, underscoring the importance of appropriate sleep duration in the delay or prevention of type 2 diabetes.

589 citations


Journal ArticleDOI
TL;DR: The scarce clinical data provided suggested that most of the DKA cases were reported in patients with type 2 diabetes (T2D), for whom this class of agents is indicated; most likely, however, they were insulin-treated patients, some with type 1 Diabetes (T1D).
Abstract: Recently, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that warns of an increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium–glucose cotransporter 2 (SGLT2) inhibitors (1). This Communication was based on 20 clinical cases requiring hospitalization captured between March 2013 and June 2014 in the FDA Adverse Event Reporting System database. The scarce clinical data provided suggested that most of the DKA cases were reported in patients with type 2 diabetes (T2D), for whom this class of agents is indicated; most likely, however, they were insulin-treated patients, some with type 1 diabetes (T1D). The FDA also identified potential triggering factors such as intercurrent illness, reduced food and fluid intake, reduced insulin doses, and history of alcohol intake. The following month, at the request of the European Commission, the European Medicines Agency (EMA) announced on 12 June 2015 that the Pharmacovigilance Risk Assessment Committee has started a review of all of the three approved SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to evaluate the risk of DKA in T2D (2). The EMA announcement claimed that as of May 2015 a total of 101 cases of DKA have been reported worldwide in EudraVigilance in T2D patients treated with SGLT2 inhibitors, with an estimated exposure over 0.5 million patient-years. No clinical details were provided except for the mention that “all cases were serious and some required hospitalisation. Although [DKA] is usually accompanied by high blood sugar levels, in a number of these reports blood sugar levels were only moderately increased” (2). With this background, it is very timely that in this issue of Diabetes Care there are two articles on this subject. Erondu et al. (3) report cases of DKA in T2D …

514 citations


Journal ArticleDOI
TL;DR: Lean male donor fecal microbiota transplantation in males with metabolic syndrome resulted in a significant improvement in insulin sensitivity in conjunction with an increased intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains.
Abstract: The worldwide prevalence of obesity and type 2 diabetes mellitus (T2DM) continues to rise at an alarming pace. Recently the potential role of the gut microbiome in these metabolic disorders has been identified. Obesity is associated with changes in the composition of the intestinal microbiota, and the obese microbiome seems to be more efficient in harvesting energy from the diet. Lean male donor fecal microbiota transplantation (FMT) in males with metabolic syndrome resulted in a significant improvement in insulin sensitivity in conjunction with an increased intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains. Such differences in gut microbiota composition might function as early diagnostic markers for the development of T2DM in high-risk patients. Products of intestinal microbes such as butyrate may induce beneficial metabolic effects through enhancement of mitochondrial activity, prevention of metabolic endotoxemia, and activation of intestinal gluconeogenesis via different routes of gene expression and hormone regulation. Future research should focus on whether bacterial products (like butyrate) have the same effects as the intestinal bacteria that produce it, in order to ultimately pave the way for more successful interventions for obesity and T2DM. The rapid development of the currently available techniques, including use of fecal transplantations, has already shown promising results, so there is hope for novel therapies based on the microbiota in the future.

502 citations


Journal ArticleDOI
TL;DR: A meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia found individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes.
Abstract: OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45–1.80]; men: pooled RR 1.58 [95% CI 1.38–1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86–2.94) in women and 1.73 (95% CI 1.61–1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35–1.73) in women and 1.49 (95% CI 1.31–1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08–1.30]; P CONCLUSIONS Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

400 citations


Journal ArticleDOI
TL;DR: Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.
Abstract: OBJECTIVE To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension. RESEARCH DESIGN AND METHODS Patients ( N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130–159 mmHg and diastolic blood pressure [DBP] 80–99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. RESULTS At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was −3.44 mmHg (95% CI −4.78, −2.09) with 10 mg empagliflozin and −4.16 mmHg (−5.50, −2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was −1.36 mmHg (95% CI −2.15, −0.56) with 10 mg empagliflozin and −1.72 mmHg (95% CI −2.51, −0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was −0.62% (95% CI −0.72, −0.52) (−6.8 mmol/mol [95% CI −7.9, −5.7]) with 10 mg empagliflozin and −0.65% (95% CI −0.75, −0.55) (−7.1 mmol/mol [95% CI −8.2, −6.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion. CONCLUSIONS Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.

375 citations


Journal ArticleDOI
TL;DR: The relationship between body weight and type 2 diabetes is more properly attributable to the quantity and distribution of body fat, and abdominal circumference and waist and hip measurements, although highly correlated with cardiometabolic risk, do not differentiate subcutaneous from visceral adipose abdominal depots and are subject to interobserver variability.
Abstract: According to the U.S. Census Bureau, an Asian is a person with origins from the Far East (China, Japan, Korea, and Mongolia), Southeast Asia (Cambodia, Malaysia, the Philippine Islands, Thailand, Vietnam, Indonesia, Singapore, Laos, etc.), or the Indian subcontinent (India, Pakistan, Bangladesh, Bhutan, Sri Lanka, and Nepal); each region has several ethnicities, each with a unique culture, language, and history. In 2011, 18.2 million U.S. residents self-identified as Asian American, with more than two-thirds foreign-born (1). In 2012, Asian Americans were the nation’s fastest-growing racial or ethnic group, with a growth rate over four times that of the total U.S. population. International migration has contributed >60% of the growth rate in this population (1). Among Asian Americans, the Chinese population was the largest (4.0 million), followed by Filipinos (3.4 million), Asian Indians (3.2 million), Vietnamese (1.9 million), Koreans (1.7 million), and Japanese (1.3 million). Nearly three-fourths of all Asian Americans live in 10 states—California, New York, Texas, New Jersey, Hawaii, Illinois, Washington, Florida, Virginia, and Pennsylvania (1). By 2060, the Asian American population is projected to more than double to 34.4 million, with its share of the U.S. population climbing from 5.1 to 8.2% in the same period (2). Although it is clear that increased body weight is a risk factor for type 2 diabetes, the relationship between body weight and type 2 diabetes is more properly attributable to the quantity and distribution of body fat (3–5). Abdominal circumference and waist and hip measurements, although highly correlated with cardiometabolic risk (6,7), do not differentiate subcutaneous from visceral adipose abdominal depots and are subject to interobserver variability. Imaging and other approaches can be used to more accurately assess fat distribution and quantify adiposity (4,8), but they are not readily available, economical, or useable on …

372 citations


Journal ArticleDOI
TL;DR: Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications in type 1 and type 2 diabetes and might play a future role in clinical risk assessment.
Abstract: OBJECTIVE Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA 1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS Medline and Embase were searched (2004–2015) for studies describing associations between HbA 1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA 1c variability, method of analysis, and diabetes type. RESULTS Seven studies evaluated HbA 1c variability among patients with type 1 diabetes and showed an association of HbA 1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA 1c variability among patients with type 2 diabetes. Higher HbA 1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA 1c variability. CONCLUSIONS HbA 1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA 1c level and might play a future role in clinical risk assessment.

Journal ArticleDOI
TL;DR: A synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus are presented.
Abstract: Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.

Journal ArticleDOI
TL;DR: The development of new-onset insulin-dependent diabetes in five patients after receiving anti-PD-1 antibodies, either as single agent or in combination with other cancer drugs is described.
Abstract: Immunotherapy targeting T-cell regulatory molecules is highly effective in multiple cancers refractory to standard chemotherapies. However, blocking inhibitory molecules on activated T cells not only increases tumor cell destruction but also can breach tolerance, enabling pathological T cells to react with self-antigens. Indeed, autoimmune endocrinopathies, including hypophysitis, hypopituitarism, and thyroiditis, have been reported in trials involving anti-CTLA-4 and anti-PD-1 monoclonal antibodies (1–3). But autoimmune diabetes has not been definitively linked to these agents. We describe the development of new-onset insulin-dependent diabetes in five patients after receiving anti-PD-1 antibodies, either as single agent or in combination with other cancer drugs. Clinical history and key laboratory findings are summarized in Table 1. Notably, while the patients presented with diverse cancer types, and some had been treated with other immunological agents, their …

Journal ArticleDOI
TL;DR: DKA and related events occurred at a low frequency in the canagliflozin type 2abetes program, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes.
Abstract: OBJECTIVE This study assessed the incidence of serious adverse events of diabetic ketoacidosis (DKA) among patients with type 2 diabetes treated with canagliflozin. RESEARCH DESIGN AND METHODS All serious adverse events of DKA and related events (ketoacidosis, metabolic acidosis, and acidosis) from 17,596 patients from randomized studies of canagliflozin through 11 May 2015 were analyzed. RESULTS Serious adverse events of DKA and related events were reported in 12 patients (0.07%), including 4 (0.07%), 6 (0.11%), and 2 (0.03%) treated with canagliflozin 100 and 300 mg and comparator, respectively; corresponding incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient-years, respectively. Most patients with DKA and related events had a blood glucose >300 mg/dL (16.7 mmol/L) at presentation of DKA, were on insulin, and had DKA-precipitating factors, including some with type 1 diabetes/latent autoimmune diabetes of adulthood. CONCLUSIONS DKA and related events occurred at a low frequency in the canagliflozin type 2 diabetes program, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes.

Journal ArticleDOI
TL;DR: Hypoglycemia is associated with an increased risk of CV events and all-cause mortality in insulin-treated patients with diabetes and the relationship between hypoglyCEmia and CV outcomes and mortality exists over a long period.
Abstract: OBJECTIVE Hypoglycemia has been associated with an increased risk of cardiovascular (CV) events and all-cause mortality. This study assessed whether, in a nationally representative population, there is an association between hypoglycemia, the risk of CV events, and all-cause mortality among insulin-treated people with type 1 diabetes (T1D) or type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This retrospective cohort study used data from the Clinical Practice Research Datalink database, and included all insulin-treated patients (≥30 years of age) with a diagnosis of diabetes. RESULTS In patients who experienced hypoglycemia, hazard ratios (HRs) for CV events in people with T1D were 1.51 (95% CI 0.83, 2.75; P = ns) and 1.61 (1.17, 2.22), respectively, for those with and without a history of CV disease (CVD) before the index date. In people with T2D, the HRs for patients with and without a history of CVD were 1.60 (1.21, 2.12) and 1.49 (1.23, 1.82), respectively. For all-cause mortality, HRs in people with T1D were 1.98 (1.25, 3.17), and 2.03 (1.66, 2.47), respectively, for those with and without a history of CVD. Among people with T2D, HRs were 1.74 (1.39, 2.18) and 2.48 (2.21, 2.79), respectively, for those with and without a history of CVD. The median time (interquartile range) from first hypoglycemia event to first CV event was 1.5 years (0.5, 3.5 years) and 1.5 years (0.5, 3.0 years), respectively, for people with T1D and T2D. CONCLUSIONS Hypoglycemia is associated with an increased risk of CV events and all-cause mortality in insulin-treated patients with diabetes. The relationship between hypoglycemia and CV outcomes and mortality exists over a long period.

Journal ArticleDOI
TL;DR: Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss and chronic glycosuria elicits an adaptive increase in energy intake.
Abstract: OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively. RESEARCH DESIGN AND METHODS Eighty-six patients with type 2 diabetes (HbA 1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min −1 ⋅ 1.73 m −2 ) received empagliflozin (25 mg/day) for 90 weeks with frequent ( n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes. RESULTS At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P r = 0.29, P CONCLUSIONS Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.

Journal ArticleDOI
TL;DR: Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.
Abstract: OBJECTIVE Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. RESEARCH DESIGN AND METHODS Study 1 was a Phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, Phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference). RESULTS The bioavailability of 1,000 mg Met DR bid was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR qd produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA 1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information. CONCLUSIONS Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.

Journal ArticleDOI
TL;DR: These studies have important implications for clinical practice and patient education and point to the need for research focused on the development of new insulin dosing algorithms based on meal composition rather than on carbohydrate content alone.
Abstract: BACKGROUND Continuous glucose monitoring highlights the complexity of postprandial glucose patterns present in type 1 diabetes and points to the limitations of current approaches to mealtime insulin dosing based primarily on carbohydrate counting. METHODS A systematic review of all relevant biomedical databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, was conducted to identify research on the effects of dietary fat, protein, and glycemic index (GI) on acute postprandial glucose control in type 1 diabetes and prandial insulin dosing strategies for these dietary factors. RESULTS All studies examining the effect of fat ( n = 7), protein ( n = 7), and GI ( n = 7) indicated that these dietary factors modify postprandial glycemia. Late postprandial hyperglycemia was the predominant effect of dietary fat; however, in some studies, glucose concentrations were reduced in the first 2–3 h, possibly due to delayed gastric emptying. Ten studies examining insulin bolus dose and delivery patterns required for high-fat and/or high-protein meals were identified. Because of methodological differences and limitations in experimental design, study findings were inconsistent regarding optimal bolus delivery pattern; however, the studies indicated that high-fat/protein meals require more insulin than lower-fat/protein meals with identical carbohydrate content. CONCLUSIONS These studies have important implications for clinical practice and patient education and point to the need for research focused on the development of new insulin dosing algorithms based on meal composition rather than on carbohydrate content alone.

Journal ArticleDOI
TL;DR: It is important for health care providers and their practice settings to have the resources and a systematic referral process to ensure that patients with type 2 diabetes receive both DSME and DSMS in a consistent manner.
Abstract: Diabetes is a chronic disease that requires a person with diabetes to make a multitude of daily self-management decisions and to perform complex care activities. Diabetes self-management education and support (DSME/S) provides the foundation to help people with diabetes to navigate these decisions and activities and has been shown to improve health outcomes (1–7). Diabetes self-management education (DSME) is the process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. Diabetes self-management support (DSMS) refers to the support that is required for implementing and sustaining coping skills and behaviors needed to self-manage on an ongoing basis. (See further definitions in Table 1.) Although different members of the health care team and community can contribute to this process, it is important for health care providers and their practice settings to have the resources and a systematic referral process to ensure that patients with type 2 diabetes receive both DSME and DSMS in a consistent manner. The initial DSME is typically provided by a health professional, whereas ongoing support can be provided by personnel within a practice and a variety of community-based resources. DSME/S programs are designed to address the patient’s health beliefs, cultural needs, current knowledge, physical limitations, emotional concerns, family support, financial status, medical history, health literacy, numeracy, and other factors that influence each person’s ability to meet the challenges of self-management. View this table: Table 1 Key definitions It is the position of the American Diabetes Association (ADA) that all individuals with diabetes receive DSME/S at diagnosis and as needed thereafter (8). This position statement focuses on the particular needs of individuals with type 2 diabetes. The needs will be similar to those of people with other types of diabetes (type 1 diabetes, prediabetes, and gestational diabetes mellitus); however, the research and examples referred to in this article focus …

Journal ArticleDOI
TL;DR: Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated.
Abstract: OBJECTIVE To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5 mg ( n = 137), empagliflozin 10 mg/linagliptin 5 mg ( n = 136), empagliflozin 25 mg ( n = 141), empagliflozin 10 mg ( n = 140), or linagliptin 5 mg ( n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA 1c at week 24. RESULTS At week 24, reductions in HbA 1c (mean baseline 7.90–8.02% [62.8–64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were −1.19% (0.06) (−13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, −1.08% (0.06) (−11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, −0.62% (0.06) (−6.8 mmol/mol [0.7]) with empagliflozin 25 mg, −0.66% (0.06) (−7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and −0.70% (0.06) (−7.6 mmol/mol [0.7]) with linagliptin 5 mg ( P 1c ≥7% (≥53 mmol/mol) had HbA 1c CONCLUSIONS Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA 1c compared with the individual components and were well tolerated.

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TL;DR: In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metform in patients with type 2 diabetes, greater improvements in glycemic control were obtained with triple therapy by the dual addition.
Abstract: OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin. RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA 1c ≥8.0% and ≤12.0% (64–108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo ( n = 176), or DAPA (10 mg/day) and placebo ( n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA 1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET. RESULTS Patients had a mean baseline HbA 1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m 2 . At week 24, the adjusted mean change from the baseline HbA 1c was –1.5% (–16.1 mmol/mol) with SAXA+DAPA+MET versus –0.9% (–9.6 mmol/mol) with SAXA+MET (difference −0.59% [–6.4 mmol/mol], P P 1c CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone.

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TL;DR: Adherence was independently associated with older age, male sex, higher education, higher income, use of mail order versus retail pharmacies, primary care versus nonendocrinology specialist prescribers, higher daily total pill burden, and lower out-of-pocket costs.
Abstract: OBJECTIVE Adults with diabetes typically take multiple medications for hyperglycemia, diabetes-associated conditions, and other comorbidities. Medication adherence is associated with improved outcomes, including reduced health care costs, hospitalization, and mortality. We conducted a retrospective analysis of a large pharmacy claims database to examine patient, medication, and prescriber factors associated with adherence to antidiabetic medications. RESEARCH DESIGN AND METHODS We extracted data on a cohort of >200,000 patients who were treated for diabetes with noninsulin medications in the second half of 2010 and had continuous prescription benefits eligibility through 2011. Adherence was defined as a medication possession ratio ≥0.8. We used a modified adherence measure that accounted for switching therapies. Logistic regression analysis was performed to determine factors independently associated with adherence. RESULTS Sixty-nine percent of patients were adherent. Adherence was independently associated with older age, male sex, higher education, higher income, use of mail order versus retail pharmacies, primary care versus nonendocrinology specialist prescribers, higher daily total pill burden, and lower out-of-pocket costs. Patients who were new to diabetes therapy were significantly less likely to be adherent. CONCLUSIONS Several demographic, clinical, and potentially modifiable system-level factors were associated with adherence to antidiabetic medications. Patients typically perceived to be healthy (those who are younger, new to diabetes, and on few other medications) may be at risk for nonadherence. For all patients, efforts to reduce out-of-pocket costs and encourage use of mail order pharmacies may result in higher adherence.

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TL;DR: Reductions in risk among moderate alcohol drinkers may be confined to women and non-Asian populations, and the possibility that reductions in risk may have been overestimated by studies using a referent group contaminated by less healthy former drinkers.
Abstract: OBJECTIVE Observational studies indicate that moderate levels of alcohol consumption may reduce the risk of type 2 diabetes. In addition to providing an updated summary of the existing literature, this meta-analysis explored whether reductions in risk may be the product of misclassification bias. RESEARCH DESIGN AND METHODS A systematic search was undertaken, identifying studies that reported a temporal association between alcohol consumption and the risk of type 2 diabetes. No restrictions were placed upon the language or date of publication. Non-English publications were, where necessary, translated using online translation tools. Models were constructed using fractional polynomial regression to determine the best-fitting dose-response relationship between alcohol intake and type 2 diabetes, with a priori testing of sex and referent group interactions. RESULTS Thirty-eight studies met the selection criteria, representing 1,902,605 participants and 125,926 cases of type 2 diabetes. A conventional noncurrent drinking category was reported by 33 studies, while five reported a never-drinking category. Relative to combined abstainers, reductions in the risk of type 2 diabetes were present at all levels of alcohol intake <63 g/day, with risks increasing above this threshold. Peak risk reduction was present between 10–14 g/day at an 18% decrease in hazards. Stratification of available data revealed that reductions in risk may be specific to women only and absent in studies that adopted a never-drinking abstention category or sampled an Asian population region. CONCLUSIONS Reductions in risk among moderate alcohol drinkers may be confined to women and non-Asian populations. Although based on a minority of studies, there is also the possibility that reductions in risk may have been overestimated by studies using a referent group contaminated by less healthy former drinkers.

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TL;DR: PA seemed to be beneficial with respect to glycemic control, diabetes-related comorbidities, and cardiovascular risk factors without an increase of adverse events, which underscore the recommendation for subjects with type 1 diabetes to perform regular PA.
Abstract: OBJECTIVE Physical activity (PA) can improve cardiovascular risk in the general population and in patients with type 2 diabetes Studies also indicate an HbA 1c -lowering effect in patients with type 2 diabetes Since reports in patients with type 1 diabetes are scarce, this analysis aimed to investigate whether there is an association between PA and glycemic control or cardiovascular risk in subjects with type 1 diabetes RESEARCH DESIGN AND METHODS A total of 18,028 adults (≥18 to P values for trend were given SAS 94 was used for statistical analysis RESULTS An inverse association between PA and HbA 1c , diabetic ketoacidosis, BMI, dyslipidemia (all P P = 00150), as well as between PA and retinopathy or microalbuminuria (both P P = 08989), whereas severe hypoglycemia with coma was inversely associated with PA ( P CONCLUSIONS PA seemed to be beneficial with respect to glycemic control, diabetes-related comorbidities, and cardiovascular risk factors without an increase of adverse events Hence, our data underscore the recommendation for subjects with type 1 diabetes to perform regular PA

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TL;DR: Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.
Abstract: OBJECTIVE This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG 0030–0430 h ). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA 1c , fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed. RESULTS In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG 0030−0430 h compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, −6.0 [−7.8] h ⋅ mmol/L [−108.3 (−140.0) h ⋅ mg/dL] vs. liraglutide 1.2 mg and −4.6 [−6.3] h ⋅ mmol/L [−83.0 (−114.2) h ⋅ mg/dL] vs. liraglutide 1.8 mg; P P 1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide ( P P CONCLUSIONS Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.

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TL;DR: Canagliflozin provided reductions in HbA1c, body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.
Abstract: OBJECTIVE This study assessed the efficacy and safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This 18-week, double-blind, phase 2 study randomized 351 patients (HbA 1c 7.0–9.0% [53–75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA 1c reduction from baseline of ≥0.4% (≥4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA 1c , body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTS More patients had both HbA 1c reduction ≥0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P 1c , body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7–6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9–1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONS Canagliflozin provided reductions in HbA 1c , body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.

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TL;DR: Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.
Abstract: OBJECTIVE To assess the efficacy/safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, patients ( N = 1,450) received canagliflozin 100 or 300 mg, or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS At week 104, reductions from baseline in A1C were −0.65%, −0.74%, and −0.55% (−7.1, −8.1, and −6.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (−4.1%, −4.2%, and 0.9%, respectively) and systolic blood pressure (−2.0, −3.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis–related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS Canagliflozin provided durable glycemic improvements compared with glimepiride, and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.

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TL;DR: There is universal agreement that HbA1c is the current gold standard for the primary clinical target, but there is no consensus as to whether other proposed glycemic metrics hold promise to provide additional clinical data or whether there should be additional targets beyond Hb a1c.
Abstract: There is no argument that improving mean levels of glycemic control as judged by assays for glycated hemoglobin (HbA(1c)) reduces the risks of microvascular complications and cardiovascular disease events in patients with type 1 and type 2 diabetes. However, observations in some trials have suggested that targeting HbA(1c) to suggested targets may not always result in improved outcomes for people with long-standing type 2 diabetes. The reasons why the glycemic control strategies that primarily use HbA(1c) in these studies did not have predicted outcomes are not clear. Thus, controversy remains as to whether there are glycemic metrics beyond HbA(1c) that can be defined as effective measures that can be used in addition to HbA(1c) to help in assessing the risk of an individual developing diabetes complications. In this regard, the concept of "glycemic variability" (GV) is one metric that has attracted a lot of attention. GV can be simply defined as the degree to which a patient's blood glucose level fluctuates between high (peaks) and low (nadir) levels. The best and most precise way to assess GV is also one that is still debated. Thus, while there is universal agreement that HbA(1c) is the current gold standard for the primary clinical target, there is no consensus as to whether other proposed glycemic metrics hold promise to provide additional clinical data or whether there should be additional targets beyond HbA(1c). Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below, Dr. Hirsch provides his argument that fluctuations in blood glucose as assessed by GV metrics are deleterious and control of GV should be a primary treatment target. In the following counterpoint narrative, Dr. Bergenstal argues that there are better markers to assess the risk of diabetes than GV and provides his consideration of other concepts.

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TL;DR: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias.
Abstract: OBJECTIVE Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin’s lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin’s lymphoma, gallbladder (F), stomach (F), and non-Hodgkin’s lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

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TL;DR: Canagliflozin added to insulin therapy improved glycemic control and decreased body weight and there was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.
Abstract: OBJECTIVE There are limited data about the effects of sodium–glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTS Individuals receiving insulin at baseline were randomized to receive placebo ( n = 690), canagliflozin 100 mg ( n = 692), or canagliflozin 300 mg ( n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m2, estimated glomerular filtration rate of 75 mL/min/1.73 m2, fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were −0.62% (95% CI −0.69, −0.54; −6.8 mmol/mol [95% CI −7.5, −5.9]; P < 0.001) and −0.73% (95% CI −0.81, −0.65; −8.0 mmol/mol [95% CI −8.9, −7.1]; P < 0.001) at 18 weeks and −0.58% (95% CI −0.68, −0.48; −6.3 mmol/mol [95% CI −7.4, −5.2]) and −0.73% (95% CI −0.83, −0.63; −8.0 mmol/mol [95% CI −9.1, −6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONS Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.