The cost-effectiveness of metformin in the US diabetes prevention program trial: Simple interpretations need not apply.

Based on previously published US Diabetes Prevention Program (DPP) cost-effectiveness analyses (CEAs) metformin continues to be promoted as "cost-effective." We review the DPP within-trial CEA to assess this claim. Treatment alternatives included placebo (plus standard lifestyle advice), branded metformin and individual lifestyle modification. We added generic metformin as an alternative. Original published CEA data were taken as given and re-analyzed according to accepted principles for calculating incremental cost-effectiveness ratios (ICERs) in the economic evaluation field. With more than two treatments as in the DPP, these require attention to the rankings of interventions according to cost or effect prior to stipulating appropriate ICERs to calculate. With proper ICERs neither branded nor generic metformin was cost-effective, regardless of the value assumed for the willingness to pay for the quality-adjusted life year outcome assessed. Metformin alternatives were technically inefficient compared to placebo or the lifestyle modification alternative. Net loss calculations indicated substantial costs/health losses to using metformin instead of the optimal lifestyle alternative in response to metformin having been inaccurately labelled "cost-effective" in the original CEA. That CEA and subsequent analyses and citations of such analyses continue to claim that both metformin and lifestyle modification are cost-effective in diabetes prevention based on DPP data. Using metformin implies substantial costs and health losses compared to the cost-effective lifestyle modification. It may be that metformin has a role in cost-effective diabetes prevention, but this has yet to be shown based on DPP data.

SGLT-2 inhibitors may be targeting higher risk patients with diabetes possibly justifying higher cost: Single center repeated cross-sectional analysis.

INTRODUCTION: We studied the use of all hypoglycemic agents in periods before and after introduction of SGLT-2 inhibitors in the USA by repeated cross sectional analysis to initially assess improvement in HbA1c control among patients with type 2 diabetes and hypertension. We sought to identify changes in glucose management related to the availability of the SGLT-2 inhibiting agents. We hypothesized that patients transitioned to SGLT-2 inhibitor-based therapy represented a higher risk group that derived benefits in terms of Hba1c control. METHODS: Deidentified records of patients seen at least twice during the relevant time periods at Joslin Clinic between January 1, 2010 and December 31, 2012 and/or between January 1, 2014 and December 31, 2016 were examined. Records required all of the following: demographic information of gender, age, height, weight, BMI, HbA1c, eGFR, blood pressure, smoking status and completed medication lists. RESULTS: 10,191 patients met criteria for analysis, 7769 seen in period 1 and 6576 in period 2. 4625 patients were seen in both periods. The group of patients defined by SGLT-2 use had significantly higher BMI and HbA1c. Notable shifts in medication use were observed as SGLT-2 use increased from none to 14%. Increased use (all p < 0.001) of GLP-1 agents (16.0 to 23.8%), insulin (56.1 to 60.5%) and statins (78.4 to 81.5%) and statistically significant decreases (all p < 0.001) in use of biguanides (69.5 to 66.3%) and sulfonylurea compounds (44.7 to 39.4%), thiazolidinediones (13.6 to 3.4%) and diuretics (32.4 to 28.9%) were observed. Statistically significant decreases (all p < 0.001) of HbA1c (7.9 to 7.8%), BMI (32.5 to 32.1), eGFR (80.6 to 77.5 ml/min) and increased systolic blood pressure (130 to 132 mm Hg) were documented. CONCLUSIONS: In the absence of glycemia treatment resistance or clinical heart failure SGLT-2 inhibitor use may not be cost effective. Enthusiasm for use of SGLT-2 inhibition should be based upon long-term cardiorenal protection rather than short-term glycemia control given limited impact upon HbA1c levels in our tertiary care type 2 diabetes population.

Prolonged glucosuria and relapse of diabetic ketoacidosis related to SGLT2-inhibitor therapy.

SGLT2 inhibitors (SGLT2i) are glucose-lowering medications which increase the renal threshold for glucose reabsorption and promote glucosuria. Treatment with these agents raises serum ketone levels, and cases of diabetic ketoacidosis (DKA) during therapy have been reported. The duration of glucosuria and inpatient course of SGLT2i-related DKA, however, is not well-characterized. We report 11 inpatient cases of SGLT2i-related DKA, including a subset of patients who experienced prolonged glucosuria and relapse of DKA during their hospitalization.

Need for a Judicious Use of Nonsteroidal Anti-inflammatory Drugs to Avoid Community-Acquired Acute Kidney Injury.

Millions of Americans use over-the-counter analgesics on a daily basis, and nearly 100 million nonsteroidal anti-inflammatory drug (NSAID) prescriptions are filled per year. In high-risk patients, these medications can disrupt kidney hemodynamics and precipitate community-acquired acute kidney injury (CA-AKI). The risk of NSAID-associated CA-AKI increases 3- to 5-fold in patients taking renin-angiotensin system inhibitors and diuretics concurrently. CA-AKI increases the risk of developing chronic kidney disease (CKD) or accelerating progression of pre-existing CKD. Importantly, many cases of NSAID-induced CA-AKI may be avoided by identifying high-risk patients and providing patient and provider education on when to avoid these medications and minimize risk.

Understanding concentrated insulins: a systematic review of randomized controlled trials.

OBJECTIVE: To compile, analyze, and summarize the literature on concentrated insulins (i.e. concentrations >100 units/mL) from randomized controlled trials and derive guidance on appropriate use of these agents. METHODS: Searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, Trialtrove (through April 2016) and ClinicalTrials.gov (through April 2017) for phase 1-4 clinical studies using concentrated insulins. Selected studies included multiple-arm, randomized controlled trials evaluating subcutaneously administered concentrated insulins. Trial registration numbers (selected studies) were searched in Medline, Embase and Google Scholar (through April 2017). Late-phase studies were graded using guidance from the Agency for Healthcare Research and Quality. RESULTS: Thirty-eight completed trials (7900 participants) and 34 qualifying publications were identified. Four marketed concentrated insulins were evaluated: two long-acting basal (insulin glargine 300 units/mL and insulin degludec 200 units/mL [IDeg200]), one rapid-acting prandial (insulin lispro 200 units/mL [ILis200]), and one prandial/basal (human regular insulin 500 units/mL). Early-phase trials established bioequivalence for IDeg200 and ILis200 with the corresponding 100 units/mL formulations. Efficacy studies showed noninferior glycemic control between comparators for long-acting basal and prandial/basal products with generally low severe hypoglycemia. Six additional concentrated insulins with completed early-phase development were also identified. CONCLUSION: Concentrated-insulin products demonstrated efficacious and safe outcomes in appropriate patients. Clinical findings (HbA1c and hypoglycemia) and methodology (initiation and titration), patient factors (insulin experience and dosing requirements) and treatment characteristics (bioequivalence, potency and device features) are important considerations. This overview of these and other factors provides essential information and guidance for using concentrated insulins in clinical practice.

Changes in treatment of hyperglycemia in a hypertensive type 2 diabetes population as renal function declines.

BACKGROUND: Cardiovascular complications associated with expensive noninsulin agents for type 2 diabetes are the focus of concern in light of the risk of kidney dysfunction with aging. Head-to-head comparisons are unavailable to guide the choice of new drugs for hyperglycemia in patients with type 2 diabetes, decreased estimated glomerular filtration rate (eGFR) and increased cardiovascular risk. A first approach would be to document current medication choices. METHODS: All prescriptions for 10 151 patients (5623 males/4528 females) with both type 2 diabetes and hypertension seen two or more times during a 5-year period (2007-12) at Joslin Diabetes Center were evaluated. {mean age 64 years [interquartile range (IQR) 64-65)], body mass index 31 kg/m2 (IQR 30-32) and mean eGFR 78 mL/min/1.73 m2 (IQR 78, 78)}. RESULTS: Insulin was used in >60% of patients, metformin in 50% and sulfonylurea derivatives in 25%. Dipeptidyl peptidase 4 (DPP4) and acarbose class drugs were prescribed in 10% of patients, GLP-1 in 8% and other classes [including thiazolidinediones (TZD)] in <5%. Patients were grouped into four drug Categories none, 447 (4%); insulin only, 3836 (38%); other than insulin, 2910 (29%) and insulin combinations, 2955 (29%). Common combinations included insulin/metformin [n = 2493 (25%)], insulin/sulfonylureas [706 (7%)], metformin/sulfonylureas [2017 (20%)], metformin/GLP1 [949 ( 9%)], metformin/DPP4 [895 (9%)] and metformin/TZD [500 (5%)]. Insulin use increased to 70% from 35% as eGFR dropped to <30 mL/min/1.73 m2; use of insulin combined with other drugs dropped to 12% from 31% and the use of other drugs alone without insulin dropped similarly to 12% from 30%. CONCLUSIONS: Reduced renal function was associated with increased use of insulin and decreased use of other anti-diabetic agents in a statistically significant progression. BMI and gender did not influence medication choice.

Sodium-glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions.

OBJECTIVE: To evaluate whether adverse event reports to the US Food and Drug Administration on incidents of ketoacidosis from use of sodium glucose cotransport inhibitors (SGLT2 inhibitors) provide insight into ways this new class of drugs is being prescribed with other antihyperglycemic agents; to examine possible mechanisms to explain ketoacidosis. DESIGN AND METHODS: Reports of adverse events concerned to SGLT2 inhibitors, namely, empagliflozin, dapagliflozin, and canagliflozin were obtained under the Freedom of Information Act for 5 years ending in August 31, 2015. The data were evaluated for incidents of ketoacidosis by looking for keywords such as diabetic ketoacidosis, ketoacidosis, lactic acidosis, acidosis, and metabolic acidosis. Results were tabulated individually for empagliflozin (n=260 adverse event reports), dapagliflozin (n=520), and canagliflozin (n=2159). Adverse events were categorized according to age, gender, and insulin use. RESULTS: There were 46, 144, and 450 reports of ketoacidosis concerned with the use of empagliflozin, dapagliflozin, and canagliflozin, respectively. The use of SGLT2 inhibitors was not strictly limited to patients with type 2 diabetes but was cut across categories of insulin use, including a total of 172 cases of SGLT2-related ketoacidosis in individuals above the age of 40 who were not on insulin. CONCLUSION: Further studies should focus to detect pleiotropic effects of SGLT2 inhibitors, particularly with other oral antihyperglycemic drugs or insulin. A review of the literature suggests that patients with type 2 diabetes with low C-peptide level may be at increased risk of ketoacidosis, particularly if they are on statins and diuretics due to hypokalemia and impaired release of insulin. More studies are warranted to further clarify these mechanisms.

Liberating A1C goals in older adults may not protect against the risk of hypoglycemia.

AIMS: Hemoglobin A1C is universally used as a marker for glycemic control and to establish glycemic goals in patients with diabetes. In the older population, experts recommend liberating A1C goals to decrease the risk of hypoglycemia. However, it's not clear which A1C level is optimal for this purpose. This study's aim was to understand the relationship between A1C levels and risk of hypoglycemia. METHODS: In a prospective study, we performed continuous glucose monitoring (CGM) on older adults on insulin. Hypoglycemia duration and A1C were measured at baseline while patients were on multiple insulin injections, and again after de-intensification to once-a-day basal insulin with non-insulin agents. RESULTS: We assessed 65 patients; mean age76±6years with on average 3.7±1.3 insulin injections/day. At baseline, 26% of the patients had A1C<7% (53mmol/mol), 42% between 7.1% and 8% (54-64mmol/mol), 21% between 8.1% and 9% (65-75mmol/mol), and 11% >9% (76mmol/mol). The duration of hypoglycemia (<70mg/dl, <60mg/dl, <50mg/dl) was not different between the A1c groups, regardless of treatment intensity (multiple insulin injections or once-a-day-basal insulin with non-insulin agents). CONCLUSIONS: A1C levels are not associated with hypoglycemia risk in older population with type-2 diabetes on insulin therapy. Higher A1C goals do not protect against hypoglycemia.

Metformin-SGLT2, Dehydration, and Acidosis Potential.

Clinicians are aware of the risks and benefits of metformin in type 2 diabetes. In geriatric populations lactic acidosis due to diminishing kidney function is an issue. The recent addition of a group of agents to control diabetes through increased glycosuria may increase the risk of dehydration and acidosis. This may happen due to gastrointestinal loss from metformin diarrhea or urine loss from diuretics. A typical example is presented.

Insulin: Making Sense of Current Options.

Newer insulin products have advanced the evolution of insulin replacement options to more accurately mimic natural insulin action. There are new, modified, and concentrated insulins; administration devices calibrated for both increased concentrations and administration accuracy to improve adherence and safety; and inhaled insulin. There are new combinations of longer-acting basal insulin and rapid-acting insulin or glucagon like protein-1 receptor agonists. Existing insulin replacement designs and methods can be updated using these tools to improve efficacy and safety. Individualized decisions to use them should be based on patient physiologic needs, self-care ability, comorbidities, and cost considerations.

Renal Function Alters Antihypertensive Regimens in Type 2 Diabetic Patients.

To determine the prevalence of multidrug antihypertensive therapy (MDAT), records were evaluated for patients with both type 2 diabetes and hypertension during a 5-year period at Joslin Diabetes Center. Hypertension control was defined as requiring multiple drugs if three or more antihypertensive drugs were used, one of which must be a diuretic (unless patient is receiving dialysis), or use of four or more antihypertensive drugs, one of which a diuretic (unless patient is receiving dialysis) was established. The objective was to determine the prevalence of multidrug requirement for hypertensive therapy in relationship to four levels of renal function estimated by the Modification of Diet in Renal Disease formula for glomerular filtration rate (GFR). Among 10,151 patients, mean estimated GFR was 80 mL/min. Using standard (ASN) classification for renal function, we noted the following breakdown of MDAT use: Estimated GFR Drugs, Mean No. ≥3 Drugs, No. (%) ≥4 Drugs, No. (%) <30 3.1 379 (67) 214 (38) 30-60 2.7 1233 (55) 538 (24) 60-90 2.0 1279 (33) 458 (12) >90 1.5 600 (17) 185 (5) Prevalence of multidrug antihypertensive therapy is markedly increased in the presence of reduced renal function.

Are you ready for more insulin concentrations?

Practitioners need to prepare for a rapid expansion of new concentrated insulins. For many years, the treatment regimens for patients have been limited to 2 concentrations (100 units/mL and 500 units/mL), which pose challenges to both patients and providers. As the new concentrated insulins are at various stages of development, this manuscript reviews the available information on the new concentrated products. This information was obtained from publications, poster presentations, abstracts, and the manufacturers for the products in earlier stages of development. To have a basis for comparison, it is important to understand the activity profile and the challenges with use of the currently available concentrated insulin, regular insulin 500 units/mL (U500R). We also examine how the newer products may assist clinicians and patients with the difficulties faced with the use of U500R.

Dynamical glucometry: use of multiscale entropy analysis in diabetes.

Diabetes mellitus (DM) is one of the world's most prevalent medical conditions. Contemporary management focuses on lowering mean blood glucose values toward a normal range, but largely ignores the dynamics of glucose fluctuations. We probed analyte time series obtained from continuous glucose monitor (CGM) sensors. We show that the fluctuations in CGM values sampled every 5 min are not uncorrelated noise. Next, using multiscale entropy analysis, we quantified the complexity of the temporal structure of the CGM time series from a group of elderly subjects with type 2 DM and age-matched controls. We further probed the structure of these CGM time series using detrended fluctuation analysis. Our findings indicate that the dynamics of glucose fluctuations from control subjects are more complex than those of subjects with type 2 DM over time scales ranging from about 5 min to 5 h. These findings support consideration of a new framework, dynamical glucometry, to guide mechanistic research and to help assess and compare therapeutic interventions, which should enhance complexity of glucose fluctuations and not just lower mean and variance of blood glucose levels.

"Glucose-at-a-Glance": New Method to Visualize the Dynamics of Continuous Glucose Monitoring Data.

The standard continuous glucose monitoring (CGM) output provides multiple graphical and numerical summaries. A useful adjunct would be a visualization tool that facilitates immediate assessment of both long- and short-term variability. We developed an algorithm based on the mathematical method of delay maps to display CGM signals in which the glucose value at time ti is plotted against its value at time ti+1. The data points are then color-coded based on their frequency of occurrence (density). Examples of this new visualization tool, along with the accompanying time series, are presented for selected patients with type 2 diabetes and non-diabetic controls over the age of 70 years. The method reveals differences in the structure of the glucose variability between subjects with a similar range of glucose values. We also observe that patients with comparable hemoglobin A1c (HbA1c) values may have very different delay maps, consistent with marked differences in the dynamics of glucose control. These differences are not accounted by the amplitude of the fluctuations. Furthermore, the delay maps allow for rapid recognition of hypo- and hyperglycemic periods over the full duration of monitoring or any subinterval. The glucose-at-a-glance visualization tool, based on colorized delay maps, provides a way to quickly assess the complex data acquired by CGM systems. This method yields dynamical information not contained in single summary statistics, such as HbA1c values, and may also serve as the basis for developing novel metrics of glycemic control.

Diabetes in long-term care facilities.

With the aging of the population and longer life expectancies, the prevalence of population with multiple chronic medical conditions has increased. Difficulty managing these conditions as people age (because of changes in physical, functional, or cognitive abilities and the complexity of many treatment regimens), has led to more individuals with multiple medical conditions admitted to the long-term care facilities. Older adults with diabetes residing in the long-term facilities represent the most vulnerable of this cohort. Studies that specifically target diabetes management in older population are lacking and those that target diabetes management in the long-term care facilities are even fewer. The lack of knowledge regarding the care of the elderly residing in long-term care with diabetes may lead to treatment failure and higher risk of hyperglycemia, as well as hypoglycemia. In aging populations, hypoglycemia has the potential for catastrophic consequences. To avoid this, the management of older population with diabetes and other medical comorbidities residing in long-term care facilities requires a more holistic approach compared with focusing on individual chronic disease goal achievement.

Assessment of barriers to improve diabetes management in older adults: a randomized controlled study.

OBJECTIVE: To evaluate whether assessment of barriers to self-care and strategies to cope with these barriers in older adults with diabetes is superior to usual care with attention control. The American Diabetes Association guidelines recommend the assessment of age-specific barriers. However, the effect of such strategy on outcomes is unknown. RESEARCH DESIGN AND METHODS: We randomized 100 subjects aged ≥69 years with poorly controlled diabetes (A1C >8%) in two groups. A geriatric diabetes team assessed barriers and developed strategies to help patients cope with barriers for an intervention group. The control group received equal amounts of attention time. The active intervention was performed for the first 6 months, followed by a "no-contact" period. Outcome measures included A1C, Tinetti test, 6-min walk test (6MWT), self-care frequency, and diabetes-related distress. RESULTS: We assessed 100 patients (age 75 ± 5 years, duration 21 ± 13 years, 68% type 2 diabetes, 89% on insulin) over 12 months. After the active period, A1C decreased by -0.45% in the intervention group vs. -0.31% in the control group. At 12 months, A1C decreased further in the intervention group by -0.21% vs. 0% in control group (linear mixed-model, P < 0.03). The intervention group showed additional benefits in scores on measures of self-care (Self-Care Inventory-R), gait and balance (Tinetti), and endurance (6MWT) compared with the control group. Diabetes-related distress improved in both groups. CONCLUSIONS: Only attention between clinic visits lowers diabetes-related distress in older adults. However, communication with an educator cognizant of patients' barriers improves glycemic control and self-care frequency, maintains functionality, and lowers distress in this population.