Cost saving analysis of prediabetes intervention modalities in comparison with inaction using Markov state transition model-A multiregional case study.

BACKGROUND: Prediabetes management is a priority for policymakers globally, to avoid/delay type 2 diabetes (T2D) and reduce severe, costly health consequences. Countries moving from low to middle income are most at risk from the T2D "epidemic" and may find implementing preventative measures challenging; yet prevention has largely been evaluated in developed countries. METHODS: Markov cohort simulations explored costs and benefits of various prediabetes management approaches, expressed as "savings" to the public health care system, for three countries with high prediabetes prevalence and contrasting economic status (Poland, Saudi Arabia, Vietnam). Two scenarios were compared up to 15 y: "inaction" (no prediabetes intervention) and "intervention" with metformin extended release (ER), intensive lifestyle change (ILC), ILC with metformin (ER), or ILC with metformin (ER) "titration." RESULTS: T2D was the highest-cost health state at all time horizons due to resource use, and inaction produced the highest T2D costs, ranging from 9% to 34% of total health care resource costs. All interventions reduced T2D versus inaction, the most effective being ILC + metformin (ER) "titration" (39% reduction at 5 y). Metformin (ER) was the only strategy that produced net saving across the time horizon; however, relative total health care system costs of other interventions vs inaction declined over time up to 15 y. Viet Nam was most sensitive to cost and parameter changes via a one-way sensitivity analysis. CONCLUSIONS: Metformin (ER) and lifestyle interventions for prediabetes offer promise for reducing T2D incidence. Metformin (ER) could reduce T2D patient numbers and health care costs, given concerns regarding adherence in the context of funding/reimbursement challenges for lifestyle interventions.

Optimizing levothyroxine treatment for subclinical hypothyroidism during pregnancy.

The onset of pregnancy places additional stress of the thyroid gland, which must produce additional thyroid hormones to support the developing foetus. Hypothyroidism, including subclinical hypothyroidism (SCH), may appear de novo at this time, or existing thyroid disease may become more severe. Accordingly, SCH is a relatively common complication of up to about 3% of pregnancies, with higher rates in some areas. There is strong evidence from systematic reviews and meta-analyses that uncontrolled SCH is associated with an increased risk of adverse pregnancy outcomes, including miscarriage, preeclampsia, and gestational diabetes. The evidence base also suggests that treatment with levothyroxine (LT4), optimized to control thyrotropin (TSH) to within its pregnancy-specific reference ranges reduces these risks. Current management guidelines provide a clear framework of intervention with LT4 in pregnant women with SCH, especially where TSH is high or where thyroperoxidase autoantibodies are present. Sub-optimal adherence to LT4 is common: it is important that patients take their LT4 correctly and that treating physicians and/or healthcare professionals manage these patients according to the latest management guidelines. The titration of LT4 is likely to occur within a range of LT4 daily doses between 25 µg and 75 µg for the majority of this population. LT4 is a narrow therapeutic index drug and small variations in dosage may produce a clinically significant change in thyroid status. Newer formulations of LT4, engineered to provide more precise and consistent dosing, and with a broad range of tablet strengths, may facilitate the precise titration of the LT4 dose for these patients.

Contribution of single-pill combinations in the management of hypertension: perspectives from China, Europe and the USA.

Uncontrolled hypertension is associated with an increased risk of adverse clinical vascular outcomes and death. Hypertension management guidelines from China and the USA recommend initiation of antihypertensive pharmacotherapy with a single drug for patients without severe hypertension at presentation. Current European hypertension guidelines take a different approach and recommend the use of combination therapy from the time of diagnosis of hypertension for most patients. This article reviews the burden of hypertension in these countries and summarises the evidence base for the use of antihypertensive combination therapy contained within a single tablet (single-pill combinations, SPC). Typically, half or less of populations from China, Europe and the USA who were found to have hypertension were aware of their condition, less than half of those receiving treatment, and fewer still achieved adequate blood pressure (BP) control. The reasons for the unaddressed burden of hypertension are complex and multifactorial, with contributions from factors related to patients, healthcare providers and healthcare systems. The use of SPCs of antihypertensive therapies helps to optimise adherence with therapy and is likely to result in superior BP control. There is a strong evidence base to support current European guideline recommendations on the initiation of antihypertensive therapy with SPCs for the majority of people with hypertension.

Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

INTRODUCTION: Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100 mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850 mg, 50/1000 mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. METHODS: The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48 h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). RESULTS: Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100 mg), 26/25 (FDC 50/850 mg), and 26/24 (FDC 50/1000 mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100 mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850 mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000 mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850 mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000 mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. CONCLUSIONS: The new generic tablet formulations of sitagliptin 100 mg and the FDCs sitagliptin/metformin 50/850 mg and 50/1000 mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). TRIAL REGISTRATION: EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

Use of levothyroxine in the management of hypothyroidism: A historical perspective.

The thyroid operates within a complex system of homeostatic regulation, where the level of thyrotropin (TSH) influences the rate of secretion of the principal thyroid hormones, thyroxine (T4) and triiodothyronine (T3). The devastating consequences of untreated thyroid dysfunction have been evident for centuries. Indeed, sources from antiquity described goitre and cretinism, two of the clinical sequelae of untreated overt thyroid disease. It was not until the first part of the 19th century that goitre and cretinism were first associated with iodine status; however, the endocrine function of the thyroid was not clearly identified until the early part of the 20th century. Three principal innovations in the 20th century supported the use of levothyroxine (LT4) replacement therapy for the management of hypothyroidism: a practical technique for the synthesis of LT4 suitable to support pharmaceutical use (late 1940s), the discovery that LT4 is converted to the active thyroid hormone, T3, in the peripheral tissues (1970), and the development of robust and sensitive assay methodology for measuring thyroid hormones in the blood (1960 onwards). Synthetic LT4, titrated to bring the level of TSH within a predefined "normal" reference range, is now established as the mainstay of treatment for hypothyroidism, and provides adequate restoration of thyroid hormone function for most people with this condition. Future research will explore further the nuances of the hypothalamic-pituitary-thyroid axis, and the place, if any, for T3 within the management of thyroid dysfunction.

Real-World Effectiveness of Beta-Blockers versus Other Antihypertensives in Reducing All-Cause Mortality and Cardiovascular Events.

Aim: The aim of the study was to compare the effectiveness of beta-blockers with other antihypertensive classes in reducing all-cause mortality, cardiovascular-related mortality and the risk of cerebrocardiovascular events. Methods: This noninterventional study was conducted within the UK Clinical Practice Research Datalink. Hypertensive patients who initiated antihypertensive monotherapy were allocated to one of five cohorts: beta-blockers; angiotensin-converting enzyme inhibitors (ACEi); angiotensin II receptor blockers (ARB); calcium channel blockers (CCB); and diuretics. Differences in outcomes were assessed using Cox proportional hazard models with competing risks. Results: A total of 44,404 patients were prescribed beta-blockers (75% atenolol), 132,545 ACEi, 12,018 ARB, 91,731 CCB, and 106,547 diuretics. At baseline, patients in the beta-blocker cohort presented more frequently with angina, arrhythmia, and atrial fibrillation. The risk of all-cause mortality was lower for those treated with ACEi, ARB, and CCB, and no difference was observed compared with diuretics (adjusted hazard ratio versus beta-blockers (98.75% CI), for ACEi 0.71 (0.61, 0.83), ARB 0.67 (0.51, 0.88), CCB 0.76 (0.66, 0.88), diuretics 1.06 (0.93, 1.22)). No differences were seen in the risk of cardiovascular mortality for patients treated with beta-blockers, ARB, CCB, and diuretics, while a lower risk in patients treated with ACEi was observed (ACEi 0.63 (0.43, 0.91), ARB 0.64 (0.32, 1.28), CCB 0.71 (0.49, 1.03), diuretics 0.97 (0.69, 1.37)). Conclusions: These data add to the limited pool of evidence from real-world studies exploring the effectiveness of beta-blockers versus other antihypertensive classes. Discrepancies to previously published studies might be partly explained by differences in the selected populations and in the follow-up time.

A novel point-of-care device accurately measures thyrotropin in whole blood, capillary blood and serum.

OBJECTIVES: Point-of-care (POC) measurement of thyrotropin (TSH) may facilitate prompt diagnosis of thyroid dysfunction. We evaluated the analytical performance of a new POC TSH assay (Wondfo). METHODS: TSH measurements were made from 730 consecutive, unselected subjects in an outpatient setting, using Wondfo in whole blood, capillary blood and serum or automated reference equipment (serum only). RESULTS: TSH measurements were user-independent. Total intra-and inter-assay variation (CV%) was 12.1 and 16.2%, respectively. Total CV% was 10.6-22.6% and 14.5-21.6% in serum and whole blood, respectively. Linearity was very good. Recovery rate was 97-127%. Prolongation of incubation time increased TSH results of 12% (13%) and 33% (35%) after 2 and 5 additional minutes in serum (blood), respectively. When measured simultaneously in two Wondfo devices, the slope of the regression line was 1.03 (serum) and 1.02 (blood), with Spearman's correlation of 0.99 for both. TSH measurements between Wondfo and reference correlated strongly (r=0.93-0.96), though TSH measurements were lower with Wondfo (slopes of plots of measurements made using the two devices were 0.94 [serum vs. serum]; 0.83 [whole blood vs. serum] and 0.64 [capillary blood vs. serum]). Depending on sample material, TSH in capillary blood was lower vs. whole blood (slope: 0.82) and for whole blood vs. serum (Wondfo and reference method; slope: 0.69 and 0.83). Total haemolysis, but not elevated bilirubin or lipemia, disrupted TSH measurement. CONCLUSIONS: The Wondfo system was straightforward to use without need for specialist technicians and demonstrated analytic performance suitable for clinical use for the diagnosis of thyroid dysfunction.

Vascular complications in prediabetes and type 2 diabetes: a continuous process arising from a common pathology.

The term, "prediabetes", describes a state of hyperglycaemia that is intermediate between true normoglycaemia and the diagnostic cut-offs for indices of glycaemia that are used to diagnose type 2 diabetes. The presence of prediabetes markedly increases the risk of developing type 2 diabetes. Numerous randomized, controlled evaluations of various agents have demonstrated significant prevention or delay of the onset of type 2 diabetes in subjects with prediabetes. Intensive lifestyle interventions and metformin have been studied most widely, with the lifestyle intervention being more effective in the majority of subjects. The application of therapeutic interventions at the time of prediabetes to preserve long-term outcomes has been controversial, however, due to a lack of evidence relating to the pathogenic effects of prediabetes and the effectiveness of interventions to produce a long-term clinical benefit. Recent studies have confirmed that prediabetes, however defined, is associated with a significantly increased risk of macrovascular and microvascular complications essentially identical to those of diabetes, and also with subclinical derangements of the function of microvasculature and neurons that likely signify increased risk of compilations in future. Normoglycaemia, prediabetes and type 2 diabetes appear to be part of a continuum of increased risk of adverse outcomes. Long-term (25-30 years) post-trial follow up of two major diabetes prevention trials have shown that short-term interventions to prevent diabetes lead to long-term reductions in the risk of complications. These findings support the concept of therapeutic intervention to preserve long-term health in people with prediabetes before type 2 diabetes becomes established.

Bioequivalence Studies of New Generic Formulations of Vildagliptin and Fixed-Drug Combination of Vildagliptin and Metformin Versus Respective Originator Products in Healthy Volunteers.

INTRODUCTION: Vildagliptin and metformin are two well-established oral antidiabetics with a complementary mechanism of action. Two new generic products, vildagliptin and its fixed-drug combination (FDC) with metformin, were tested for bioequivalence versus the approved originator reference products (Galvus® and Eucreas®). METHODS: Three randomized studies with two-treatment, two-period, two-sequence crossover design were conducted in healthy adults. One study evaluated vildagliptin 50 mg tablets as single dose under fasting conditions. Vildagliptin-metformin FDC tablet strengths of 50/850 mg and 50/1000 mg were evaluated in separate studies as single dose under fed conditions, given 30 min after a standardized high-fat, high-calorie breakfast following 10 h overnight fasting. Blood samples for analysis were collected until 24 h after dosing in each study period. Bioequivalence between test (T) and reference (R) products required 90% confidence interval (CIs) for the geometric least square (LS) mean T/R ratio to be within 80-125% for the pharmacokinetic parameters, maximum plasma concentration (Cmax), and area under the curve (AUC0-t). RESULTS: The 90% CIs of geometric LS means of T/R ratio for Cmax and AUC0-t with vildagliptin tablets of 50 mg were 92.22-103.94% and 99.00-102.66%, respectively; corresponding results with FDC tablets for 50/850 mg tablets were 94.81-115.41% and 95.28-106.00% for vildagliptin and 90.87-101.18% and 90.56-100.09% for metformin; for 50/1000 mg tablets Cmax and AUC0-t were 105.56-122.30% and 98.30-107.55%, respectively, for vildagliptin and 92.14-103.73% and 94.60-101.81%, respectively, for metformin. Other parameters such as AUC0-∞, time to maximum concentration (Tmax), and terminal half-life (t1/2) were comparable between test and reference products. Adverse events (AEs), mainly vomiting, were reported without relevant difference between test and reference products in each study. AEs were generally mild and transient. No severe or serious AEs occurred. CONCLUSIONS: The new generic drug products of vildagliptin and the FDCs of vildagliptin and metformin demonstrated bioequivalence to the approved originator products and are therefore expected to provide similar therapeutic effects.

Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations.

Lifelong treatment with levothyroxine (LT4) is the mainstay of management for individuals with hypothyroidism. Many hypothyroid patients start LT4 treatment at a low dose (e.g. 25-50 µg), especially the elderly, those with residual thyroid function, those with low body weight, and those with significant (especially cardiac) comorbidities. Almost half of patients on LT4 replacement therapy demonstrate either under- or over-treatment. Many LT4 preparations have relatively large intervals between tablet strengths at the lower end of their dose ranges (providing 25 µg, 50 µg, and 75 µg tablets), which may represent a barrier to achieving the optimum maintenance treatment for some patients. The availability of intermediate tablet strengths of LT4 in the 25-75 µg range may facilitate precise and effective dose titration of LT4 and may also enable convenient maintenance regimens based on a single LT4 tablet daily, to support adherence to therapy.

Effectiveness of bisoprolol versus other ß-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink.

Aim: To compare blood pressure (BP) and safety outcomes in patients with hypertension initiating bisoprolol, versus other ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, calcium channel blockers or diuretics. Materials & methods: New user cohort study. Patients initiating bisoprolol were matched with up to four patients, in each comparator cohort using propensity score. BP outcomes were compared using linear mixed models and safety outcomes using Cox proportional hazards. Results: Differences in average systolic and diastolic BP variation were ≤3 mmHg between bisoprolol versus the compared classes. No difference was observed in risk of diabetes, obesity or erectile dysfunction. An increased dyslipidemia risk was only observed versus diuretics (hazard ratio: 0.76; 98.75% CI: 0.58, 0.99). Conclusion: No differences in BP variation and safety outcomes.

An anchored simulated treatment comparison of uptitration of amlodipine compared with a low-dose combination treatment with amlodipine 5 mg/bisoprolol 5 mg for patients with hypertension suboptimally controlled by amlodipine 5 mg monotherapy.

OBJECTIVE: To compare changes in systolic and diastolic blood pressures (SBP, DBP) from baseline to following 8 weeks of treatment with a low dose combination of amlodipine 5 mg plus bisoprolol 5 mg versus up titration to the maximum daily dose of amlodipine 10 mg, in hypertensive patients uncontrolled by amlodipine 5 mg. METHODS: Individual patient data (IPD) from a randomized clinical trial (RCT) comparing the combination versus amlodipine 5 mg (EudraCT Number: 2019-000751-13) and aggregated data (AgD) from a published RCT comparing amlodipine 10 mg versus amlodipine 5 mg were utilized in an anchored simulated treatment comparison (STC). The RCT with IPD was used to create models assessing how patients might respond to the combination if they were more comparable to those patients in the RCT with AgD. A population-adjusted indirect comparison of the treatment strategies was then conducted, using amlodipine 5 mg as an anchor. RESULTS: In the efficacy analyses, a total of 261 patients were included in the amlodipine 10 mg arm of the RCT with AgD; and a total of 178 patients in the low-dose combination arm of the RCT with IPD. Respectively, in the Amlodipine 10 mg arm and in the low-dose combination arm, the mean age was 54.3 years-old (Standard deviation [SD] 10.6), and 57.1 years-old (13.7); 8.7% and 18.8% of patients were diabetics; and the mean baseline SBP/DBP was 149.3 (12.0)/96.5 (4.7) mmHg, and 148.8 (8.2)/90.2 (7.6) mmHg. The final model for SBP and DBP included the following variables: baseline SBP, baseline DBP, duration of hypertension, age, concomitant diabetes, sex, smoking history (final model for SBP only), and body mass index (final model for DBP only). Mean treatment differences (standard error [SE]) at 8 weeks between the combination and uptitration were -1.6 mmHg (1.9) for SBP; and -3.3 mmHg (1.3) for DBP. CONCLUSION: In this indirect comparison, a more important decrease was observed in DBP with the low-dose combination as compared to the alternative therapeutic approach of up-titration from amlodipine 5 mg to amlodipine 10 mg. No meaningful difference was seen for SBP.

Low awareness and under-diagnosis of hypothyroidism.

Hypothyroidism is a common condition with a prevalence that varies according to local dietary iodine availability, gender and age. The symptoms of hypothyroidism are generally nonspecific, with considerable overlap with other conditions and with the consequences for the health of advancing age. These symptoms are not useful for diagnosing hypothyroidism and a thyroid function test is required for a firm clinical diagnosis. Lack of knowledge and understanding of hypothyroidism, and a tendency for many people to attribute the symptoms of hypothyroidism to other causes have led to substantial unawareness and often late diagnosis of hypothyroidism. Large observational studies and meta-analyses have shown that about 4-7% of community-derived populations in the USA and Europe have undiagnosed hypothyroidism. About four cases in five of these are subclinical hypothyroidism, with the remainder being overt hypothyroidism. The prevalence of undiagnosed hypothyroidism is higher in older subjects, in women, and some ethnic groups, consistent with diagnosed disease. More research is needed to quantify the clinical burden of undiagnosed hypothyroidism around the world, with educational efforts aimed at the public and healthcare professionals aimed at identifying and managing these individuals.

Triiodothyronine alongside levothyroxine in the management of hypothyroidism?

The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of combinations of LT4 and T3 to provide a superior outcome to LT4 monotherapy for people with hypothyroidism, especially those with residual symptoms despite thyrotropin-optimized LT4. This review seeks to provide an overview of currently available evidence on combination (LT4 + T3) therapy to be used for personalized medicine in patients with hypothyroidism. A number of randomized, controlled trials (RCTs) have failed to demonstrate superiority for the combination therapy approach, largely due to non-physiological T3 doses. However, patients with hypothyroidism are highly heterogeneous in terms of their residual thyroid function, individual set points for optimal thyroid homeostasis and for the presence or absence of polymorphisms in deiodinase enzymes in tissues that activate and deactivate circulating thyroid hormones. Accordingly, these RCTs may have failed to demonstrate benefits of combination therapy in individual hypothyroid phenotypes. The pharmacokinetics of LT4 and T3 also differ, which is a barrier to their co-administration. Future clinical trials using LT4 + T3 tablets better suited for combination therapy will resolve the outstanding research questions relating to the place of LT4 + T3 combination therapy in the management of hypothyroidism.

Real world clinical experience with a new formulation of levothyroxine engineered to meet new and stricter regulatory requirements.

OBJECTIVES: A new LT4 formulation (Euthyrox [LT4 NF]) was developed to meet new regulatory standards, and has replaced the older formulation (LT4 OF) in a number of countries. We evaluated the possibility of tolerability/safety concerns associated with the switch by analysing spontaneous adverse event (AE) reports before and after switching. METHODS: We examined spontaneous reports of adverse events (AE) from 18 countries generated from individual case safety reports (ICSRs) submitted to the pharmaceutical sponsor's global safety database, over one year before/one year after the switch. RESULTS: There was no clear pattern relating to the numbers of ICSRs received before and after the switch across the countries. ICSRs contained a total of 634 AE relating to thyroid imbalance (82 serious) with LT4 OF over the period of one year; 343 such AE (60 serious) were reported for LT4 NF. The most common thyroid imbalance AE for LT4 OF concerned hypothyroidism or hyperthyroidism, unspecified thyroid function test abnormalities, and dosing issues. More AE of any aetiology were reported for LT4 NF (5098) vs. LT4 OF (4439), although the number of serious AE was lower for LT4 NF vs. LT4 OF (457 and 580, respectively). Fatigue, dizziness, headache, palpitations, and nausea were among the most common AE reported for each formulation. The nature of AE was comparable between formulations. CONCLUSIONS: No new safety concerns arose concerning the updated LT4 formulation in the 18 countries. Careful counselling of patients and adherence to routine thyroid care is important.

Metformin for diabetes prevention: update of the evidence base.

We have conducted a narrative review based on a structured search strategy, focusing on the effects of metformin on the progression of non-diabetic hyperglycemia to clinical type 2 diabetes mellitus. The principal trials that demonstrated a significantly lower incidence of diabetes in at-risk populations randomized to metformin (mostly with impaired glucose tolerance [IGT]) were published mainly from 1999 to 2012. Metformin reduced the 3-year risk of diabetes by -31% in the randomized phase of the Diabetes Prevention Program (DPP), vs. -58% for intensive lifestyle intervention (ILI). Metformin was most effective in younger, heavier subjects. Diminishing but still significant reductions in diabetes risk for subjects originally randomized to these groups were present in the trial's epidemiological follow-up, the DPP Outcomes Study (DPPOS) at 10 years (-18 and -34%, respectively), 15 years (-18 and -27%), and 22 years (-18 and -25%). Long-term weight loss was also seen in both groups, with better maintenance under metformin. Subgroup analyses from the DPP/DPPOS have shed important light on the actions of metformin, including a greater effect in women with prior gestational diabetes, and a reduction in coronary artery calcium in men that might suggest a cardioprotective effect. Improvements in long-term clinical outcomes with metformin in people with non-diabetic hyperglycemia ("prediabetes") have yet to be demonstrated, but cardiovascular and microvascular benefits were seen for those in the DPPOS who did not vs. did develop diabetes. Multiple health economic analyses suggest that either metformin or ILI is cost-effective in a community setting. Long-term diabetes prevention with metformin is feasible and is supported in influential guidelines for selected groups of subjects. Future research will demonstrate whether intervention with metformin in people with non-diabetic hyperglycemia will improve long-term clinical outcomes.

The cost-effectiveness of metformin in pre-diabetics: a systematic literature review of health economic evaluations.

Objectives: Our aim was to systematically identify and appraise cost-effectiveness studies of metformin in prediabetic subjects.Methods: A systematic literature review was conducted and reported according to standard guidlines. The search was conducted in PubMed, Embase, International Society for Pharmacoeconomics and Outcomes Research (ISPOR) presentation database and the Cost-Effectiveness Analysis (CEA) and Center for Reviews and Dissemination (CRD) registries. All cost-effectiveness studies assessing metformin in prediabetic patients were included.Results: Twenty-three reports were included. Metformin and intensive lifestyle changes (ILC) interventions were always cost-effective compared to placebo. ILC was cost-effective and sometimes dominant compared to metformin. Metformin was cost-saving compared to ILC in the short and medium-term. Although, in the long term, metformin was more expensive than ILC in terms of direct medical costs, when indirect non-medical costs are included, metformin less expensive than ILC. One study reported that for patients with Body Mass Index (BMI) higher than 30 kg/m2, metformin is a cost-effective strategy compared to placebo and ILC. However, this finding was not confirmed by other retrieved studies.Conclusion: ILC is cost-effective compared to metformin and, both of them are cost-effective compared to placebo. Metformin may be cost-saving in the short- to medium-term and possibly in the long-term.

Observational study of the efficacy of prolonged-release metformin in people with prediabetes.

Objectives: Prediabetes is characterized by elevation of indices of blood glucose that is insufficient to provoke a diagnosis of type 2 diabetes, but markedly increases the risk of developing type 2 diabetes in the future. Lifestyle interventions are the main therapeutic intervention for the management of prediabetes. Current guidelines also support treatment of prediabetes with metformin for selected subgroups of patients, and metformin has a therapeutic indication for this use in a number of countries.Methods: We performed an observational, non-interventional study of the effects on glycaemia of prolonged-release metformin (Glucophage XR, referred to henceforth as metformin XR) in 686 subjects with prediabetes. Metformin was prescribed according to physicians' usual care practices, and the study duration was 12 weeks.Results: Mean (SD) fasting plasma glucose (FPG) at baseline was 6.2 (0.4) mmol/L [111 (8) mg/dL) and was reduced by -0.55 (0.7) mmol/L [-10 (13) mg/dL] after 12 weeks of metformin XR. FPG was normalized to below the American Diabetes Association cut-off for the diagnosis of prediabetes (<5.7 mmol/L [100 mg/dL]) in 43% of subjects. Increasing age, increasing body mass index, not following a weight-loss diet and alcohol use predicted a lower probability of normalized FPG. Metformin was well tolerated, with most side effects occurring in the gastrointestinal system, as expected.Conclusions: Metformin XR normalized FPG in about two-fifths of subjects with prediabetes. These real-world data add further support a role for metformin in the management of prediabetes, in line with current guidelines in this area.

Global epidemiology of prediabetes - present and future perspectives.

Prediabetes is defined as an intermediate state of hyperglycaemia with glucose levels above the normal state but below the diagnostic levels of diabetes. It is increasingly recognised as an important metabolic state, as individuals with prediabetes are at high risk of developing overt diabetes and its associated complications. A better understanding of prediabetes could help with earlier identification, thereby allowing earlier intervention, potentially lowering the number of individuals who go on to develop diabetes. The definitions and screening criteria for prediabetes differ between guidelines published by different organisations, resulting in estimations of prevalence that can vary widely from one another. Despite these differences, these estimates suggest that the number of individuals affected by prediabetes is increasing rapidly in all areas of the world. This short review compares and contrasts the diagnostic criteria for screening of prediabetes, the impact of various glycaemic measures on prevalence estimates, and discusses current and future trends in the global prevalence estimates of prediabetes.