Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus M. A. Bethel1,2,∗ , W. Xu3,∗ & M. J. Theodorakis1 1 Diabetes Trials Unit, University of Oxford, Churchill Hospital, Oxford, UK 2 Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA 3 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long-term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk. Keywords: antidiabetic drug, clinical trial, type 2 diabetes Date submitted 4 October 2013; date of first decision 9 October 2014; date of final acceptance 9 October 2014
Introduction The increasing prevalence of type 2 diabetes mellitus constitutes a leading global public health concern. Persons with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) characterized by postprandial and mild fasting hyperglycaemia, respectively, are at increased risk for the development of diabetes and are an ideal population to target for interventions which prevent or delay the onset of type 2 diabetes. Lifestyle interventions are proven strategies for reducing diabetes incidence [1–6] and have few adverse effects, but long-term adherence is difficult to maintain, limiting their effectiveness. Pharmacologic agents have also shown benefit with respect to diabetes prevention, often over several years, but some have additional off-target effects that may be beneficial or have known or unknown potential for harm. In this review, we seek to elucidate the totality of the risk/benefit profile for each drug tested for diabetes prevention according to the available evidence base. Because potential mid- and long-term adherence to injectable therapies is particularly hard to achieve, especially for such a mostly healthy population, we have primarily focused on orally administered compounds, but also included injectable therapeutic modalities with emerging clinical trial data which show promise.
Methods Source articles were identified in PubMed Central (including MEDLINE); EMBASE; Cochrane Central Register of Correspondence to: Michael J. Theodorakis, FRCP, Diabetes Trials Unit, University of Oxford, Churchill Hospital, Old Road, Headington OX3 7LJ, UK. E-mail: [email protected] ∗ These
authors have contributed equally to this article.
Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL), up to 1 March 2013. We searched the English language literature using the keywords ‘randomized clinical trial’, ‘IGT’, ‘IFG’ or ‘type 2 diabetes incidence’. Out of 168 articles which were identified in total, we opted to primarily focus on those pertinent to large scale outcomes trials, which are generally considered the best to guide evidence-based decisions; in addition, we placed specific emphasis on having a follow-up time period of at least 2 years, allowing assessment of the durability of any treatment effect and more complete safety evaluation. There were only four randomized controlled clinical trials (RCTs) of pharmacologic agents, which have enrolled >1000 patients, provided a minimum of 2 years follow-up and used progression to diabetes as a part of the primary outcome: the Diabetes Prevention Program (DPP), comparing lifestyle modification to metformin; the Study to Prevent Non-insulin-dependent Diabetes Mellitus (STOP-NIDDM) using acarbose; the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial (NAVIGATOR); the Diabetes REduction Assessment with Ramipril and Rosiglitazone Medication (DREAM). We have also included the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, which enrolled both people with and a smaller group of people without diabetes (n = 1456, 12% of patients in ORIGIN) who had IFG or IGT at baseline, to assess the impact of either omega-3 fatty acids or insulin glargine in reducing a composite endpoint of myocardial infarction (MI), stroke or cardiovascular death, albeit this was not a trial designed with an intention to treat IFG/IGT patients. Therefore, we have included a total of five large scale RCTs in our analysis. Using these fundamental RCTs as a solid basis for identifying key pharmacologic agents
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review article of interest to diabetes mellitus prevention, we then searched the same literature databases for prospective clinical trials or meta-analyses describing off-target effects by using the terms ‘adverse event’, ‘cancer’, ‘fracture’, ‘pancreatitis’, ‘weight’, ‘hypoglycaemia’ and ‘cardiovascular disease’, in combination with each medication identified in the initial search. Although this review has primarily focused on published evidence from the large-scale RCTs, we have also reviewed data from smaller scale, well powered prospective clinical trials, whose relevant outcomes could contribute to our analysis and broaden clinical perception of current trends in potential therapeutic intervention before diabetes becomes clinically manifest.
Results Key characteristics of the five major diabetes prevention trials are summarized in Table 1. The evidence for diabetes prevention and for proven or suspected off-target effects is described below for each pharmacologic agent, along with a concise description of the pharmacology and clinical safety of each medicine. Pertinent published data from smaller scale trials are also presented in each drug class.
Glucose-lowering Pharmacological Agents Biguanides (Metformin). Action and current clinical use. Metformin is first line recommended therapy for type 2 diabetes according to the International Diabetes Federation Global Guideline for type 2 Diabetes [7], in agreement with similar guidelines from the American Diabetes Association (ADA), as well as the European Association for the Study of Diabetes (EASD) [8]. Metformin does not modulate insulin secretion, but improves glycaemic control by inhibiting hepatic glucose production and gluconeogenesis, as well as by improving peripheral (muscle) tissue insulin sensitivity. There has been very active debate as to the rationale and benefit for using metformin as a pharmacological agent to delay or prevent diabetes progression. Well designed, RCTs such as the Glucose Lowering in Non-diabetic Hyperglycaemia Trial (GLINT) [8] are aiming at providing definitive answers in the future. On the basis of recent published evidence [9], in the United States alone, 1 in 12 adults have a combination of glucose dysmetabolism and risk factors that may justify consideration of metformin treatment for diabetes prevention. A plethora of trials are registered in clinicaltrials.gov as exploring the possible impact of metformin in individuals at varying glucose tolerant states. Findings from RCTs – benefit. From 1996, the DPP Research Group conducted a large RCT, enrolling participants at high risk for the development of type 2 diabetes from 27 US centres [2]. Eligible participants had a fasting plasma glucose between 95 and 125 mg/dl (5.3 and 6.9 mmol/l; ≤125 mg/dl–6.9 mmol/l — in the American Indian clinics) and 2 h glucose values after a standard 75 g oral glucose tolerance test (OGTT) between 140 and 199 mg/dl (7.8–11.05 mmol/l). In 3234 participants randomly assigned to intensive lifestyle intervention, metformin
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or placebo, the trial showed a 31% reduction in the primary outcome of development of diabetes with metformin treatment over a mean 2.8 year follow-up, similar in men and women and in all racial and ethnic groups. Long-term follow-up of the participants in the Diabetes Prevention Program Outcomes Study (DPPOS) showed a similar diabetes incidence rate in all groups (5.9 per 100 person-years for lifestyle, 4.9 for metformin and 5.6 for placebo), indicating that metformin therapy delayed diagnosis of diabetes, but did not reverse the underlying disease progression [10]. Similarly, metformin has conclusively been shown not to prevent the gradual decline in 𝛽-cell function, a hallmark of type 2 diabetes progression [11,12]. Findings from RCTs – risk. Metformin therapy is generally well tolerated and its well known gastrointestinal side effects are not typically treatment limiting. In DPP, metformin was associated with increased gastrointestinal symptoms (77.8 compared with 30.7 events/100 person-years on placebo), including diarrhea, flatulence, nausea and vomiting [2], but adherence to treatment was only slightly lower in the active therapy group. Lactic acidosis, the most severe side effect of biguanides, is rare with metformin. A Cochrane review of 347 comparative trials showed no fatal or non-fatal cases of lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patient-years in the non-metformin group [13]. Nonetheless, clinical caution is used for patients with severely limited renal function or severe heart failure. Findings from RCTs – off-target benefits. Two major off-target benefits have been postulated for metformin: reduced incidence of cardiovascular disease (CVD) and cancer prevention. Metformin has been shown to have favorable effects on a number of cardiovascular risk factors, including lipids, body weight, blood pressure and platelet function [14–17], and was shown in overweight participants in the United Kingdom Prospective Diabetes Study (UKPDS) to be associated with a decreased risk of myocardial infarction compared to other intensive therapy arms without metformin [18] [hazard ratio (HR) 0.61, 95%-confidence interval (CI) 0.41–0.89; p = 0.01]. The risk reduction for myocardial infarction persisted in the metformin group during 10 years of post-trial observational follow-up (HR 0.67, 95%-CI 0.51–0.89; p = 0.005), despite an early loss of glycated haemoglobin (HbA1c) differences between treatment groups, suggesting a legacy effect of early intensive glucose-lowering therapy with metformin for obese patients [19]. However, a cardioprotective effect of metformin in excess of that conferred by its glucose-lowering ability has not been confirmed, based on meta-analyses from large and small scale trials [20–22]. To date, no such prospective cardiovascular outcome trial with metformin has been performed. Metformin’s association with improved cancer incidence also has biologic plausibility. Preclinical studies have shown that metformin can inhibit the growth of cancer cells in vitro and in vivo and provide evidence for a direct, insulin-independent antitumour effect [23–25]. Epidemiologic evidence from large cohort metformin studies suggests benefit for several types of cancers [26,27]. A meta-analysis of 11 observational studies
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2.8
31%
Risk reduction of diabetes progression (%)
2 h ≥200 mg/dl (11.1 mmol/l)‡
FPG ≥126 mg/dl (7.0 mmol/l) or 2 hr ≥200 mg/dl (11.1 mmol/l)
Definition of diabetes
Median follow-up for incident diabetes (years)
Incident diabetes diagnosed on an annual OGTT
Incident diabetes diagnosed with annual OGTT or semiannual fasting plasma glucose test
Primary outcome
54
25%
3.3
31
51
IGT (2-h plasma glucose concentration between 140 and 200 mg/dl (7.8-11.1 mmol/l) after a 75 g glucose load and a fasting plasma glucose concentration between 101 and 140 mg/dl; 5.65–7.8 mmol/l)
34
IGT (a plasma glucose concentration of 95–125 mg/dl (5.3–6.9 mmol/l) in the fasting state and 140–200 mg/dl (7.8–11.1 mmol/l) 2 h after a 75-g oral glucose load)†
Eligible participants
Acarbose
STOP-NIDDM (n = 1429) [41]
BMI (kg/m2 )
Metformin*
intervention(s)
Mean age (years)
DPP (n = 3234)[2]
Pharmacologic
Table 1. Pharmacologic interventions for the prevention of diabetes.
NAVIGATOR (n = 9306) [71]
Nateglinide: no effect Valsartan: 14%
Rosiglitazone: 62%
5.0
FPG ≥126 mg/dl (7.0 mmol/l) or 2 h ≥200 mg/dl (11.1 mmol/l), confirmed by a second test
30%
6.2
Either 1. Two consecutive FPG levels within a 4-month period >126 mg/dl (7.0 mmol/l); OR 2. a diagnosis of diabetes made by a physician (a), plus use of a pharmacologic antidiabetic agent (b), plus evidence of a FPG of ≥126 mg/dl (7.0 mmol/l), or any blood glucose ≥200 mg/dl (11.1 mmol/l) OR 3. evidence (a) of at least one capillary glucose ≥200 mg/dl (11.1 mmol/l) confirmed by FPG ≥7126 mg/dl (7.0 mmol/l) or (b) of a random glucose ≥200 mg/dl (11.1 mmol/l) FPG ≥7126 mg/dl (7.0 mmol/l) OR 2 h plasma glucose >200 mg/dl; 11.1 mmol/l) during either the first or second OGTT after the end of usual follow-up visit
CV end-points
Placebo: 29.9
Valsartan: 30 Incident diabetes (FPG semi-annually for 3 year, then annually; annual OGTTs), extended and core cardiovascular outcomes§
Insulin glargine: 29.8
63.5
Subjects with a prior CV event; angina + documented ischaemia; albuminuria; left ventricular hypertrophy; angiographic evidence of >50% stenosis of a coronary, carotid or lower extremity artery; or an ankle/brachial index 50 years old with IFG, IGT or early type 2 diabetes in addition to other cardiovascular risk factors, to receive insulin glargine (with a target fasting blood glucose level of ≤5.3 mmol/l or standard care and to receive n-3 fatty acids or placebo with the use of a 2 × 2 factorial design) [81]. Median follow-up was 6.2 years. Rates of incident cardiovascular outcomes were similar in both groups. In the subset of participants with IFG or IGT at baseline, incident diabetes was diagnosed approximately 3 months after therapy was stopped among 30 vs. 35% of 1456 participants without baseline diabetes [odds ratio (OR) 0.80; 95% confidence interval (CI), 0.64–1.00; p = 0.05]. The development of new diabetes within the trial in people without diabetes at baseline was reduced by 28%. Findings from RCTs – risk. Rates of severe hypoglycaemia were 1.00 vs. 0.31 per 100 person-years between the insulin glargine and standard-care groups, respectively. Median weight increased by 1.6 kg in the insulin group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (HR 1.00; 95%-CI, 0.88–1.13; p = 0.97). These data imply that, apart from the trial showing no impact of (either omega-3 fatty acids or) insulin glargine in reducing a composite CV end-point of acute myocardial infraction, stroke or CV death, 15 IGT patients have to be systematically treated with basal insulin for 6 years to prevent just one from progressing to diabetes. The role of insulin glargine as a risk factor for cancer is controversial in human studies and current results from epidemiological analysis are weak. The theoretical basis for such a biological link stems from possible aberrant stimulation of insulin and insulin-like growth factor (IGF) receptors by insulin analogues compared with endogenous insulin. The ubiquitous insulin and IGF receptors belong to the receptor tyrosine kinase superfamily and upon ligand activation trigger trans-phosphorylation of the kinase domains, thus initiating intracellular signaling pathways for metabolic as well as
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review article mitogenic processes, involving cell proliferation and differentiation. In a recent comprehensive meta-analysis including data from available observational studies and RCTs evaluating the relationship of insulin glargine and cancer risk, 448,928 study participants and 19,128 cancer patients were identified [82]. Insulin glargine use was associated with a lower odds of cancer compared with non-glargine insulin use (OR 0.81, 95%-CI 0.68–0.98, p = 0.03) and did not increase the odds of breast cancer (OR 0.99, 95%-CI 0.68–1.46, p = 0.96). Compared with non-glargine insulin, no significant association was found between insulin glargine and prostate cancer, pancreatic cancer and respiratory tract cancer. ORIGIN also did not support a direct link between insulin glargine therapy and cancer risk. Therefore prospective clinical studies are needed to evaluate the possible tumour growth-promoting effects of glargine and other insulin analogs. Other insulins. Early insulinization to prevent diabetes progression had also been studied in a large, multicenter, controlled trial which randomized 382 newly diagnosed individuals with type 2 diabetes in China [83], having a fasting plasma glucose between 7.0 and 16.7 mmol/l. The patients were randomly assigned to either insulin treatment with multiple daily injections (MDI) or insulin pump-subcutaneous infusion (SCI) or to treatment with oral antidiabetic agents (OAD) for 2–5 weeks. Glycaemic control was achieved faster and in a higher percentage of the patients in the insulin-treated arms compared with the OAD arm, while a year later, the target glycaemic control in the insulin-treated groups was maintained in a significantly higher percentage of patients (51.1, 44.9 and 26.7% in the SCI, MDI and OAD groups, respectively; p = 0.0012), despite having discontinued drug therapy. However, the study has come under intense criticism, because of major limitations, including its questionable generalizability to non-Asian populations and because of the use of drug classes such as sulfonylureas in the control group, which greatly impacted on the ability to definitively discern any protective effects of insulin therapy. Incretin-based Therapies. Action and current clinical use. Insulinotropic gut-derived incretin peptides glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted in response to nutrient ingestion and account for almost 70% of postprandial insulin excursions. By potentiating insulin-dependent insulin secretion and having multiple trophic actions on islets and other target tissues, they affect complex pathophysiologic processes of type 2 diabetes in a harmonized fashion [84,85]. They promote efficient glucose disposal in peripheral tissues such as muscle, directly reduce hepatic glucose production by decreasing glucagon, increase insulin secretion, directly inhibit gastric emptying, and centrally modulate appetite and energy homeostasis [86]. Incretin-based therapies address some of the challenges associated with traditionally available OADs. In addition to improving 𝛽-cell function, stimulating insulin secretion and inhibiting glucagon secretion, incretin mimetic agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. For both sub-classes of these drugs, intensive mid-to-large scale trials
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review article are currently in progress, to assess their potential effect on IFG/IGT populations. Incretin enhancers (DPP-IV inhibitors: sitagliptin, vildagliptin). Drugs of this sub-class augment availability of endogenously secreted active incretin peptides, by inhibiting the enzyme responsible for their rapid degradation in vivo. In this manner, they enhance biologically active peptides’ duration of action, allowing them to exert their effects longer within the physiological concentration range, as opposed to the supra-physiological levels achieved by injecting GLP-1 receptor agonists. They generally lower HbA1c by an average of 0.6–0.7% and they are weight neutral. Findings from RCTs – benefit and risk. Data from small scale studies show that both sitagliptin and vildagliptin improve 𝛽-cell function in patients with abnormal glucose metabolism [87,88], but neither has been studied for diabetes prevention. The ongoing DPP-4 Inhibition and TZD for DM Prevention (DInT–DM) trial is a double blind, placebo-controlled trial of 45 participants randomized to sitagliptin 100 mg daily, either as monotherapy or in combination with pioglitazone 15 mg/day compared to placebo for 9 months. Incretin Mimetics (GLP-1 Receptor Agonists: Exenatide, Liraglutide) Findings from RCTs – benefit and risk. As opposed to orally acting DPP-IV inhibitors, the GLP-1 receptor agonists mimic the effects of the native GLP-1 and are administered parenterally, thus achieving true pharmacological concentrations targeting islet and peripheral receptors. Although no large scale clinical trials for diabetes have been completed, exenatide has been tested in smaller studies in IFG/IGT participants. In 152 obese participants with NGT, IFG or IGT (the latter two categories comprised 25% of the patient population), exenatide normalize glucose tolerance in 77%, compared to 56% of those receiving placebo [89]. The majority of adverse events were mild or moderate in severity: nausea and diarrhea were experienced by 25 and 14% of those given exenatide, compared to just 4 and 3% of those that received placebo. In an open-label, clinical trial [90] in 50 individuals without diabetes, with abdominal obesity and IFG or IGT, 3 months of exenatide therapy was associated with reduced triglycerides compared to metformin (Δ-exenatide: −25.5 ± 45.7 mg/dl vs. Δ-metformin: −2.9 ± 22.8 mg/dl, p = 0.032), but no changes in microvascular endothelial function indices, C-reactive protein, circulating oxidized LDL or vascular cell adhesion molecule-1. A large international study currently in progress, the Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) trial, will evaluate the potential of liraglutide to induce and maintain weight loss over 56 weeks in obese or overweight participants with co-morbidities [91]. Furthermore, the aim is to investigate the long-term potential of liraglutide to delay the onset of type 2 diabetes in participants diagnosed with IGT at baseline. Primary outcome measures include: change from baseline in body weight; proportion of participants losing at least 5% of baseline body weight; and proportion of participants with onset of type 2 diabetes. On the basis of BMI and IGT status, 3600 participants will be randomized to either 68 weeks (56 weeks of randomized treatment followed by a 12 week re-randomized treatment
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period) or 160 weeks of treatment (160 week treatment will only be applicable to participants with IGT status at baseline). The trial is expected to be completed by 2015. Findings from RCTs – risks. Mild, transient gastrointestinal discomfort is commonly observed by any incretin-based therapy, but especially pronounced with GLP-1 receptor agonists [92]. Although mild hypoglycaemia can occur, this is usually in combination with other hypoglycaemic therapies [93]. The risk for acute pancreatitis and pancreatic cancer when using incretin-based therapies has received close attention, as introduction of such therapies in diabetes management is expanding [94–97]. Reports of aberrant microscopic morphology and pancreatic histopathology in cadaveric tissue specimens from individuals having received DPP-IV inhibitors (most of them) or injectable incretin mimetics, have attracted strong criticism for methodological inconsistencies. The possible causality of potentially increased propensity to pancreatic inflammation is complicated by the mere fact that diabetes and its pathophysiology are associated with higher proportion of individuals experiencing pancreatitis. Although signals for such side effects have emerged early after incretin-based therapies received market authorization, conclusive evidence in regards to pancreatitis and/or cancer risk potentially conferred by these therapies will only be available in the coming years, when completion of the large scale multi-national outcome trials with sitagliptin, exenatide and liraglutide is achieved. Notably, preclinical studies in many experimental animal models which were treated with 10 times or higher doses of those compounds have failed to provide a credible association with either chronic inflammation or cancer. A meta-analysis among 268,561 US patients with acute pancreatitis, showed that only 2.6% used exenatide. In unadjusted and adjusted analyses, patients who did not use exenatide were more likely to be hospitalized for acute pancreatitis but the difference was not statistically significant in either analysis [98]. Among 209,306 patients in the pancreatic cancer analysis, 0.070% were diagnosed with pancreatic cancer, and 0.88% had at least 1 year of continuous exenatide exposure prior to the diagnosis. Those with exenatide exposure had higher rates of pancreatic cancer compared with those without (0.081 vs. 0.070% in unadjusted analysis). In both unadjusted and adjusted analyses, the difference was not statistically significant. Further analysis was recently carried out in 25 studies where exenatide or liraglutide were used [99]. Neither exenatide nor liraglutide were associated with an increased risk of acute pancretitis, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 [95%-CI 0.29–2.60, I(2) = 0%] and for liraglutide was 1.35 [95%-CI 0.70–2.59, I(2) = 0%]. Liraglutide was not associated with an increased risk for thyroid cancer [OR 1.54, 95%-CI 0.40–6.02, I(2) = 0%]. For exenatide, no thyroid malignancies were reported. Therefore, current available published evidence is insufficient to confirm an increased risk of pancreatitis or cancer associated with GLP-1 receptor agonists [100]. Findings from RCTs – off-target benefits. GLP-1 receptor agonists uniquely result in long-term reduction in blood pressure of almost 2–7 mmHg, albeit at a cost of slight increase in heart
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rate, especially with long-acting, weekly administered preparations. Similarly, a more favorable lipid profile is achieved, especially in regards to LDL-cholesterol and triglyceride lowering.
Non-glucose-lowering Pharmacological Agents Antihypertensive Drugs. Findings from RCTs – benefit. While the cardiovascular benefits of renin–angiotensin system (RAS) inhibitors, including angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors has been well documented in patients with type 2 diabetes [101–104], they have also been postulated to have an effect on blood glucose. Subgroup analyses of several antihypertensive trials have shown that the risk for type 2 diabetes development in patients with hypertension is lower for those treated with RAS blockade than for those who received thiazide diuretics, 𝛽-blockers or the calcium channel blocker amlodipine [105,106]. Only ramipril and valsartan have been studied in appropriately designed and powered outcomes trials to examine their effect on diabetes incidence. In DREAM, ramipril did not significantly affect the primary composite of diabetes or death and had no effect on the incidence of diabetes alone, despite having an association with regression to normoglycaemia compared to placebo [107] (HR 1.16, 95%-CI, 1.07–1.27; p = 0.001). Similarly, ramipril did not improve the cardiovascular composite outcome measured in DREAM (HR 1.08, 95% CI 0.76–1.52, p = 0.68) [107]. In NAVIGATOR, valsartan did reduce diabetes incidence [108] (33.1 vs. 36.8% in the placebo group, p < 0.001), equivalent to a 14% risk reduction. There was no excess of renal dysfunction or hyperkalemia in the valsartan group, but hypotension-related adverse events were more common in the valsartan group than in the placebo group (42.4 vs. 35.9%; p < 0.001). It should be noted that, in a meta-analysis of ACE inhibitors for prevention of new onset type 2 diabetes [109], which included nine RCTs with 92,404 patients (72,128 people without diabetes at baseline), compared with control group, incidence of new-onset diabetes was significantly reduced in the ACE inhibitors group (OR 0.80, 95%-CI 0.71–0.91), irrespective of achieved blood pressure levels at the follow-up. In addition, a similar meta-analysis [110] investigated the effect of ARBs and included 11 RCTs with 79,773 patients (59,862 people without diabetes at baseline). Compared to control group, incidence of new-onset diabetes was significantly reduced in ARBs group (OR 0.79, 0.74–0.84) and various categories of ARBs subgroup. Compared to control group, incidence of new-onset diabetes was significantly reduced in ARBs group, irrespective of achieved blood pressure level. Findings from RCTs – off-target benefits. Both ramipril and valsartan have been examined within meta-analyses to evaluate their potential effect on cancer outcomes. The RAS is increasingly being recognized as a potential mediator of cancer biology [111]. Both type 1 and type 2 angiotensin receptors are important regulators of cellular proliferation, angiogenesis and inflammation [112]. In a meta-analysis of 14 trials primarily conducted for cardiovascular outcomes, ACE inhibitor therapy showed no increase in cancer incidence (RR 1.01, 95%-CI
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0.95–1.07, p = 0.78), cancer death (RR 1.00, 95% CI 0.88–1.13, p = 0.95) or gastrointestinal cancer (RR 1.09, 95%-CI 0.88–1.35, p = 0.43) [113]. Similarly, a meta-analysis of 15 ARB trials showed no excess of cancer incidence compared to controls either overall (OR 1.00, 95%-CI 0.95–1.04) or when individual ARBs were examined [114]. Orlistat. The XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study [115] was a multicentre, randomized, double blind placebo-controlled parallel group prospective study performed in Sweden over a period of 4 years, to investigate the effect of orlistat compared to lifestyle modification for prevention of type 2 diabetes in obese patients. Obese patients with IGT (21% of the cohort) showed an overall significant reduction of progression to diabetes of 18.8% in the orlistat group, compared to 28.8% in the placebo group (p < 0.005), along with a favorable and sustainable effect on cardiometabolic risk profile. The primary side effects of the drug are gastrointestinal-related, and include steatorrhea, faecal incontinence and frequent or urgent bowel movements. Oily stools and flatulence can be controlled by reducing the dietary fat content [116]. Animal data have linked orlistat with aberrant crypt foci, colonic lesions believed to be one of the earliest precursors of colon cancer, however such risk has not been shown in humans [117]. Aspirin. High doses of antiinflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in people with insulin resistance and type 2 diabetes. These drugs were initially used, in daily doses >2 g, as glucose-lowering agents in the pre-insulin era and recent evidence implicates potent non-specific antagonism of the inhibitor kinase-𝛽 (IKK𝛽) in this mechanism [118]. No conclusive evidence exists, but one study on the potential effect on aspirin enriched regimens upon prevention of type 2 diabetes has now been completed and data analysis is ongoing. The purpose of this placebo-controlled, randomized study in 70 participants, was to determine whether CVD risk markers, 𝛽-cell function and insulin sensitivity could be improved by targeting mechanisms of both glucose intolerance and CVD, using aspirin (325 mg q.d.) or an antioxidant (lipoic acid, 600 mg b.i.d.), or an angiotensin II receptor blocker (olmesartan, 40 mg q.d.) in individuals with IGT [119]. L-arginine.
A double blind, parallel study of oral l-arginine (6.4 g/day), was conducted in 142 randomized patients with IGT [120]. The treatment was maintained for 18 months. However, l-arginine as compared to placebo, did not reduce the cumulative incidence of diabetes (21.4 and 20.8%, respectively, HR 1.04, 95%-CI 0.58–1.86).
Discussion Our review provides a comprehensive outline of studies investigating potential impact of antidiabetic or other medications upon the rate or progression of dysglycaemia pathophysiology from IGT to type 2 diabetes. Within the relevant literature, we identified only five large outcomes trials examining progression to diabetes with seven different pharmacologic agents.
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Table 2. Qualitative summary of effect of pharmacologic agents studied for diabetes prevention. Pharmacologic agent
Diabetes incidence
Cardiovascular disease
Cancer
Fracture
Metformin Acarbose Rosiglitazone Nateglinide Ramipril Valsartan Insulin
↓ ↓ ↓ No effect No effect ↓ ↓
↓ ↓ ↑ No effect ↓ ↓ No effect
↓ No effect No effect No effect
↑ No effect
Other
↑ Non-fatal congestive heart failure
↑ Hypoglycaemia ↑ Body weight
↓, decreased risk; ↑, increased risk; -, no data available to assess risk.
Although it is important to note key differences in the enrolled populations (e.g. differing glucose entry criteria result in varying risk of diabetes progression, varying degrees of cardiovascular risk, wide age range), the message that some agents provide large reductions in progression to diabetes while others provide none at all is still relevant. Rosiglitazone showed the largest treatment effect (62% risk reduction), followed by metformin (31%), acarbose (25%) and valsartan (14%). None has been able to show a durable effect, evidenced by a continued reduction in diabetes risk during a washout period after drug discontinuation. Thus, only a delay in the time to diabetes diagnosis has been shown, but not a modification in the underlying course of disease progression. Lifestyle intervention is considered effective in the short term. In the DPP, diabetes incidence rates were lower in the intensive lifestyle intervention group, compared to either the metformin or the placebo group. Diabetes incidence in the 10-year follow-up study was reduced by 34% in the lifestyle group and by 18% in the metformin group compared with placebo. As shown during follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Despite this data, emerging evidence from studies such as the China Da Qing Diabetes Prevention Outcome Study [121,122], investigating the effects of 6 years of lifestyle intervention in people with IGT over period greater than 20 years, do suggest that long-term reduction in diabetes incidence, CVD-mortality, all-cause mortality and retinopathy is possible with lifestyle intervention. The choice of a pharmacologic intervention to reduce the progression to diabetes in high-risk patients [123] must take into account the complete balance of risk and benefit for each drug (Table 2). While rosiglitazone gives the largest benefit, its use is associated with short-term increases in weight and peripheral edema and possible long-term increases in fracture risk in postmenopausal women, myocardial infarction and heart failure. Although there is no current data from prospective RCTs to assess the adverse long-term risks, the weight of the epidemiological risk is strong enough to advise caution, particularly when there are other options available. Both metformin and acarbose seem to present a better balance, with reasonable diabetes risk reduction, no evidence of cardiovascular harm, and, for metformin, the possibility of a cancer benefit. According to the most recent recommendation by the National Institute for Clinical Excellence in the UK [124], metformin is recommended for prevention of type 2 diabetes in
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adults at high risk whose either blood glucose measure (fasting plasma glucose or HbA1c) shows they are still progressing towards type 2 diabetes despite their participation in an intensive lifestyle-change program or for those unable to participate in lifestyle-change programs. Acarbose has been approved for use for diabetes prevention in China and many other countries, and an ADA consensus conference statement recommended that metformin be considered in addition to lifestyle interventions for patients at high risk of progression to diabetes, defined as: both IGT and IFG plus 1 other risk factor, such as HbA1c >6%, hypertension, low levels of high-density lipoprotein, elevated triglycerides or diabetes in a first-degree relative, obesity,
Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus M. A. Bethel1,2,∗ , W. Xu3,∗ & M. J. Theodorakis1 1 Diabetes Trials Unit, University of Oxford, Churchill Hospital, Oxford, UK 2 Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA 3 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long-term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk. Keywords: antidiabetic drug, clinical trial, type 2 diabetes Date submitted 4 October 2013; date of first decision 9 October 2014; date of final acceptance 9 October 2014
Introduction The increasing prevalence of type 2 diabetes mellitus constitutes a leading global public health concern. Persons with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) characterized by postprandial and mild fasting hyperglycaemia, respectively, are at increased risk for the development of diabetes and are an ideal population to target for interventions which prevent or delay the onset of type 2 diabetes. Lifestyle interventions are proven strategies for reducing diabetes incidence [1–6] and have few adverse effects, but long-term adherence is difficult to maintain, limiting their effectiveness. Pharmacologic agents have also shown benefit with respect to diabetes prevention, often over several years, but some have additional off-target effects that may be beneficial or have known or unknown potential for harm. In this review, we seek to elucidate the totality of the risk/benefit profile for each drug tested for diabetes prevention according to the available evidence base. Because potential mid- and long-term adherence to injectable therapies is particularly hard to achieve, especially for such a mostly healthy population, we have primarily focused on orally administered compounds, but also included injectable therapeutic modalities with emerging clinical trial data which show promise.
Methods Source articles were identified in PubMed Central (including MEDLINE); EMBASE; Cochrane Central Register of Correspondence to: Michael J. Theodorakis, FRCP, Diabetes Trials Unit, University of Oxford, Churchill Hospital, Old Road, Headington OX3 7LJ, UK. E-mail: [email protected] ∗ These
authors have contributed equally to this article.
Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL), up to 1 March 2013. We searched the English language literature using the keywords ‘randomized clinical trial’, ‘IGT’, ‘IFG’ or ‘type 2 diabetes incidence’. Out of 168 articles which were identified in total, we opted to primarily focus on those pertinent to large scale outcomes trials, which are generally considered the best to guide evidence-based decisions; in addition, we placed specific emphasis on having a follow-up time period of at least 2 years, allowing assessment of the durability of any treatment effect and more complete safety evaluation. There were only four randomized controlled clinical trials (RCTs) of pharmacologic agents, which have enrolled >1000 patients, provided a minimum of 2 years follow-up and used progression to diabetes as a part of the primary outcome: the Diabetes Prevention Program (DPP), comparing lifestyle modification to metformin; the Study to Prevent Non-insulin-dependent Diabetes Mellitus (STOP-NIDDM) using acarbose; the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial (NAVIGATOR); the Diabetes REduction Assessment with Ramipril and Rosiglitazone Medication (DREAM). We have also included the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, which enrolled both people with and a smaller group of people without diabetes (n = 1456, 12% of patients in ORIGIN) who had IFG or IGT at baseline, to assess the impact of either omega-3 fatty acids or insulin glargine in reducing a composite endpoint of myocardial infarction (MI), stroke or cardiovascular death, albeit this was not a trial designed with an intention to treat IFG/IGT patients. Therefore, we have included a total of five large scale RCTs in our analysis. Using these fundamental RCTs as a solid basis for identifying key pharmacologic agents
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review article of interest to diabetes mellitus prevention, we then searched the same literature databases for prospective clinical trials or meta-analyses describing off-target effects by using the terms ‘adverse event’, ‘cancer’, ‘fracture’, ‘pancreatitis’, ‘weight’, ‘hypoglycaemia’ and ‘cardiovascular disease’, in combination with each medication identified in the initial search. Although this review has primarily focused on published evidence from the large-scale RCTs, we have also reviewed data from smaller scale, well powered prospective clinical trials, whose relevant outcomes could contribute to our analysis and broaden clinical perception of current trends in potential therapeutic intervention before diabetes becomes clinically manifest.
Results Key characteristics of the five major diabetes prevention trials are summarized in Table 1. The evidence for diabetes prevention and for proven or suspected off-target effects is described below for each pharmacologic agent, along with a concise description of the pharmacology and clinical safety of each medicine. Pertinent published data from smaller scale trials are also presented in each drug class.
Glucose-lowering Pharmacological Agents Biguanides (Metformin). Action and current clinical use. Metformin is first line recommended therapy for type 2 diabetes according to the International Diabetes Federation Global Guideline for type 2 Diabetes [7], in agreement with similar guidelines from the American Diabetes Association (ADA), as well as the European Association for the Study of Diabetes (EASD) [8]. Metformin does not modulate insulin secretion, but improves glycaemic control by inhibiting hepatic glucose production and gluconeogenesis, as well as by improving peripheral (muscle) tissue insulin sensitivity. There has been very active debate as to the rationale and benefit for using metformin as a pharmacological agent to delay or prevent diabetes progression. Well designed, RCTs such as the Glucose Lowering in Non-diabetic Hyperglycaemia Trial (GLINT) [8] are aiming at providing definitive answers in the future. On the basis of recent published evidence [9], in the United States alone, 1 in 12 adults have a combination of glucose dysmetabolism and risk factors that may justify consideration of metformin treatment for diabetes prevention. A plethora of trials are registered in clinicaltrials.gov as exploring the possible impact of metformin in individuals at varying glucose tolerant states. Findings from RCTs – benefit. From 1996, the DPP Research Group conducted a large RCT, enrolling participants at high risk for the development of type 2 diabetes from 27 US centres [2]. Eligible participants had a fasting plasma glucose between 95 and 125 mg/dl (5.3 and 6.9 mmol/l; ≤125 mg/dl–6.9 mmol/l — in the American Indian clinics) and 2 h glucose values after a standard 75 g oral glucose tolerance test (OGTT) between 140 and 199 mg/dl (7.8–11.05 mmol/l). In 3234 participants randomly assigned to intensive lifestyle intervention, metformin
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or placebo, the trial showed a 31% reduction in the primary outcome of development of diabetes with metformin treatment over a mean 2.8 year follow-up, similar in men and women and in all racial and ethnic groups. Long-term follow-up of the participants in the Diabetes Prevention Program Outcomes Study (DPPOS) showed a similar diabetes incidence rate in all groups (5.9 per 100 person-years for lifestyle, 4.9 for metformin and 5.6 for placebo), indicating that metformin therapy delayed diagnosis of diabetes, but did not reverse the underlying disease progression [10]. Similarly, metformin has conclusively been shown not to prevent the gradual decline in 𝛽-cell function, a hallmark of type 2 diabetes progression [11,12]. Findings from RCTs – risk. Metformin therapy is generally well tolerated and its well known gastrointestinal side effects are not typically treatment limiting. In DPP, metformin was associated with increased gastrointestinal symptoms (77.8 compared with 30.7 events/100 person-years on placebo), including diarrhea, flatulence, nausea and vomiting [2], but adherence to treatment was only slightly lower in the active therapy group. Lactic acidosis, the most severe side effect of biguanides, is rare with metformin. A Cochrane review of 347 comparative trials showed no fatal or non-fatal cases of lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patient-years in the non-metformin group [13]. Nonetheless, clinical caution is used for patients with severely limited renal function or severe heart failure. Findings from RCTs – off-target benefits. Two major off-target benefits have been postulated for metformin: reduced incidence of cardiovascular disease (CVD) and cancer prevention. Metformin has been shown to have favorable effects on a number of cardiovascular risk factors, including lipids, body weight, blood pressure and platelet function [14–17], and was shown in overweight participants in the United Kingdom Prospective Diabetes Study (UKPDS) to be associated with a decreased risk of myocardial infarction compared to other intensive therapy arms without metformin [18] [hazard ratio (HR) 0.61, 95%-confidence interval (CI) 0.41–0.89; p = 0.01]. The risk reduction for myocardial infarction persisted in the metformin group during 10 years of post-trial observational follow-up (HR 0.67, 95%-CI 0.51–0.89; p = 0.005), despite an early loss of glycated haemoglobin (HbA1c) differences between treatment groups, suggesting a legacy effect of early intensive glucose-lowering therapy with metformin for obese patients [19]. However, a cardioprotective effect of metformin in excess of that conferred by its glucose-lowering ability has not been confirmed, based on meta-analyses from large and small scale trials [20–22]. To date, no such prospective cardiovascular outcome trial with metformin has been performed. Metformin’s association with improved cancer incidence also has biologic plausibility. Preclinical studies have shown that metformin can inhibit the growth of cancer cells in vitro and in vivo and provide evidence for a direct, insulin-independent antitumour effect [23–25]. Epidemiologic evidence from large cohort metformin studies suggests benefit for several types of cancers [26,27]. A meta-analysis of 11 observational studies
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2.8
31%
Risk reduction of diabetes progression (%)
2 h ≥200 mg/dl (11.1 mmol/l)‡
FPG ≥126 mg/dl (7.0 mmol/l) or 2 hr ≥200 mg/dl (11.1 mmol/l)
Definition of diabetes
Median follow-up for incident diabetes (years)
Incident diabetes diagnosed on an annual OGTT
Incident diabetes diagnosed with annual OGTT or semiannual fasting plasma glucose test
Primary outcome
54
25%
3.3
31
51
IGT (2-h plasma glucose concentration between 140 and 200 mg/dl (7.8-11.1 mmol/l) after a 75 g glucose load and a fasting plasma glucose concentration between 101 and 140 mg/dl; 5.65–7.8 mmol/l)
34
IGT (a plasma glucose concentration of 95–125 mg/dl (5.3–6.9 mmol/l) in the fasting state and 140–200 mg/dl (7.8–11.1 mmol/l) 2 h after a 75-g oral glucose load)†
Eligible participants
Acarbose
STOP-NIDDM (n = 1429) [41]
BMI (kg/m2 )
Metformin*
intervention(s)
Mean age (years)
DPP (n = 3234)[2]
Pharmacologic
Table 1. Pharmacologic interventions for the prevention of diabetes.
NAVIGATOR (n = 9306) [71]
Nateglinide: no effect Valsartan: 14%
Rosiglitazone: 62%
5.0
FPG ≥126 mg/dl (7.0 mmol/l) or 2 h ≥200 mg/dl (11.1 mmol/l), confirmed by a second test
30%
6.2
Either 1. Two consecutive FPG levels within a 4-month period >126 mg/dl (7.0 mmol/l); OR 2. a diagnosis of diabetes made by a physician (a), plus use of a pharmacologic antidiabetic agent (b), plus evidence of a FPG of ≥126 mg/dl (7.0 mmol/l), or any blood glucose ≥200 mg/dl (11.1 mmol/l) OR 3. evidence (a) of at least one capillary glucose ≥200 mg/dl (11.1 mmol/l) confirmed by FPG ≥7126 mg/dl (7.0 mmol/l) or (b) of a random glucose ≥200 mg/dl (11.1 mmol/l) FPG ≥7126 mg/dl (7.0 mmol/l) OR 2 h plasma glucose >200 mg/dl; 11.1 mmol/l) during either the first or second OGTT after the end of usual follow-up visit
CV end-points
Placebo: 29.9
Valsartan: 30 Incident diabetes (FPG semi-annually for 3 year, then annually; annual OGTTs), extended and core cardiovascular outcomes§
Insulin glargine: 29.8
63.5
Subjects with a prior CV event; angina + documented ischaemia; albuminuria; left ventricular hypertrophy; angiographic evidence of >50% stenosis of a coronary, carotid or lower extremity artery; or an ankle/brachial index 50 years old with IFG, IGT or early type 2 diabetes in addition to other cardiovascular risk factors, to receive insulin glargine (with a target fasting blood glucose level of ≤5.3 mmol/l or standard care and to receive n-3 fatty acids or placebo with the use of a 2 × 2 factorial design) [81]. Median follow-up was 6.2 years. Rates of incident cardiovascular outcomes were similar in both groups. In the subset of participants with IFG or IGT at baseline, incident diabetes was diagnosed approximately 3 months after therapy was stopped among 30 vs. 35% of 1456 participants without baseline diabetes [odds ratio (OR) 0.80; 95% confidence interval (CI), 0.64–1.00; p = 0.05]. The development of new diabetes within the trial in people without diabetes at baseline was reduced by 28%. Findings from RCTs – risk. Rates of severe hypoglycaemia were 1.00 vs. 0.31 per 100 person-years between the insulin glargine and standard-care groups, respectively. Median weight increased by 1.6 kg in the insulin group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (HR 1.00; 95%-CI, 0.88–1.13; p = 0.97). These data imply that, apart from the trial showing no impact of (either omega-3 fatty acids or) insulin glargine in reducing a composite CV end-point of acute myocardial infraction, stroke or CV death, 15 IGT patients have to be systematically treated with basal insulin for 6 years to prevent just one from progressing to diabetes. The role of insulin glargine as a risk factor for cancer is controversial in human studies and current results from epidemiological analysis are weak. The theoretical basis for such a biological link stems from possible aberrant stimulation of insulin and insulin-like growth factor (IGF) receptors by insulin analogues compared with endogenous insulin. The ubiquitous insulin and IGF receptors belong to the receptor tyrosine kinase superfamily and upon ligand activation trigger trans-phosphorylation of the kinase domains, thus initiating intracellular signaling pathways for metabolic as well as
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review article mitogenic processes, involving cell proliferation and differentiation. In a recent comprehensive meta-analysis including data from available observational studies and RCTs evaluating the relationship of insulin glargine and cancer risk, 448,928 study participants and 19,128 cancer patients were identified [82]. Insulin glargine use was associated with a lower odds of cancer compared with non-glargine insulin use (OR 0.81, 95%-CI 0.68–0.98, p = 0.03) and did not increase the odds of breast cancer (OR 0.99, 95%-CI 0.68–1.46, p = 0.96). Compared with non-glargine insulin, no significant association was found between insulin glargine and prostate cancer, pancreatic cancer and respiratory tract cancer. ORIGIN also did not support a direct link between insulin glargine therapy and cancer risk. Therefore prospective clinical studies are needed to evaluate the possible tumour growth-promoting effects of glargine and other insulin analogs. Other insulins. Early insulinization to prevent diabetes progression had also been studied in a large, multicenter, controlled trial which randomized 382 newly diagnosed individuals with type 2 diabetes in China [83], having a fasting plasma glucose between 7.0 and 16.7 mmol/l. The patients were randomly assigned to either insulin treatment with multiple daily injections (MDI) or insulin pump-subcutaneous infusion (SCI) or to treatment with oral antidiabetic agents (OAD) for 2–5 weeks. Glycaemic control was achieved faster and in a higher percentage of the patients in the insulin-treated arms compared with the OAD arm, while a year later, the target glycaemic control in the insulin-treated groups was maintained in a significantly higher percentage of patients (51.1, 44.9 and 26.7% in the SCI, MDI and OAD groups, respectively; p = 0.0012), despite having discontinued drug therapy. However, the study has come under intense criticism, because of major limitations, including its questionable generalizability to non-Asian populations and because of the use of drug classes such as sulfonylureas in the control group, which greatly impacted on the ability to definitively discern any protective effects of insulin therapy. Incretin-based Therapies. Action and current clinical use. Insulinotropic gut-derived incretin peptides glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted in response to nutrient ingestion and account for almost 70% of postprandial insulin excursions. By potentiating insulin-dependent insulin secretion and having multiple trophic actions on islets and other target tissues, they affect complex pathophysiologic processes of type 2 diabetes in a harmonized fashion [84,85]. They promote efficient glucose disposal in peripheral tissues such as muscle, directly reduce hepatic glucose production by decreasing glucagon, increase insulin secretion, directly inhibit gastric emptying, and centrally modulate appetite and energy homeostasis [86]. Incretin-based therapies address some of the challenges associated with traditionally available OADs. In addition to improving 𝛽-cell function, stimulating insulin secretion and inhibiting glucagon secretion, incretin mimetic agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. For both sub-classes of these drugs, intensive mid-to-large scale trials
doi:10.1111/dom.12401 7
review article are currently in progress, to assess their potential effect on IFG/IGT populations. Incretin enhancers (DPP-IV inhibitors: sitagliptin, vildagliptin). Drugs of this sub-class augment availability of endogenously secreted active incretin peptides, by inhibiting the enzyme responsible for their rapid degradation in vivo. In this manner, they enhance biologically active peptides’ duration of action, allowing them to exert their effects longer within the physiological concentration range, as opposed to the supra-physiological levels achieved by injecting GLP-1 receptor agonists. They generally lower HbA1c by an average of 0.6–0.7% and they are weight neutral. Findings from RCTs – benefit and risk. Data from small scale studies show that both sitagliptin and vildagliptin improve 𝛽-cell function in patients with abnormal glucose metabolism [87,88], but neither has been studied for diabetes prevention. The ongoing DPP-4 Inhibition and TZD for DM Prevention (DInT–DM) trial is a double blind, placebo-controlled trial of 45 participants randomized to sitagliptin 100 mg daily, either as monotherapy or in combination with pioglitazone 15 mg/day compared to placebo for 9 months. Incretin Mimetics (GLP-1 Receptor Agonists: Exenatide, Liraglutide) Findings from RCTs – benefit and risk. As opposed to orally acting DPP-IV inhibitors, the GLP-1 receptor agonists mimic the effects of the native GLP-1 and are administered parenterally, thus achieving true pharmacological concentrations targeting islet and peripheral receptors. Although no large scale clinical trials for diabetes have been completed, exenatide has been tested in smaller studies in IFG/IGT participants. In 152 obese participants with NGT, IFG or IGT (the latter two categories comprised 25% of the patient population), exenatide normalize glucose tolerance in 77%, compared to 56% of those receiving placebo [89]. The majority of adverse events were mild or moderate in severity: nausea and diarrhea were experienced by 25 and 14% of those given exenatide, compared to just 4 and 3% of those that received placebo. In an open-label, clinical trial [90] in 50 individuals without diabetes, with abdominal obesity and IFG or IGT, 3 months of exenatide therapy was associated with reduced triglycerides compared to metformin (Δ-exenatide: −25.5 ± 45.7 mg/dl vs. Δ-metformin: −2.9 ± 22.8 mg/dl, p = 0.032), but no changes in microvascular endothelial function indices, C-reactive protein, circulating oxidized LDL or vascular cell adhesion molecule-1. A large international study currently in progress, the Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) trial, will evaluate the potential of liraglutide to induce and maintain weight loss over 56 weeks in obese or overweight participants with co-morbidities [91]. Furthermore, the aim is to investigate the long-term potential of liraglutide to delay the onset of type 2 diabetes in participants diagnosed with IGT at baseline. Primary outcome measures include: change from baseline in body weight; proportion of participants losing at least 5% of baseline body weight; and proportion of participants with onset of type 2 diabetes. On the basis of BMI and IGT status, 3600 participants will be randomized to either 68 weeks (56 weeks of randomized treatment followed by a 12 week re-randomized treatment
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period) or 160 weeks of treatment (160 week treatment will only be applicable to participants with IGT status at baseline). The trial is expected to be completed by 2015. Findings from RCTs – risks. Mild, transient gastrointestinal discomfort is commonly observed by any incretin-based therapy, but especially pronounced with GLP-1 receptor agonists [92]. Although mild hypoglycaemia can occur, this is usually in combination with other hypoglycaemic therapies [93]. The risk for acute pancreatitis and pancreatic cancer when using incretin-based therapies has received close attention, as introduction of such therapies in diabetes management is expanding [94–97]. Reports of aberrant microscopic morphology and pancreatic histopathology in cadaveric tissue specimens from individuals having received DPP-IV inhibitors (most of them) or injectable incretin mimetics, have attracted strong criticism for methodological inconsistencies. The possible causality of potentially increased propensity to pancreatic inflammation is complicated by the mere fact that diabetes and its pathophysiology are associated with higher proportion of individuals experiencing pancreatitis. Although signals for such side effects have emerged early after incretin-based therapies received market authorization, conclusive evidence in regards to pancreatitis and/or cancer risk potentially conferred by these therapies will only be available in the coming years, when completion of the large scale multi-national outcome trials with sitagliptin, exenatide and liraglutide is achieved. Notably, preclinical studies in many experimental animal models which were treated with 10 times or higher doses of those compounds have failed to provide a credible association with either chronic inflammation or cancer. A meta-analysis among 268,561 US patients with acute pancreatitis, showed that only 2.6% used exenatide. In unadjusted and adjusted analyses, patients who did not use exenatide were more likely to be hospitalized for acute pancreatitis but the difference was not statistically significant in either analysis [98]. Among 209,306 patients in the pancreatic cancer analysis, 0.070% were diagnosed with pancreatic cancer, and 0.88% had at least 1 year of continuous exenatide exposure prior to the diagnosis. Those with exenatide exposure had higher rates of pancreatic cancer compared with those without (0.081 vs. 0.070% in unadjusted analysis). In both unadjusted and adjusted analyses, the difference was not statistically significant. Further analysis was recently carried out in 25 studies where exenatide or liraglutide were used [99]. Neither exenatide nor liraglutide were associated with an increased risk of acute pancretitis, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 [95%-CI 0.29–2.60, I(2) = 0%] and for liraglutide was 1.35 [95%-CI 0.70–2.59, I(2) = 0%]. Liraglutide was not associated with an increased risk for thyroid cancer [OR 1.54, 95%-CI 0.40–6.02, I(2) = 0%]. For exenatide, no thyroid malignancies were reported. Therefore, current available published evidence is insufficient to confirm an increased risk of pancreatitis or cancer associated with GLP-1 receptor agonists [100]. Findings from RCTs – off-target benefits. GLP-1 receptor agonists uniquely result in long-term reduction in blood pressure of almost 2–7 mmHg, albeit at a cost of slight increase in heart
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rate, especially with long-acting, weekly administered preparations. Similarly, a more favorable lipid profile is achieved, especially in regards to LDL-cholesterol and triglyceride lowering.
Non-glucose-lowering Pharmacological Agents Antihypertensive Drugs. Findings from RCTs – benefit. While the cardiovascular benefits of renin–angiotensin system (RAS) inhibitors, including angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors has been well documented in patients with type 2 diabetes [101–104], they have also been postulated to have an effect on blood glucose. Subgroup analyses of several antihypertensive trials have shown that the risk for type 2 diabetes development in patients with hypertension is lower for those treated with RAS blockade than for those who received thiazide diuretics, 𝛽-blockers or the calcium channel blocker amlodipine [105,106]. Only ramipril and valsartan have been studied in appropriately designed and powered outcomes trials to examine their effect on diabetes incidence. In DREAM, ramipril did not significantly affect the primary composite of diabetes or death and had no effect on the incidence of diabetes alone, despite having an association with regression to normoglycaemia compared to placebo [107] (HR 1.16, 95%-CI, 1.07–1.27; p = 0.001). Similarly, ramipril did not improve the cardiovascular composite outcome measured in DREAM (HR 1.08, 95% CI 0.76–1.52, p = 0.68) [107]. In NAVIGATOR, valsartan did reduce diabetes incidence [108] (33.1 vs. 36.8% in the placebo group, p < 0.001), equivalent to a 14% risk reduction. There was no excess of renal dysfunction or hyperkalemia in the valsartan group, but hypotension-related adverse events were more common in the valsartan group than in the placebo group (42.4 vs. 35.9%; p < 0.001). It should be noted that, in a meta-analysis of ACE inhibitors for prevention of new onset type 2 diabetes [109], which included nine RCTs with 92,404 patients (72,128 people without diabetes at baseline), compared with control group, incidence of new-onset diabetes was significantly reduced in the ACE inhibitors group (OR 0.80, 95%-CI 0.71–0.91), irrespective of achieved blood pressure levels at the follow-up. In addition, a similar meta-analysis [110] investigated the effect of ARBs and included 11 RCTs with 79,773 patients (59,862 people without diabetes at baseline). Compared to control group, incidence of new-onset diabetes was significantly reduced in ARBs group (OR 0.79, 0.74–0.84) and various categories of ARBs subgroup. Compared to control group, incidence of new-onset diabetes was significantly reduced in ARBs group, irrespective of achieved blood pressure level. Findings from RCTs – off-target benefits. Both ramipril and valsartan have been examined within meta-analyses to evaluate their potential effect on cancer outcomes. The RAS is increasingly being recognized as a potential mediator of cancer biology [111]. Both type 1 and type 2 angiotensin receptors are important regulators of cellular proliferation, angiogenesis and inflammation [112]. In a meta-analysis of 14 trials primarily conducted for cardiovascular outcomes, ACE inhibitor therapy showed no increase in cancer incidence (RR 1.01, 95%-CI
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0.95–1.07, p = 0.78), cancer death (RR 1.00, 95% CI 0.88–1.13, p = 0.95) or gastrointestinal cancer (RR 1.09, 95%-CI 0.88–1.35, p = 0.43) [113]. Similarly, a meta-analysis of 15 ARB trials showed no excess of cancer incidence compared to controls either overall (OR 1.00, 95%-CI 0.95–1.04) or when individual ARBs were examined [114]. Orlistat. The XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study [115] was a multicentre, randomized, double blind placebo-controlled parallel group prospective study performed in Sweden over a period of 4 years, to investigate the effect of orlistat compared to lifestyle modification for prevention of type 2 diabetes in obese patients. Obese patients with IGT (21% of the cohort) showed an overall significant reduction of progression to diabetes of 18.8% in the orlistat group, compared to 28.8% in the placebo group (p < 0.005), along with a favorable and sustainable effect on cardiometabolic risk profile. The primary side effects of the drug are gastrointestinal-related, and include steatorrhea, faecal incontinence and frequent or urgent bowel movements. Oily stools and flatulence can be controlled by reducing the dietary fat content [116]. Animal data have linked orlistat with aberrant crypt foci, colonic lesions believed to be one of the earliest precursors of colon cancer, however such risk has not been shown in humans [117]. Aspirin. High doses of antiinflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in people with insulin resistance and type 2 diabetes. These drugs were initially used, in daily doses >2 g, as glucose-lowering agents in the pre-insulin era and recent evidence implicates potent non-specific antagonism of the inhibitor kinase-𝛽 (IKK𝛽) in this mechanism [118]. No conclusive evidence exists, but one study on the potential effect on aspirin enriched regimens upon prevention of type 2 diabetes has now been completed and data analysis is ongoing. The purpose of this placebo-controlled, randomized study in 70 participants, was to determine whether CVD risk markers, 𝛽-cell function and insulin sensitivity could be improved by targeting mechanisms of both glucose intolerance and CVD, using aspirin (325 mg q.d.) or an antioxidant (lipoic acid, 600 mg b.i.d.), or an angiotensin II receptor blocker (olmesartan, 40 mg q.d.) in individuals with IGT [119]. L-arginine.
A double blind, parallel study of oral l-arginine (6.4 g/day), was conducted in 142 randomized patients with IGT [120]. The treatment was maintained for 18 months. However, l-arginine as compared to placebo, did not reduce the cumulative incidence of diabetes (21.4 and 20.8%, respectively, HR 1.04, 95%-CI 0.58–1.86).
Discussion Our review provides a comprehensive outline of studies investigating potential impact of antidiabetic or other medications upon the rate or progression of dysglycaemia pathophysiology from IGT to type 2 diabetes. Within the relevant literature, we identified only five large outcomes trials examining progression to diabetes with seven different pharmacologic agents.
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Table 2. Qualitative summary of effect of pharmacologic agents studied for diabetes prevention. Pharmacologic agent
Diabetes incidence
Cardiovascular disease
Cancer
Fracture
Metformin Acarbose Rosiglitazone Nateglinide Ramipril Valsartan Insulin
↓ ↓ ↓ No effect No effect ↓ ↓
↓ ↓ ↑ No effect ↓ ↓ No effect
↓ No effect No effect No effect
↑ No effect
Other
↑ Non-fatal congestive heart failure
↑ Hypoglycaemia ↑ Body weight
↓, decreased risk; ↑, increased risk; -, no data available to assess risk.
Although it is important to note key differences in the enrolled populations (e.g. differing glucose entry criteria result in varying risk of diabetes progression, varying degrees of cardiovascular risk, wide age range), the message that some agents provide large reductions in progression to diabetes while others provide none at all is still relevant. Rosiglitazone showed the largest treatment effect (62% risk reduction), followed by metformin (31%), acarbose (25%) and valsartan (14%). None has been able to show a durable effect, evidenced by a continued reduction in diabetes risk during a washout period after drug discontinuation. Thus, only a delay in the time to diabetes diagnosis has been shown, but not a modification in the underlying course of disease progression. Lifestyle intervention is considered effective in the short term. In the DPP, diabetes incidence rates were lower in the intensive lifestyle intervention group, compared to either the metformin or the placebo group. Diabetes incidence in the 10-year follow-up study was reduced by 34% in the lifestyle group and by 18% in the metformin group compared with placebo. As shown during follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Despite this data, emerging evidence from studies such as the China Da Qing Diabetes Prevention Outcome Study [121,122], investigating the effects of 6 years of lifestyle intervention in people with IGT over period greater than 20 years, do suggest that long-term reduction in diabetes incidence, CVD-mortality, all-cause mortality and retinopathy is possible with lifestyle intervention. The choice of a pharmacologic intervention to reduce the progression to diabetes in high-risk patients [123] must take into account the complete balance of risk and benefit for each drug (Table 2). While rosiglitazone gives the largest benefit, its use is associated with short-term increases in weight and peripheral edema and possible long-term increases in fracture risk in postmenopausal women, myocardial infarction and heart failure. Although there is no current data from prospective RCTs to assess the adverse long-term risks, the weight of the epidemiological risk is strong enough to advise caution, particularly when there are other options available. Both metformin and acarbose seem to present a better balance, with reasonable diabetes risk reduction, no evidence of cardiovascular harm, and, for metformin, the possibility of a cancer benefit. According to the most recent recommendation by the National Institute for Clinical Excellence in the UK [124], metformin is recommended for prevention of type 2 diabetes in
10 Bethel et al.
adults at high risk whose either blood glucose measure (fasting plasma glucose or HbA1c) shows they are still progressing towards type 2 diabetes despite their participation in an intensive lifestyle-change program or for those unable to participate in lifestyle-change programs. Acarbose has been approved for use for diabetes prevention in China and many other countries, and an ADA consensus conference statement recommended that metformin be considered in addition to lifestyle interventions for patients at high risk of progression to diabetes, defined as: both IGT and IFG plus 1 other risk factor, such as HbA1c >6%, hypertension, low levels of high-density lipoprotein, elevated triglycerides or diabetes in a first-degree relative, obesity,
