Prevention of T2DM: Pharmacological Interventions

In the world about 381x106 individuals have type 2 diabetes (T2DM) and an approximately a similar number have impaired glucose tolerance (IGT). The latter is a high-risk population with 40-50% of them developing, sooner or later in life, overt diabetes. Preventing this progression is paramount to relief medical, societal, economic, and personal burdens associated with chronic hyperglycemia. Lifestyle intervention can effectively reduce the conversion from IGT to T2DM, though achieving and maintaining healthy lifestyle and lower body weight is difficult. Even when these challenging goals are achieved a significant percentage of individuals still convert to T2DM underscoring the need for more effective preventative strategies. Pharmacologic intervention, at least, in subjects “resistant” to lifestyle modification may provide an opportunity to modify the main pathogenetic mechanisms of T2DM, i.e. insulin sensitivity and beta-cell function as these alterations are already apparent in IGT subjects. To this purpose both insulin sensitizers and/or agents acting on the beta cell may be suitable for early treatment and pharmacologic prevention.

Insulin-sensitizing agents

Metformin improves insulin sensitivity at the level of the liver and to a less extent on peripheral tissues, while it does not exert a direct effect on insulin secretion. The Diabetes Prevention Program (DPP) [1] showed that the use of metformin, 850 mg twice daily, was associated with 31% reduction in IGT conversion to T2DM (compared with 58% reduction with lifestyle intervention) as well as reduced incidence of the metabolic syndrome. Similar results have been reported in the Indian DPP (26% reduction) [2]. The effect of metformin was maintained as far as the treatment was continued, whereas metformin withdrawal was associated with rapid increase in T2DM conversion rate [3]. According to an ADA consensus metformin should be used in individuals with HbA1c ≥6%, BMI ≥30 kg/m2, age≤60-yrs because of high T2DM risk [4]. The Glucose Lowering in Non-diabetic Hyperglycaemia Trial (GLINBT) - a large study to be performed in case of positive results form an on-going pilot study - may provide support to this position.

Thiazolidinediones (TZDs) improve insulin action on peripheral tissues (particularly on adipose tissue) and, to a lower extent, on the liver. A potential protective beta-cell effect has been claimed. In the DPP, troglitazone (not any more available) reduced conversion rate by 23% [5]. This results is lower than the one initially reported in women with previous gestational diabetes in the TRIPOD study where troglitazone reduced T2DM incidence from 45 to 20% (RR 0.45, 95% CI 0.25–0.83), an effect that persisted 8 months after stopping study medications [6]. Upon troglitazone withdrawal from the market, pioglitazone was used (PIPOD study) confirming the preventive effect [7]. These findings have been corroborated by the results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study, in which rosiglitazone reduced progression from IGT/IFG to T2DM by 60%, an effect that was particularly pronounced in obese subjects [8]. Pioglitazone (45 mg/day) has been tested in the ACT NOW trial to show a 72% reduction in the conversion of IGT to T2DM [9]. In spite of their efficacy, side effects (fluid retention, heart failure, and bone fractures) and cost has not yielded official recommendation to support their use. Lower TZD dose may reduce the risk of side effects and if combined with metformin still exert a significant reduction in the conversion rate to T2DM as reported in the CANOE study [10].

Agents addressing beta-cell defect

Classic insulin secretagogues such as gliclazide (Fasting Hyperglycemia Study) and nateglinide (NAVIGATOR trial) did not provide any significant reduction in the conversion rate of IGT to T2DM [11][12]. Whether this is due to short living effect of sulfonylureas (and their derivatives) or potential negative effects on beta-cell survival is not known. Preclinical studies with incretin-based therapies (DDP4-inhibitors and GLP1-receptor agonists) have raised more expectations because of evidence of preservation of β-cell mass and function in pre-clinical studies. In humans, short-term clinical trials (max duration, 12 week) have only documented a modest effect on glucose homeostasis, which was lost after treatment discontinuation. Whether longer periods of DPP-4 inhibition in individuals with prediabetes can preserve β-cell function and reduce conversion toward overt T2DM remains to be evaluated. As compared to DPP-4 inhibitors, GLP-1RAs can favour body weight loss, which in turn could also exert a favorable effect on T2DM prevention. In obese individuals with IFG or IGT, exenatide together with lifestyle intervention for 24 weeks was associated with a greater degree of reversion toward normal glucose tolerance. Similarly, 20-week treatment with liraglutide was associated with an 84–96% reduction in the prevalence of pre-diabetes. All these studies, however, are of short in duration and small in size, which, along with elevated cost of these drugs, make incretin-based treatment still a not validated pharmacologic intervention in high-risk individuals [13].

Body weight lowering agents

Obesity, and visceral obesity in particular, is a main triggering factor in the development of T2DM. Even moderate body weight loss may exert a major effect on reducing T2DM risk. Therefore, pharmacologic intervention aiming at reducing body weight is looked at as promising prevention strategy, although pharmacologic agents for body weight control remain scanty and of limited efficacy. Orlistat, an inhibitor of pancreatic and gastrointestinal lipases that prevents the absorption of approximately 30% of dietary fat, along with some reduction in body weight has been shown to reduce the incidence of T2DM by 37.3% (XENical in the prevention of Diabetes in Obese Subjects trial) [14].

Reduced intestinal glucose absorption

Alpha-glucosidase inhibitors such as acarbose and voglibose have been shown to decrease conversion from IGT to T2DM. In the Study TO Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM), the use of acarbose was associated with a 25% reduction in risk of progression to T2DM over 3.3 years [15]. Interestingly, a favourable effect on newly developed hypertension and cardiovascular events was claimed. Confirmation of these results is awaited from the Acarbose Cardiovascular Evaluation (ACE) trial, which results are expected in 2018 [16].

Insulin

In the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial insulin glargine was administered over a median time of 7 years to a number of subjects with non-diabetic hyperglycemia [17]. Three months after therapy cessation a 20% relative reduction in diabetes was found as compared to subjects using oral agents (30% vs. 35%) with low risk of hypoglycaemia. The limited size of the effect and the need of daily insulin injections are unlikely to make this an attractive prevention strategy.

To date, taking into consideration efficacy, safety and cost, metformin appears to be the more suitable drug for pharmacologic prevention of T2DM. However, in order to provide benefit adherence to long-term treatment is necessary. As for lifestyle modification this may not be an easy task. In the DPP study, about 75% of the participants in the metformin arm took what was considered to be the prescribed dose. This rate dropped to 57% in the follow-up study. Whether a combination of lower dose of pioglitazone and metformin may increase the risk-to-benefit ratio would require more information on top of that provided by the CANOE trial. Specific studies will need to be gathered with respect of incretin-based therapies, particularly on the light of new long-acting formulations. In all cases, however, use of pharmacological agents for prevention of T2DM will require careful assessment of the risk/benefit profile, personal implications, and costs. With the exception of metformin (and insulin in the ORIGIN trial), none of the available pharmacologic drugs have been given for more than 3 years, so that the potential adverse effects of long-term treatment in an asymptomatic population remain largely unknown. It must be also considered the need of continuing the treatment since, upon drug discontinuation, the incidence of diabetes tends to return to pre-treatment rate. It is for this reason that one could argue whether treating pre-diabetic subjects really means preventing the disease or merely anticipating treatment before conventional diagnosis.

References

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  8. ^ DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105. Erratum in: Lancet 2006;368(9549):1770.

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