Prediabetes

Canadian Journal of Cardiology 34 (2018) 615e623

Review

Prediabetes Aditya K. Khetan, MD, and Sanjay Rajagopalan, MD Harrington Heart and Vascular Institute, Division of Cardiovascular Medicine, Cleveland, Ohio, USA

  RESUM E

ABSTRACT The burden of diabetes is expected to rise from 415 million individuals in 2015 to 642 million individuals by 2040. Most individuals pass through a phase of prediabetes before developing full-blown diabetes. Insulin resistance, impaired incretin action, and insulin hypersecretion are central to the pathophysiology of prediabetes. Individuals older than 40 years of age and other high-risk individuals should be screened for diabetes with fasting plasma glucose and/or hemoglobin A1c. For those diagnosed with prediabetes, the goal of treatment should be restoring euglycemia, because there are data showing that restoring normoglycemia during prediabetes and early diabetes can produce lasting remission. The preferred approach for this is intensive lifestyle intervention, which besides reducing progression to diabetes, has also been shown to reduce all-cause mortality in a long-term follow-up study. The best evidence for a pharmacological approach is with metformin. Other drugs that have shown efficacy include thiazolidinediones, alpha-glucosidase inhibitors, orlistat, basal insulin, and valsartan. However, except for metformin, none of these drugs are currently recommended for this purpose. Newer agents such as glucagon-like peptide-1 agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors also have considerable promise in this area. Bariatric surgery can be offered to patients with metabolic syndrome and body mass index of 30-35.

On s’attend à ce que le fardeau du diabète passe de 415 millions de personnes en 2015 à 642 millions de personnes en 2040. La plupart des diabète avant de de velopper un individus traversent une phase de pre ritable diabète. L’insulinore sistance, la de gradation de l’activite  des ve tines et l’hyperse cre tion d’insuline sont au centre de la physioincre diabète. Les personnes de plus de 40 ans et les autres pathologie du pre es à un risque e leve  devraient subir un de pistage du personnes expose mie plasmatique à jeun ou de l’he moglodiabète au moyen de la glyce e (A1c), ou les deux. Chez les personnes ayant un diagnostic bine glyque diabète, l’objectif du traitement devrait être le re tablissement de de pre mie, puisque des donne es montrent que le re tablissement de la l’euglyce mie au cours du pre diabète et du diabète pre coce peut normoglyce mission durable. L’approche privile gie e pour atteindre entraîner une re cet objectif de traitement demeure l’intervention intensive sur le mode re e de vie qui, en plus de ralentir la progression du diabète, s’est ave duire la mortalite  toutes causes confondues lors d’une efficace pour re tude de suivi à long terme. Les meilleures donne es probantes e  de la metformine. d’approche pharmacologique montrent l’efficacite dicaments qui ont de montre  leur efficacite , notons : Parmi les autres me les thiazolidinediones, les inhibiteurs des alpha-glucosidases, l’orlistat, l’insuline basale et le valsartan. Toutefois, à l’exception de la metfordicaments n’est actuellement recommande à mine, aucun de ces me cents tels que les agonistes des re cepteurs cette fin. Des agents plus re GLP-1 (glucagon-like peptide-1) et les inhibiteurs de la DPP-4 (dipeptidyl galement très prometteurs dans ce domaine. La peptidase 4) sont e chirurgie bariatrique peut être offerte aux patients atteints du syndrome tabolique dont l’indice de masse corporelle se situe entre 30 et 35. me

A large number of people exposed to a small risk may generate many more cases than a small number exposed to a high risk.

to an estimated yearly global health expenditure of USD$673 billion. At current rates, this number is expected to rise to 642 million individuals by 2040.2 In Canada alone, the number of people living with diabetes rose from 1.3 million in 2000 to 2.5 million in 2010, and is projected to rise to 3.7 million by 2020. The corresponding costs are projected to rise from $6.3 billion in 2000 to $16.9 billion annually in 2020.3 Altering this trajectory can be achieved in part by targeting people with prediabetes, which affects nearly 3 times the number of people with T2DM.4

dGeoffrey Rose The Strategy of Preventive Medicine Oxford University Press, 19921

It is estimated that in 2015, type 2 diabetes mellitus (T2DM) affected 415 million individuals worldwide, leading Received for publication October 31, 2017. Accepted December 10, 2017. Corresponding author: Dr Sanjay Rajagopalan, Harrington Heart and Vascular Institute, University Hospitals, Case Cardiovascular Research Institute, Wolstein Research Building, Rm 4405, Cleveland, Ohio 44106, USA. Tel.: þ1-216-844-3800. E-mail: [email protected] See page 621 for disclosure information.

Identification of High-Risk Individuals With Prediabetes There are differences North American and European guidelines approaches to diagnose prediabetes. The Canadian Diabetes Association recommends screening all individuals

https://doi.org/10.1016/j.cjca.2017.12.030 0828-282X/
2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

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Table 1. High-risk individuals for developing prediabetes Overweight adults (BMI > 25 or > 23 in Asian American individuals) who have 1 or more of the following risk factors: First-degree relative with diabetes High-risk race/ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander) Women who were diagnosed with GDM History of CVD Hypertension HDL cholesterol < 35 mg/dL (2 mmol/L) and/or a triglyceride level > 250 mg/dL (13.9 mmol/L) Women with polycystic ovary syndrome Physical inactivity Other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans) BMI, body mass index; CVD, cardiovascular disease; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein. Modified from the American Diabetes Association6 with permission from the American Diabetes Association. Copyright
2017 American Diabetes Association. All rights reserved.

older than 40 years of age with fasting plasma glucose and/or hemoglobin A1c (HbA1c).5 Similarly, the American Diabetes Association recommends screening all individuals older than 45 years of age, and certain high -risk individuals younger than the age of 45 years with a diagnostic blood sugar test (either one of fasting plasma glucose, 2-hour oral glucose tolerance test, or HbA1c can be used).6 Criteria for high risk are summarized in Table 1. For those with normal results, repeat testing is recommended at a minimum of 3-year intervals, whereas individuals with prediabetes should have yearly testing. European guidelines, meanwhile, recommend screening the general and high-risk population with a T2DM risk score.7 For those with a high value the European guidelines recommend following this with an oral glucose tolerance test, or a combination of fasting plasma glucose and HbA1c. There are various T2DM risk scores available, with a recent systematic review suggesting that they are all fairly comparable.8 Currently, despite the high burden of prediabetes (for example, 1 in 3 US adults has prediabetes), universal screening is not recommended. This is primarily because of a lack of high-quality evidence that the prognosis of diabetes can be improved through universal screening. One could argue that such evidence might be difficult to accrue, because one would need to perform a study over many decades. Because T2DM represents a high-risk condition in many individuals and because of the implications of this disease for disability, including so-called glycemic dysutility (ie, the burden of medications on quality of life), the prevention of T2DMdparticularly with simple interventionsdcould translate into benefit if the proposed measures are low cost and have minimal adverse effects. Future studies involving patients with prediabetes might be well served by including patients at high risk for future cardiovascular complications, such as those with elevated coronary artery calcium score or nonalcoholic steatohepatitis.9,10 Rationale for Targeting Patients With Prediabetes at High Risk for Cardiovascular Complications Because nearly all patients with T2DM pass through an extensive phase of prediabetes (average duration of nearly 10 years), targeting prediabetes with effective interventions can

Canadian Journal of Cardiology Volume 34 2018

significantly alter the natural history of T2DM (Fig. 1).11 There is substantial evidence that even after the diagnosis of diabetes, there are delays in treatment intensification. If there were safe and effective therapies, this protracted period of waiting for eventual diabetes could be instead spent in altering the trajectory of inevitability.12 Insulin resistance and impaired incretin action is well recognized as central to the pathophysiology of prediabetes and diabetes.13 Insulin hypersecretion to compensate for peripheral insulin resistance is obligatory and maintains euglycemia for a while, but because of the eventual and inevitable deterioration in b-cell function, there is unmasking of diabetes with as much as 90% of b-cell function being compromised at the time of diagnosis.14-16 Because of this long incubation period, prediabetes provides an exceptionally wide window of opportunity to alter the natural history of diabetes.17 There are data to suggest that restoration of normoglycemia during prediabetes or very early T2DM is an effective deterrent against future progression (Fig. 2). For instance, in the Diabetes Prevention Program (DPP), in patients who did not develop diabetes during the course of the study, attainment of normoglycemia (fasting and after oral glucose load) during the trial was associated with a 56% reduction in T2DM irrespective of the approach taken to accomplish this goal.18 The intensive insulin therapy (IIT) regimens discussed later under the Intensive Insulin Therapy section are also good examples of the concept that early restoration of normoglycemia can prevent T2DM very effectively.19,20 In selecting people to target for preventive therapy with medications, it is important to account for medication dysutility, which is a quantitative estimate of treatment burden. Treatment burden in the primary prevention setting largely stems from 5 factorsdcost of treatment, potential for adverse effects, inconvenience of taking a daily pill, inconvenience of obtaining a prescription, and perceived loss of autonomy.21 Incorporating medication disutility into treatment models can help understand the balance between expected benefits of treatment and the burden of treatment. An oral pill such as metformin has a low treatment burden. The medicationassociated dysutility is estimated at 0.00404, or approximately 1.47 days lost of high-quality life per year.22 Insulin, in contrast, is associated with a high treatment burden of 0.05 (equivalent to 18.2 days of high-quality life lost per year). The age of introduction of treatment is another important consideration because treating affected individuals who are younger leads to greater gain of lifetime quality-adjusted life years.22 It is therefore most reasonable to target younger individuals for preventive therapy, with a drug that has a low medication disutility. This is likely to lead to more net benefit than treating

Figure 1. Natural history of prediabetes and diabetes.

Khetan and Rajagopalan Prediabetes

A

617

B

C

Figure 2. Reversing the course of diabetes. Natural history of prediabetes (A) without interventions, (B) with interventions successful in decreasing progression from prediabetes to diabetes, and (C) with interventions that restore and maintain normoglycemia. Rx, prescription. Modified from Phillips et al.17 with permission from the American Diabetes Association. Copyright ª 2014 American Diabetes Association. All rights reserved.

1.0

study in low-risk overweight diabetic patients, in which the the median follow up of 9.6 years might have been insufficient to see a mortality benefit.34 In all of these studies, subjects were recruited on the basis of an impaired glucose tolerance test. In 2011, the Zensharen study showed that patients with isolated impaired fasting glucose (5.5-7.0 mmol/L), who did not have impaired glucose tolerance or hemoglobin A1c > 5.6%, had a much lower rate of diabetes incidence during follow-up, which was not significantly improved with lifestyle intervention.28 This might represent an example in which inclusion of a low-risk patient

Prevention of Type 2 Diabetes There are multiple approaches to preventing diabetes, with comprehensive lifestyle intervention and metformin being the best studied. Major randomized lifestyle intervention trials are summarized in Table 2.26

65

55

75

QALYs gained from treatment

−0.5

The Da Qing study, published in 1997, was the first study to show that diet and/or exercise-based interventions can reduce progression from prediabetes to diabetes.30 Two other major studies that followed, the Finnish diabetes prevention program (2001) and the US DPP (2002) had similar results.25,31 In the DPP trial, a 5-kg weight loss over time accounted for 55% reduction in the risk of diabetes over the mean of 3.2 years of follow-up in this high-risk population. All 3 studies showed that lifestyle interventions can not only reduce the progression from prediabetes to diabetes during the period of active intervention, but showed sustained benefit for many years afterward; 13 years in the Finnish study, 15 years in the US study, and 20 years in the Da Qing study, respectively.18,24,32 Moreover, in the Da Qing study, upon 23 years of follow-up there was a significant reduction in all-cause mortality and cardiovascular mortality.23 The all-cause and cardiovascular mortality curves started to separate after 10-12 years of follow up, and became statistically significant at the 23-year mark. Considering that serious complications and cardiovascular risk from T2DM take years to develop, the delayed appearance of a mortality benefit is hardly surprising.33 Moreover, these results might also help explain the lack of a mortality benefit in other intensive lifestyle studies such as the Look Action for Health in Diabetes (Look AHEAD)

45

0.5

Comprehensive lifestyle intervention

Age at Diagnosis

0.0

older individuals with multiple medications (including insulin) that have a high medication disutility (Fig. 3). From a practical perspective, for early identification of patients with prediabetes at highest risk for cardiovascular complications, the incorporation of subsets might be reasonable. These include features of insulin resistance such as marked visceral adiposity (increased waist circumference or waist/hip ratio), ethnicity (Asian American and Hispanic ethnicity), and surrogate markers associated with high cardiovascular risk including elevated coronary artery calcium score and hepatic steatosis.

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Patient Treatment Burden (QALYs per year of use)

Figure 3. Glycemic dysutility. Quality-adjusted life years (QALYs) gained with a 1% reduction in hemoglobin A1c level (8.5% to 7.5%) across age and burden of treatment. Modified from Vijan et al.32 with permission from JAMA Internal Medicine. Copyright ª 2014 American Medical Association. All rights reserved.

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Canadian Journal of Cardiology Volume 34 2018

Table 2. Major randomized lifestyle intervention trials Study

Location (year)

n

Intervention

Duration of intervention

Results

Da Qing study

China (1997)

577

4 groups: control, diet, exercise, or diet and exercise. Participants were counselled every 3 months

6 years (1986-1992)

Finnish T2DM prevention study24

Finland (2001)

522

Diet and exercise. After 2 years, the intervention group achieved a mean weight loss of 3.5 kg

4 years (median)

US (2002)

3234

3 groups: placebo, metformin (850 mg daily), or ILI

2.8 years (average)

Prevention of T2DM by lifestyle intervention26

Japan (2005)

458

Intervention (2.1 kg weight loss) vs control (0.4 kg weight loss; P < 0.001). Lifestyle counselling every 3-4 months

4 years

Indian diabetes prevention program-127

India (2006)

531

4 groups: control, lifestyle, metformin (250 mg BID), or metformin and ILI. Personal visits every 6 months, phone call every month

2.5 years (median)

Zensharen study28

Japan (2011)

641

Intervention vs control; 9 visits in LSM group over 3 years

3 years

Mobile phone messaging29

India (2013)

537

Mobile phone messaging vs standard care (lifestyle advice at baseline only)

20.2 months (mean)

30%-40% reduction in T2DM incidence in all 3 treatment arms at the end of the intervention. At 23 years of follow-up, the HR for CV mortality was 0.59 (95% CI, 0.36-0.96; P ¼ 0.033), whereas the HR for all-cause mortality was 0.71 (95% CI, 0.51-0.99; P ¼ 0.049) 58% reduction in T2DM incidence after 3.2 years of follow-up. At 13 years of follow-up, the HR for diabetes was 0.61 (95% CI, 0.478-0.789; P < 0.001) Compared with placebo, T2DM incidence reduced by 58% in the ILI group and 31% in the metformin group, after 2.8 years of follow-up 9% incidence of T2DM in the control group, vs 3% in the intervention group. Reduction in BMI only partly accounted for the reduced T2DM incidence in the intervention group T2DM incidence in intervention groups 40%, compared with 55% in control (3-year follow-up). No added benefit of combining ILI and metformin. Lifestyle intervention reduced diabetes risk independent of weight loss 16.6% incidence of T2DM in the control group, vs 12.2% in the intervention group (HR, 0.56; 95% CI, 0.360.87). HR 0.41 for patients with IGT, HR 0.24 for patients with HbA1c > 5.6%. HR 1.17 for patients with isolated IFG 18 incidence of T2DM in the treatment group, vs 27% in the control group (HR, 0.64; 95% CI, 0.45-0.92; P ¼ 0.015). NNT of 11

23

Diabetes prevention program25

BID, twice daily; BMI, body mass index; CI, confidence interval; CV, cardiovascular; HbA1c, hemoglobin A1c; HR, hazard ratio; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ILI, intensive lifestyle intervention; LSM, lifestyle modification; NNT, number needed to treat; T2DM, type 2 diabetes mellitus; US, United States.

population with low levels of insulin resistance might represent a subset who might not respond as well to lifestyle intervention. Pharmacological therapies Major randomized trials involving pharmacological agents for prevention of diabetes are summarized in Table 3.46 Metformin. Metformin was first studied in the DPP in 2002, which showed that compared with placebo, metformin

reduced the incidence of diabetes mellitus by 31% over 2.8 years of follow-up at a dose of 850 mg once daily. Importantly in the DPP study, metformin was inferior to lifestyle intervention (goals of at least a 7% weight loss and at least 150 minutes of physical activity per week, which was accomplished through an intensive program of coaching, frequent contact, and supervised physical activity, all of which was individualized), which reduced incidence of T2DM by 58% (95% confidence interval [CI], 48%-66%). Over a period of 3 years, whereas 13.9 persons would have to receive metformin, only

Class of drugs

Study 35

Location (year)

DREAM36

International (2006)

Indian Diabetes Prevention Program-237

Duration of intervention

Troglitazone vs placebo. Women with previous gestational DM were enrolled

2.5 years

5269

Rosiglitazone (8 mg daily) vs placebo

3 years

India (2009)

407

3 years

CANOE38

Canada (2010)

207

LSM and pioglitazone vs LSM and placebo 2 groups: rosiglitazone (2 mg BID) and metformin (500 mg BID) vs placebo

ACT NOW39

US (2011)

602

STOP-NIDDM40

International (2002)

Voglibose for prevention of DM41

Japan (2009)

Insulin

ORIGIN42

International (2012)

12,537

Incretin-based

SCALE43

International (2015)

Others

XENDOS44

NAVIGATOR45

Alpha glucosidase inhibitors

US (2002)

Intervention

266

Thiazolidinediones

TRIPOD

n

3.9 years

Pioglitazone vs placebo

2.4 years

1429

Acarbose (100 mg TID) vs placebo

3.3 years

1780

Voglibose (0.2 mg TID) vs placebo

48 weeks

DM/prediabetes and CV risk factors enrolled (11.6% patients had prediabetes). Insulin glargine vs placebo

6.2 years

3731

Overweight patients enrolled (61% had prediabetes); liraglutide (3 mg daily) vs placebo

56 weeks

Sweden (2004)

3305

Overweight patients enrolled (21% had prediabetes); orlistat and LSM vs placebo and LSM

4 years

International (2010)

9306

2  2 factorial design: nateglinide vs placebo, valsartan vs placebo

5 years

Results 5.4% T2DM incidence in treatment group, vs 12.1% in placebo group. Benefit mediated by preservation of b-cell function, because insulin resistance was reduced 11.6% T2DM incidence in treatment group, vs 26.0% in placebo group. Significantly increased heart failure in treatment group 30% incidence of T2DM in both groups, no benefit of pioglitazone 14% T2DM incidence in treatment group, vs 39% in placebo (66% relative reduction). NNT of 4, no significant increase in adverse effects 2.1% T2DM incidence in treatment group, vs 7.6% in placebo. Significantly increased weight gain and edema in treatment group 32% T2DM incidence in treatment group, vs 42% in placebo. Increased flatulence and diarrhea with acarbose 5.6% T2DM incidence in treatment group, vs 12.0% in placebo Patients in the insulin arm were 28% less likely to have T2DM, 2 year passive follow-up showed a legacy effect, with a significant difference persisting. No difference in CV outcomes Among those with prediabetes at baseline, 69.2% had normoglycemia in treatment group, vs 32.7% in control group Among those with prediabetes at baseline, 8.3% developed diabetes in the orlistat arm vs 14.2% in the placebo arm (HR, 0.48). Increased weight loss with orlistat (5.8 vs 3.0 kg with placebo; P < 0.001) Nateglinide did not decrease risk of diabetes. Valsartan modestly reduced incidence of diabetes (33.1% vs 36.8%; HR, 0.86; 95% CI, 0.80-0.92; P < 0.001)

Khetan and Rajagopalan Prediabetes

Table 3. Major T2DM prevention trials using drugs

ACT NOW, Actos Now for Prevention of Diabetes; BID, twice per day; CANOE, Canadian Normoglycemia Outcomes Evaluation; CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; HR, hazard ratio; LSM, lifestyle modification; NNT, number needed to treat; ORIGIN, Outcome Reduction With Initial Glargine Intervention; SCALE, Satiety and Clinical Adiposity d Liraglutide Evidence in Nondiabetic and Diabetic Individuals; STOP-NIDDM, Study to Prevent NIDDM Trial; T2DM, type 2 diabetes mellitus; TID, 3 times per day; TRIPOD, Troglitazone In the Prevention Of Diabetes trial; US, United States; XENDOS, Xenical in the Prevention of Diabetes in Obese Subjects. 619

620

6.9 persons would have to participate in the lifestyleintervention program to prevent 1 case of diabetes. Subsequently, the Indian Diabetes Prevention Programme1 in 2006 showed that in a leaner, younger, and more insulin-resistant Asian Indian population, metformin reduced the relative risk of T2DM by 26.4% (95% CI, 19.1-35.1; P ¼ 0.029) after 3 years of follow-up.27 Although lifestyle modification as well as metformin groups showed similar reduction in diabetes incidence, additional use of metformin with lifestyle modification did not yield any additional benefit. Of note, in this study metformin was used at a lower dose of 250 mg twice daily. Thiazolidinediones. Thiazolidinediones have a long history of use in insulin resistance. These drugs have been recognized for > 2 decades as excellent insulin sensitizers. Troglitazone was the first drug in this class to be studied as the fourth arm of the DPP study. However, because of hepatotoxicity, this arm was discontinued early. Subsequently rosiglitazone and pioglitazone were studied intensively in prospective randomized controlled clinical trials. In the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial (2006), the first large multinational diabetes prevention trial, rosiglitazone (8 mg daily) significantly reduced the incidence of T2DM (hazard ratio, 0.40; 95% CI, 0.35-0.46; P < 0.0001), with 50% of individuals in the treatment group achieving normoglycemia, vs 30% in placebo arm.47 However, there was a significant increase in heart failure in the treatment group (0.5% vs 0.1%; P ¼ 0.01). Also mean body weight was increased by 2.2 kg more in the rosiglitazone group than in the placebo group (P < 0.001). In the much later CANOE trial (2010), patients with impaired glucose tolerance were randomized to lower dose rosiglitazone (2 mg twice per day) combined with metformin vs placebo, leading to a similar 66% relative reduction in T2DM incidence, but without any significant increase in adverse effects.38 Importantly, the absolute risk reduction was 26% (range, 14%-37%), yielding a number needed to treat of 4 (range, 2.70-7.14). In a follow-up study of DREAM, after a median of 1.6 years after the end of the trial, a similar incidence of the primary outcome of diagnosis of diabetes or regression to normoglycemia was observed; a pattern suggestive of a delay in the development of T2DM rather than a disease-modifying preventive effect.48 These findings are also consistent with a detailed substudy in CANOE, in which a number of glycemic parameters were studied every year for the entire duration of the study. Glycemic parameters and insulin sensitivity improved in the rosiglitazone/metformin arm in year 1, but deteriorated in the years thereafter, similar to the placebo arm.49 The Actos Now for Prevention of Diabetes (ACT NOW) study (2011), conducted in the United States, showed that pioglitazone significantly reduced the incidence of T2DM, albeit at the cost of weight gain (3.9 kg vs 0.77 kg; P < 0.001) and edema.39 However, the Indian Diabetes Prevention Programme-2 (2009) study reported that pioglitazone (mean dose of 30 mg) had no additional benefit beyond that gained from lifestyle modification.37 Because the ACT NOW study did not have a lifestyle modification component, the effect of pioglitazone might be truly attenuated by lifestyle

Canadian Journal of Cardiology Volume 34 2018

modification in the Indian study. Alternatively, ethnic differences or compliance issues (the weight gain with pioglitazone was modest compared with previous studies) could possibly account for the differences. The concerns related to bladder cancer (which seems to not to be a valid concern for the most patients), fluid retention at higher doses and attrition of effect with discontinuation have prevented the widespread use of thiazolidinediones.50,51 Incretin-based therapies. The Satiety and Clinical Adiposity e Liraglutide Evidence in Nondiabetic and Diabetic Individuals (SCALE) trial showed that liraglutide (3 mg subcutaneous injection daily) in overweight patients can lead to significant weight loss (difference of 5.6 kg; 95% CI, 6.0 to 5.1; P < 0.001, at week 56; 63.2% and 33% of liraglutide group lost at least 5% or 10% of body weight compared with 27.1% and 10.6%, respectively in the placebo group; P < 0.001), with corresponding improvement in metabolic parameters, including lower incidence of prediabetes and diabetes.43 Six other smaller studies (2 with DPP-4 inhibitors, 4 with glucagon-like peptide-1 analogues), with a total of 417 participants, had too few events to make meaningful conclusions and were judged to be of very low quality in a recent Cochrane review.52 The DPP-4 inhibitors are attractive drugs for the prevention of T2DM because of the overall safety of these drugs (no weight gain or hypoglycemia). Other drugs. Alpha glucosidase inhibitors, acarbose and voglibose, which act by inhibiting the absorption of carbohydrates have both been shown to reduce progression to diabetes.40,41 In addition, acarbose reduces risk of myocardial infarction (hazard ratio, 0.09; 95% CI, 0.01-0.72; P ¼ 0.02).53 Orlistat, when used in addition to lifestyle modification, can result in additional weight loss (5.8 vs 3.0 kg with placebo; P < 0.001) and reduction in progression to diabetes.44 In the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, basal insulin showed a modest reduction in progression to diabetes from prediabetes, however, it was accompanied by significant weight gain and hypoglycemia, which are unacceptable for a prevention drug.42 In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which had a 2  2 factorial design, nateglinide, a short acting insulin secretagogue, showed no reduction in the incidence of diabetes whereas valsartan showed a modest reduction in the incidence of diabetes.45,54 The results from NAVIGATOR complement the findings of DREAM, which showed that ramipril significantly increased regression to normoglycemia, although that did not translate to decreased incidence of diabetes.36 Intensive insulin therapy. In early T2DM, IIT for a short duration (2-4 weeks) can lead to remission of T2DM in 80% of recipients.20 A systematic review in 2013 found 7 studies (2 randomized controlled trials) that studied short term IIT in T2DM, and reported that 46% of patients maintained drugfree remission at 12 months (42% at 2 years).19 Although it is well known that b-cell dysfunction contributes to worsening glycemic control, glucotoxicity and lipotoxicity can lead to further b-cell dysfunction.55 A study in China compared a

Khetan and Rajagopalan Prediabetes

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strategy of using IIT or oral hypoglycemic agents to achieve and maintain normoglycemia in type 2 diabetic patients for 2 weeks, after which treatment was discontinued and patients were maintained using diet and exercise alone.56 At 1 year, remission rates were significantly higher in the continuous subcutaneous insulin arm (51.1%) compared with the oral hypoglycemic agents arm (26.7%; P < 0.00001). One of the strongest predictors of successful remission of diabetes with IIT is early intervention, particularly if the duration of diabetes is < 2 years.57

2. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017;128:40-50.

Metabolic surgery

5. Ekoe J-M, Punthakee Z, Ransom T, et al. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada: screening for type 1 and type 2 diabetes. Can J Diabetes 2013;37:S12-5.

Although multiple studies have shown regression of T2DM when obese patients (body mass index [BMI] > 30) with diabetes undergo bariatric surgery, no study has specifically evaluated a population with prediabetes.58 We found one study that reported outcomes in obese participants (BMI 30-35) with metabolic syndrome.59 In this study, 80 obese patients were randomized to laparoscopic adjustable gastric band vs lifestyle modification; 38% in each group had metabolic syndrome. At 2 years, the surgical group had significantly more weight loss than the control group. Moreover, the prevalence of metabolic syndrome decreased to 23% (8 patients) in the control group, vs 3% (1 patient) in the surgical group (P < 0.002). Obesity guidelines in Canada note that emerging data suggest bariatric surgery could play a role in obese patients (BMI 30-35) with comorbidities, however highlight the need for further investigation.60 More recent US guidelines make a grade C recommendation to offer bariatric surgery to obese patients (BMI > 30) with metabolic syndrome.61 Conclusions Despite the well-established evidence base for treatment of prediabetes, there is substantial under-recognition and undertreatment of the problem. There is high-quality evidence for lifestyle intervention and selected drugs in the prevention of T2DM. The introduction of incretin-based therapies will allow additional options for the prevention of T2DM in patients at high risk for progression. The optimal time to intervene is at the stage of impaired glucose tolerance/ impaired fasting glucose with early and complete restoration of normoglycemia. The option of waiting until diabetes emerges and to initiate therapy at that stage, rather than treating individuals with prediabetes in lieu of the risks and costs is no longer valid, because of the variety of low-risk options. The real world translation of the evidence for diabetes prevention arguably represents the biggest opportunity to stem the pandemic of diabetes and improve global cardiovascular health. Disclosures The authors have no conflicts of interest to disclose. References 1. Rose G, et al. The Strategy of Preventive Medicine. United Kingdom: Oxford University Press, 1992.

3. Canadian Diabetes Association (Canada). The cost of diabetes in Canada. Available at: http://www.diabetes.ca/CDA/media/documents/publicationsand-newsletters/advocacy-reports/economic-tsunami-cost-of-diabetes-incanada-english.pdf. Accessed March 21, 2018. 4. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta GA: Department of Health and Human Services, 2014.

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