Prevention or Delay of type 2 Diabetes Mellitus

Identifying individuals at increased risk 

Defining categories of increased risk for diabetes

Epidemiology of risk

Clinical trials for the prevention of type 2 diabetes

The role of lifestyle modification in diabetes prevention/delay

The role of pharmacological therapy in diabetes prevention/delay

Recommendations

The management of obesity for the prevention of prediabetes

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(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations
All persons with multiple risk factors for diabetes should be offered structured education regarding diabetes prevention and be offered a screening test for type 2 diabetes. (See: Screening and Diagnosis of type 2 Diabetes and Intermediate Hyperglycaemia)	A
Offer intensive interventions supporting lifestyle changes to prevent/delay the onset of T2DM in high-risk adults (those with IFG/IGT). These interventions are cost-effective and should be supported by public health policies and 3rd party payers	A
Offer intensive lifestyle interventions as part of a structured programme that is based on proven principles. Use this to support the individual with IGT/IFG to: 1. Achieve and maintain weight loss >5% 2. Modify dietary patterns focusing on: a. Reducing energy from fat to ≤30% b. Reducing energy from saturated fat to ≤10% c. Increasing fiber intake ≥15 g/1 000 kcal 3. Increase moderate intensity physical activity ≥ 150 minutes per week  Frequent contact and follow-up improves intervention success	A
Consider metformin for individuals who have deteriorating FPG or 2-h PG after 6 months, and: 1. Have participated in an intensive lifestyle intervention programme, or 2. Have been unable to participate in an intensive lifestyle intervention programme Especially those who: a. Are less than 60 years old b. Have a history of gestational diabetes c. Have a BMI > 35 kg/m2 d. Have combined IFG and IGT e. Have the metabolic syndrome Continue to support the individual with intensive lifestyle interventions	A
Monitor IFG/IGT every 6-12 months and intensify lifestyle interventions and the metformin dose if blood glucose does not improve. If metformin is ineffective consider an alternative drug (acarbose or orlistat)	B
Persons with IFG/IGT must be screened for other cardiovascular risk factors, including metabolic syndrome (See: Cardiovascular Risk and the Management of Dyslipidaemia in Patients with Type 2 Diabetes Mellitus). These risk factors must be managed optimally	A

INTRODUCTION

Diabetes is a worldwide pandemic associated with significant morbidity and mortality. The global incidence of diabetes is projected to increase to 642 million by 2040.¹ 

Early detection of those at risk for the development of diabetes and early intervention strategies can prevent the progression to diabetes and its associated microvascular and macrovascular complications. 

This section focuses on diabetes prevention in easily defined groups at high risk for progression to type 2 diabetes i.e those with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), as prospective randomised prevention trials have focused almost exclusively on this group.

IDENTIFYING INDIVIDUALS AT INCREASED RISK

The risk factors for the development of diabetes are listed in Screening and Diagnosis of type 2 Diabetes and Intermediate Hyperglycaemia and is duplicated here for convenience in Table I.

Multiple scoring systems exist for predicting risk and to identify individuals for diabetes screening; however these tend to be ethnic specific and not universally applicable.² There is no risk scoring system available for South Africa. 

IFG and IGT are categories of intermediate hyperglycaemia which easily and clearly define individuals and populations at high risk for progression to diabetes and cardiovascular disease (CVD), and therefore represent a group that can and have been targeted for prevention strategies. 

This does not imply that individuals without IFG or IGT, who have other risk factors listed in Table I are not at risk, and they should also be targeted with lifestyle interventions for prevention. The ideal method of identifying people at highest risk for diabetes and CVD would be a risk assessment tool which uses all the risk factors in Table I, and includes plasma glucose as a continuous variable rather than a categorical one; this has not been developed yet.

Table I: Risk factors for type 2 diabetes³

Age >45 years

All adults at any age who are overweight (BMI> 25 kg/m2 or > 23 kg/m2 in Asians), plus one or more additional risk factors:   Previous IFG or IGT Physical inactivity High-risk race/ethnicity (Asian and Coloured) First degree relative with diabetes History of cardiovascular disease Hypertension [Blood pressure (BP) ≥ 140/90 mmHg] or treatment for hypertension Dyslipidaemia (low HDL and/or high triglycerides) Polycystic ovarian syndrome History of gestational diabetes or having delivered a baby > 4 kg Other conditions associated with insulin resistance (e.g. severe obesity, acanthosis nigricans)

An OGTT is preferred in high risk individuals as it is a more sensitive test, and is the only method to diagnose IGT which is a strong risk factor for CVD.

DEFINING CATEGORIES OF INCREASED RISK FOR DIABETES

The diagnosis of IFG and IGT have been discussed in Weight Management in type 2 Diabetes. In summary plasma glucose as a risk factor for future diabetes is a continuous variable, meaning that the higher the plasma glucose, even in the so-called normal range, the higher is the risk for future diabetes. 

The cut-points that define IFG (6.1 to 6.9 mmol/L) and IGT (2-h PG 7.8 to 11.0 mmol/L) are arbitrary cut-points that define higher risk based on, inter-alia, the feasibility of public health interventions. In this regard, the ADA has chosen to define IFG using a lower cut-point (FPG 5.6 to 6.9 mmol/L) for intervention. 

The ADA has also chosen to include HbA_1c values in the abnormal but non-diabetic range (5.7 to 6.4%) in the category of prediabetes, together with IFG and IGT. SEMDSA has aligned itself with the WHO position which is to retain the FPG cut-point of 6.0 mmol/L for IFG and to not include HbA_1c to define intermediate hyperglycaemia. 

Rather, a FPG or 2-h PG measurement is recommended for individuals with HbA_1c 5.7% to 6.4% when intervention is planned. The term prediabetes, when used, will refer to the two categories of intermediate hyperglycaemia namely IFG and IGT. The measurement of insulin levels plays no role in the assessment of prediabetes in clinical practice.

EPIDEMIOLOGY OF RISK

According to an ADA expert panel, the lifetime risk of people with IFG or IGT developing diabetes was 70%.² A meta-analysis of prospective studies showed that the annual incidence of diabetes in individuals with isolated IFG or IGT was 6-9% and 4-6% per year respectively. 

The incidence in persons with both IFG and IGT was significantly higher (15-19%/year).⁴ Another meta-analysis of prospective studies reported that the rates of progression to diabetes (number per 1000 person-years) for the categories HbA_1c 6.0-6.4%, ADA defined IFG, WHO defined IFG, IGT and combined IFG+IGT was 35.6, 35.5, 47.4, 45.5 and 70.4 respectively.

In South African Indians with IGT, the annual incidence of diabetes was found to be 12.6% per year over four years.⁵ Women with a history of gestational diabetes also have a particularly high risk of progressing to diabetes (20-60% over the 5 to 10 years after the pregnancy).² 

The South African National Health and Nutrition Examinations Survey (SANHANES) in 2012 determined that the national prevalence of HbA_1c values between 6.0 to 6.4% is 8.9% for the population older than 15 years, representing about 5 million individuals at risk for diabetes. In this regard it is noteworthy that HbA_1c in this range identifies a much smaller population with prediabetes than do IFG and IGT.⁶

IFG and IGT are also risk factors for CVD. A meta-analysis of 53 prospective cohort studies with 1 611 339 individuals followed over 9 years reported that the relative risk (RR) for composite cardiovascular endpoints was ~1.3 for either IFG or IGT. All cause mortality was significantly higher for IGT compared to IFG.⁷ The metabolic syndrome (See: Cardiovascular Risk and the Management of Dyslipidaemia) is an independent risk factor for CVD (RR 2.0) so it follows that individuals with IFG/IGT with the metabolic syndrome are equally at high risk.^8,9

CLINICAL TRAILS FOR THE PREVENTION OF TYPE 2 DIABETES 

A number of well-designed intervention studies using lifestyle (diet and exercise) or drug therapy have been conducted. Trials that implemented lifestyle modification only such as the Finnish Diabetes Prevention Study (DPS) and the Chinese Da Qing Study have both conclusively shown that the development of type 2 diabetes in people with pre-diabetes can be prevented by making changes in the diet to promote moderate weight loss, and by increasing their level of physical activity.^10,11

The Finnish DPS established a precedent for effectively altering lifestyle in patients with a high risk for diabetes. It studied 522 subjects with IGT using the 1999 WHO criteria (FPG < 7.8 mmol/l; 2 hrs post glucose load 7.8-11.1 mmol/l). The intensive lifestyle modification group showed a 58% relative risk reduction in the progression to diabetes as compared to controls, and continued effects were seen as a result of lifestyle change.¹⁰

In the Da Qing study, 577 Chinese subjects with IGT were randomised for 6 years either to a control group, dietary intervention, exercise, or a combination of diet and exercise,and followed over 6 years. Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (HR 0.49; 95% CI 0.33-0.73) during the active intervention period and a 43% lower incidence (HR 0.57; 0.41-0.81) over a 20 year period.^11,12

After 23 years of followup they were able to show that mortality in this group with IGT was related to progression to diabetes; delaying the diagnosis of diabetes was associated with lower mortality.¹³ Thus, a 6-year lifestyle intervention showed the long-term clinical benefits for patients with IGT and provides further justification for adoption of lifestyle interventions.

Other trials have implemented pharmacological interventions and/or lifestyle interventions to delay or prevent the onset of diabetes and these include, the U.S-based Diabetes Prevention Program (DPP),¹⁴ the Troglitazone in Prevention of Diabetes Trial (TRIPOD),^15,18 Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial,¹⁹ the STOP-NIDDM Trial,²⁰ the Indian Diabetes Prevention Programme (Indian DPP),²¹and the Actos Now for Prevention of Diabetes (ACT Now) trial.²²

The US-DPP investigated the efficacy of intensive, behavioural lifestyle modification using individualised and group therapy to achieve and maintain >7% body weight loss and physical activity equivalent to at least 150 min/week of moderate intensity exercise.^1,2,3,4,15 

After 2.8 years, lifestyle intervention decreased the incidence of type 2 diabetes by 58% compared with 31% in the metformin-treated group. The DPP Outcomes Study (DPPOS) followed up surviving participants from the DPP. 

The the original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin. During a mean follow-up of 15 years, diabetes incidence was reduced by 27% in the lifestyle intervention group (<0·0001) and by 18% in the metformin group (p=0·001), compared with the placebo group. 

At year 15, the cumulative incidences of diabetes were 55% in the lifestyle group, 56% in the metformin group, and 62% in the placebo group. Lifestyle intervention or metformin significantly reduced diabetes development over 15 years and supports the strategy of diabetes prevention.²³

The Indian DPP study reported a 28.5% relative risk reduction in progression to diabetes with lifestyle intervention and a 26.4% reduction with metformin 250 mg twice daily versus controls. This dose of metformin when added to lifestyle modification, yielded no further benefit for progression to diabetes.²¹

The TRIPOD (TRoglitazone In the Prevention Of Diabetes) study in Hispanic women with GDM showed a reduction of 55% after 30 months, which was maintained at 8 months following discontinuation of the drug.

The STOP-NIDDM (Study to Prevent Non-Insulin Dependent Diabetes Mellitus) showed a 25% relative reduction of developing diabetes in those treated with acarbose versus placebo after 3.3 years. The trial also showed that targeting postprandial hyperglycaemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events.²⁴

Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension.²⁴ However, 31% of patients in the acarbose arm withdrew due to side-effects and the number of CV events was low.²⁰ In a placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT).  Nevertheless the results remain significant.

The XENDOS (XENical in the prevention of Diabetes in Obese Subjects) showed a relative reduction of 37.3% in those treated with orlistat and lifestyle modification versus placebo; the best reduction was noted in the IGT group where the incidence of diabetes was reduced by 45% over 4 years.²⁵

The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) showed a reduction of 60% in those treated with rosiglitazone (but an increase in oedema and heart failure) versus ramipril and placebo after 3 years.¹⁹

The ACT NOW (ACTos NOW for the prevention of diabetes) study showed a reduction in the risk of conversion to diabetes of 72% versus placebo over 2.4 years.²² More recently, in a study of people without diabetes but with insulin resistance and cerebrovascular disease, pioglitazone halved the progression to type 2 diabetes. Concerns with the side effects of pioglitazone (more oedema, weight gain and higher fracture rate) compared to placebo still remain.^22,26

Table II: Summary of trials for prevention of Type 2 diabetes

STUDY, n, type	THERAPY	RELATIVE RISK REDUCTION
Finnish Diabetes Prevention Study (FDPS), n=522, RCT	Diet + Exercise	58%
Da Qing Study, n=577, RCT	Diet Exercise Diet + Exercise	31% 46% 42% (51%)
US-Diabetes Prevention Program (DPP) n= 1079, RCT	Diet + Exercise Metformin 850mg bd	58% 31%
Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM), n=5269, RCT	Rosiglitazone + Diet + Exercise + Ramipril	60%
Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP- NIDDM) trial, n=1418, RCT	Acarbose	25%
Actos now (ACT NOW) for prevention of Diabetes Study, n=602, RCT	Pioglitazone	81%
Indian DPP, n=531, RCT	Diet + Exercise Metformin 250mg bd Diet, Exercise + Metformin 250mg bd	28.5% 26.4% 28.2%

THE ROLE OF LIFESTYLE MODIFICATION IN DIABETES PREVENTION/DELAY

Interventions supporting lifestyle changes delay the onset of T2DM in high-risk adults and are very effective; the number needed-to-treat to prevent one new case of diabetes is 6.4 over 1.8–4.6 years.²⁴ The DPP lifestyle intervention has been criticised for being too intensive and expensive, yet cost analyses show it to be very cost-effective.²⁸ In fact transitional research examining the implementation of lifestyle intervention programmes in the “real-world” setting, using less intensive approaches and scalable models for intervention such as group interventions have consistently demonstrated their effectiveness and cost effectiveness.^29,30

The key components of effective and successful lifestyle intervention programmes for the prevention of diabetes have included:

1. Weight management in overweight and obese individuals with the aim of achieving and maintaining a >5% weight loss by reducing caloric intake. Lesser degrees of weight loss are still beneficial. Data from the U.S. DPP study showed that each kilogram of mean weight loss is associated with a reduction of ∼16% in future diabetes incidence. Real-world data showed mean weight loss of -2.6% over 12 months was beneficial.²⁹
2. Key dietary changes which are beneficial independent of weight loss:
   • a. Reduce energy from fat to ≤30%
   • b. Reduce energy from saturated fat to ≤10%
   • c. Increased fiber intake ≥15 g/1 000 kcal
3. Increase moderate intensity physical activity (e.g. brisk walking) to ≥30 min/day or 150 minutes per week 

Success of a lifestyle intervention programme is directly related to the degree in which the programme is structured, and adheres to the suggested dietary and exercise guidelines, programme intensity (frequency of contact), and the degree of uptake by the community.^29,30 However, even low intensity programmes that lead to only moderate weight loss can still have a considerable impact in lowering diabetes risk in a population. From a public health perspective, this is an important finding, especially for resource constrained settings.³¹

The strategies for supporting successful behaviour change and the healthy behaviours recommended for people with prediabetes are largely identical to those for people with diabetes. Given their training and experience, providers of DSME and DSMS are particularly well equipped to assist people with prediabetes in developing and maintaining behaviours that can prevent or delay the onset of diabetes. 

Evidence from studies in low/middle income countries show that structured lifestyle education programmes delivered by allied health professionals (e.g. nurses, pharmacists), can be as effective as those led by clinicians.³¹ In addition, group delivery of intensive lifestyle intervention content in community settings can reduce overall programme costs while still producing weight loss and diabetes risk reduction.³²

THE ROLE OF PHARMACOLOGICAL THERAPY IN DIABETES PREVENTION/DELAY 

The exact role of drug therapy in the prevention of diabetes remains unclear. Controversial issues include the duration of drug therapy and whether drugs alter or reverse the underlying disease process and actually prevent progression to diabetes, as opposed to delaying or masking it. 

Data from the studies above indicate that benefit from glucose lowering drugs is lost when the treatment is stopped, implying that treatment may need to be taken indefinitely. The ideal drug for diabetes prevention should be safe, effective, inexpensive, demonstrate reversal of the underlying pathophysiologic process and improve clinical outcomes such as cardiovascular morbidity and mortality.³³ 

Since none of the drugs studied thus far can fulfil these criteria, the mainstay of therapy still remains intensive lifestyle intervention with diet and exercise. Based on the available trials, four of the pharmacologic agents can be considered for the prevention of type 2 diabetes. These include metformin, acarbose, orlistat and pioglitazone. 

Pioglitazone is available as a generic and is relatively inexpensive. However side-effects such as weight gain and oedema and its cumulative effect over time on long bone fractures limit its use, (patients will need to take the drug for many years). Acarbose was very effective and reduced CV events, but the dropout rate in the STOP-NIDDM trial was very high because of the drugs poor GI tolerability. 

There is also no generic formulation and the drug remains expensive. Orlistat has the same limitations as acarbose i.e side-effects and cost. Metformin has strong evidence to support its use, has a long, proven safety profile, is well tolerated and is also the least expensive drug option. The evidence from the US-DPP showed clearly that intensive lifestyle modification was superior to metformin in preventing and delaying the progression to diabetes. 

Also, in the US-DPP there were identifiable subgroups with differential responses to metformin: 

• Persons older than 60 years did not benefit from metformin
• Persons with a BMI ≥ 35 kg/m² had a better response than those with a lower BMI
• In women with a history of gestational diabetes, metformin was as effective as intensive lifestyle intervention (50% reduction in progression)³⁴

In the Indian-DPP metformin 250 mg BD was as effective as lifestyle modification, which was less intensive than in the US-DPP.

RECOMMENDATIONS 

All persons with multiple risk factors for type 2 diabetes should receive education about lifestyle modification to prevent diabetes. Persons with IFG and/or IGT are at high risk for progression to diabetes and CVD, and should be offered structured intensive lifestyle interventions programmes with the aim of >5% weight loss, dietary modifications and at least moderate intensity exercise for >150 minutes per week.

IFG/IGT should be reassessed every 6-12 months and if the trajectory towards diabetes does not reverse, then pharmacological therapy should be considered.

Pharmacological intervention should be considered for subgroups a) who have a very high risk of progression to diabetes, or b) are known to derive particular benefit with metformin therapy. 

Metformin standard-release should therefore be considered for individuals who have deteriorating FPG or 2-h PG who:

a.Have been participating in an intensive lifestyle intervention programme 

OR

b. Have not been able to participate in an intensive lifestyle intervention programme

Especially if he/she:

• Is < 60 years old
• Has a history of gestational diabetes
• Has a BMI > 35 kg/m²
• Has both IFG and IGT
• Has the metabolic syndrome

The dose of standard-release metformin employed in the Indian DPP was 500 mg daily while the US-based DPP used 1700 mg daily, both in divided doses.^14,21 The individual will need to be counselled that the drug is being used “off-label”. Acarbose and orlistat are alternatives to using metformin but are more expensive. Follow the manufacturers directions for use.

Monitor the FPG and/or 2-h PG every 3 to 6 months and increase the dose if these are deteriorating. Stop therapy if there is no response and consider alternative therapies (acarbose, orlistat).

THE MANAGEMENT OF OBESITY FOR THE PREVENTION OF PREVENTION OF DIABETES

Retrospective data analysis from bariatric surgery trials have shown a significant reduction in the prevalence of type 2 diabetes and pre-diabetes among morbidly obese patients who have undergone bariatric surgery. However, in view of its costs, related morbidity and other long term effects, it cannot be recommended for the management of prediabetes alone.³⁵

High doses of liraglutide have also demonstrated reduction of the rates of prediabetes in a weight loss trial of obese subjects.³⁶ There are no published diabetes prevention trials with GLP-1 agonists compared to lifestyle intervention. The role of obesity in type 2 diabetes is discussed in Weight Management in type 2 Diabetes.

Authors: Pankaj Joshi and Aslam Amod
Editor: Imran Paruk

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