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Vol. 220. Issue 5.
Pages 305-314 (June - July 2020)
Vol. 220. Issue 5.
Pages 305-314 (June - July 2020)
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When does diabetes start? Early detection and intervention in type 2 diabetes mellitus
¿Cuándo empieza la diabetes? Detección e intervención tempranas en diabetes mellitus tipo 2
F. Gómez-Peraltaa,
Corresponding author

Corresponding author.
, C. Abreua, X. Cosb,c, R. Gómez-Huelgasd
a Unidad de Endocrinología y Nutrición, Hospital General de Segovia, Segovia, Spain
b Innovation and Health in Primary Care Barcelona City, Gerència Barcelona Ciutat, Institut Català de la Salut, Barcelona, Spain
c Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain
d Departamento de Medicina Interna, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga (UMA), Málaga, Spain
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Table 1. Individual factors of type 2 diabetes mellitus – prediabetes with high cardiovascular risk.

Type 2 diabetes mellitus (DM2) is a progressive disease whose pathophysiological changes occur several years before its detection. An approach based on the pathophysiological development of DM2 and its complications emphasises the importance of early and intensive intervention, not only to prevent beta-cell dysfunction but also to act on the potential associated cardiovascular risk factors before reaching the blood glucose thresholds currently set for diagnosing DM2. In the field of recently diagnosed DM2, the VERIFY study has shown that early treatment combined with metformin-vildagliptin provides relevant improvements in long-term glycaemic control and can positively affect the disease's progression.

Diabetes mellitus
Cardiovascular risk

La diabetes mellitus tipo 2 (DM2) es una enfermedad progresiva cuyos cambios fisiopatológicos se producen varios años antes de su detección. Un abordaje basado en el desarrollo fisiopatológico de la DM2 y sus complicaciones enfatiza la importancia de una intervención temprana e intensiva, no solo para prevenir la disfunción de las células β, sino también para actuar sobre los posibles factores de riesgo cardiovascular asociados antes de alcanzar los umbrales glucémicos fijados actualmente para el diagnóstico de la DM2. En el terreno de la DM2 de reciente diagnóstico, el estudio VERIFY ha mostrado que el tratamiento precoz combinado con metformina-vildagliptina proporciona mejoras relevantes en el control glucémico a largo plazo y puede influir positivamente en la evolución de la enfermedad.

Palabras clave:
Diabetes mellitus
Riesgo cardiovascular
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In recent years, the prevalence of type 2 diabetes mellitus (DM2) has continued to increase alarmingly, with a resulting increase in associated morbidity and mortality and the corresponding economic impact.1,2 The diagnosis and treatment of DM2 is frequently delayed with deleterious consequences. The mean delay from the start of microangiopathic complications to the diagnosis of DM2 has been estimated at 6–13 years.3 For macrovascular complications, this delay can be dramatically longer, revealing cardiovascular disease (CVD) risk factors 25 years before the definitive diagnosis.4

Data from the study conducted in Spain indicated that 5.3 million individuals (13.8% of the Spanish population older than 18 years) had DM2, 2.3 million of whom (43% of the total) might be unaware of the diagnosis.5 Other studies have shown that, even with confirmatory biochemical data in the previous year, a third of individuals with DM2 have not been informed of this diagnosis.6

It is currently known that the progressive loss of β-cell function and its claudication is the key element in the biochemical diagnosis. However, other important pathophysiological bases for DM2, such as insulin resistance and a proinflammatory state, start decades earlier and determine a marked increase in CVD risk factors at the time of diagnosis based on current biochemical criteria.7 Recognizing a dysglycemic state (“prediabetes”) between normal glucose tolerance and DM2,8 based mainly on biochemical criteria, represents an advance for the development of prevention programs. However, going beyond a purely glucocentric viewpoint of DM2, we should try to improve our detection of individuals with DM2 and, more specifically, those with a high CVD risk factors associated with this complex syndrome in earlier phases and through the use of additional parameters (genetic, additional biochemical and clinical). This approach would help reduce the associated morbidity and mortality, beyond the biochemical diagnosis of DM2.9

Moreover, progress has been made in developing various antidiabetic drugs; however, the metabolic control of patients remains deficient.1 Recent studies have shown that intensive therapy, which can be combined and multifactorial, can reduce long-term complications, avoiding the accumulation of risk known as “metabolic legacy”, even in individuals with a firm diagnosis.10 However, the real data indicate a delay of several years in therapy intensification to reach optimal control objectives.11,12

This approach, based on the pathophysiological development of DM2 and its complications, emphasizes the importance of early and intensive intervention, not only to prevent β-cell dysfunction but also to improve the associated CVD risk factors. This change in paradigm is expected to promote the development of new strategies for effectively controlling this pandemic disease.

Definition of diabetes and the epidemiology of its associated cardiovascular risk

DM2 is defined as a progressive disease characterized by insulin resistance and pancreatic β-cell failure, which results in a chronic hyperglycemic state.8 Diabetes mellitus affects approximately 451 million individuals worldwide, with a predicted increase by 2045 to almost 693 million; 87–91% of the cases will be diagnosed as DM2.1 This pandemic is worrying, because DM2 increases the risk of acute and chronic complications, deeply affects patients’ quality of life and represents a significant economic burden for the healthcare system.13

However, the risk resulting from arteriosclerotic damage begins to accumulate years before the diagnosis and with glycemic control values lower than those required for diagnosing diabetes. This is demonstrated by the epidemiological association between high CVD risk and HbA1c levels below 6.5%14,15 and fasting plasma glucose levels below 126mg/dL.16,17

Abnormal insulin secretion in DM2: associated genetic factors

The β-cell-centered model recognizes that the genetic predisposition to dysfunctional β-cells in the context of unhealthy life habits, leads to the loss of β-cell mass, which claudicate with insufficient insulin secretion for the requirements of a state of insulin resistance (Fig. 1). The genetic burden is attributed to polygenic variants (polymorphisms) that predispose patients to insulin resistance and impaired insulin secretion disorder18,19 and other more recently identified mechanisms such as susceptibility to environmental factors,8 immune system inflammation,20 physiological factors that increase the demand or damage β cells and a proatherogenic lipid profile.21 In particular, polymorphisms in gene TCF7L2 have been related to a progressive loss of insulin secretion and the development of DM2 due to an altered response to incretin hormones (GLP-1).22,23

Figure 1.

Mechanisms of progressive deterioration of β-cells in DM2 in the early stage and in the advanced stages.40,42–45

Abbreviation: FFA, free fatty acids.


However, the weight of known genetic factors in the development and progression of DM2 is limited compared with those derived from lifestyle habits. A prospective study with more than 5000 participants found that a greater genetic risk of diabetes was associated with an age 2.5years younger at the diagnosis of DM2 and was also associated with the start of insulin therapy 2.15years earlier.24 Given that the population had a mean age of 62years at the time of the diagnosis, the high-risk genetic profile does not seem to provide striking differences.

Metabolic disorders in DM2: diabetic dyslipidemia

Despite the fact that hyperglycemia is the distinctive manifestation of DM2, and its dependent biochemical values are the accepted for the diagnosis, the pathophysiological complex of insulin resistance/insulin deficiency translates into other intermediary metabolism alterations. Atherogenic or diabeticdyslipidemia is one of those disorders and confers a high CVD risk,25 appearing years before the glycemic abnormalities currently accepted for the diagnosis.4

Since the initial description of preventive medicine strategies, lipid markers such as hypertriglyceridemia, reduced HDL cholesterol levels and its quotient have been recognized as risk markers for prediabetes26 and its subsequent CVD risk factors.27

DM2 as a progressive disease: from prediabetes to diabetes

DM2 develops in individuals with a genetic or acquired predisposition to insulin resistance and β-cell dysfunction and who are exposed to factors such as excessive caloric intake, lack of exercise and other environmental factors. As a result, these individuals progress from normal glucose tolerance (NGT) to dysglycemia (impaired glucose tolerance and/or abnormal fasting glucose) and, ultimately, to established DM2.28 A number of authors have therefore proposed an approach focused on delaying the deterioration of glycemic control based on preserving β-cell function starting in the initial phases.29,30

In the phases prior to the diagnosis of diabetes, insulin resistance determines endogenous hyperinsulinism. This situation has specific clinical manifestations, including the polycystic ovary syndrome31 and idiopathic postprandial hypoglycemia,32 which precedes DM2 in a significant number of patients. These manifestations can be defined as “herald conditions” of DM2, along with gestational diabetes. The state of hyperinsulinemia promotes proatherosclerotic and procoagulant activity. There is therefore an increasingly obvious need for DM2 treatment directed not only to achieving euglycemia but also to changing the course of the disease, reversing the processes of insulin resistance and its consequences.

From an understanding of diabetes focused on glucose levels to one focused on the underlying pathophysiology and its associated cardiovascular risk

Currently, the diagnosis of diabetes is based on plasma glucose levels,33 and the diagnostic thresholds have been fixed according to the incidence of the microvascular complications of diabetes, including retinopathy.34 However, while the diagnostic criteria for DM2 are based on the risk of developing microvascular complications, it has been shown that individuals with abnormal baseline glucose levels and/or impaired glucose tolerance have a high risk of developing atherosclerotic CVD.35,36

The relationship between insulin sensitivity and insulin secretion in prediabetes

There have been several patient cohorts in which the progression of the prediabetic state to the development of DM2 has been analyzed. These studies have demonstrated that individuals with high insulin sensitivity rarely show abnormal glucose tolerance.37–40 Individuals with higher insulin resistance are still glucose tolerant only if their pancreas is capable of reacting with compensatory insulin hypersecretion. A partial compensatory hypersecretion characterizes individuals within the range of impaired glucose tolerance, while individuals with lower insulin secretion usually present DM2.41

Changes in β-cell overload during the development of DM2

In the initial stage, an increased demand for insulin secretion is produced under conditions of insulin resistance due to excess caloric intake, physical inactivity or obesity, producing a modest change in β-cell mass, which translates into an increase in the workload for individual β cells. In this compensatory phase, the resulting hyperinsulinemia, coupled with hypertension and dyslipidemia, promotes atherosclerosis. With time, this excess workload results in cell dysfunction and/or cell death, with a progressive reduction in the total functional mass of the β cells. Once the cell mass decreases, the workload on the residual β cells is exaggerated, creating a vicious cycle such that when these cells can no longer compensate, glycemic levels diagnostic of DM2 are reached, increasing the risk of microvascular complications. Therefore, an option for preventing both the micro and macrovascular complications would be to reduce the workload of the β cells during a stage prior to the onset of diabetes.41

The mechanisms of progressive deterioration of β-cell in DM2 are summarized in Fig. 2.

Figure 2.

Progressive development of type 2 diabetes. Abbreviations: CVDRFs: cardiovascular disease risk factors; DM2: type 2 diabetes mellitus; HBP: high blood pressure.

The importance of early treatment in DM2

Classical intervention studies have demonstrated the importance of glycemic control for reducing the risk of microvascular complications.46 New antidiabetic drugs have only recently been able to demonstrate benefits in macrovascular complications.47 The microvascular complications, including nephropathy, retinopathy and neuropathy, are strongly related to glycated hemoglobin (HbA1c). However, macrovascular complications can present in patients with HbA1c levels <7.0% and even in patients with dysglycemia.14,15 The glucotoxicity and lipotoxicity that precede prolonged hyperglycemia and β-cell dysfunction are early and reversible pathophysiological events, suggesting that early treatment could change the course of hyperglycemia and prevent or delay the long-term complications.48

Data from various studies confirm the importance of early treatment in DM2, given that:

  • There is an independent and continuous relationship between glycemic control (HbA1c) and ischemic heart disease, which is present with HbA1c levels <6.5%.49

  • Each 1% increase in HbA1c is associated with a 15–20% increase in CVD risk.50,15

  • In individuals without diabetes, there is a relationship between HbA1c levels (≥5.5–6%) and heart failure.51

  • Abnormal blood glucose levels under fasting conditions have been associated with increased mortality16,52 and increased long-term CVD risk.53

  • Increases in metabolic risk factors 20 years or more before the diagnosis of DM2 have been demonstrated.4

Therefore, early intervention to improve insulin resistance and other CVD risk factors is important for 2 reasons: (1) the reduction in β-cell workload to prevent the loss of β-cells and the development of DM2 and (2) the improvement in hyperinsulinemia prevents the progression of atherosclerosis.54

Individualized strategies for detecting DM2

Several questionnaires have been designed to detect individuals at risk for DM2 (prediabetes).55 These questionnaires are relatively easy to fill out and even had tools available online from the websites of the main scientific societies. However, for the US population, the current prediabetes detection tools can identify 59% and 81% of the population older than 40 and of 60years, respectively, as individuals at high risk for prediabetes.56 Therefore, the exclusive use of these tools makes effective strategies for intervention and follow-up unfeasible.

Longitudinal studies with long follow-ups have indicated that some forms of prediabetes appear early, have a slow progression but are associated with high CVD risk factors; others start in advanced ages and progress to diabetes without significantly increasing the morbidity and mortality.57 The challenge consists in differentiating an almost purely biochemical disorder from the complex syndrome with a high CVD risk that DM2 represents.

The clinical, biochemical and possibly (in the near future) genetic identification of individuals at high risk would enable more intensive and tailored treatment strategies and follow-up.

Some familial, clinical and biochemical factors can be used for individualize the diagnosis, follow-up and intervention for DM2/prediabetes of high CVD risk factors (Table 1).58

Table 1.

Individual factors of type 2 diabetes mellitus – prediabetes with high cardiovascular risk.

Genotypic approach 
First-degree relative with diabetes 
Race/ethnicity of high risk (e.g., African-American, Latino) 
History of cardiovascular disease 
Herald conditions 
Women with polycystic ovary syndrome 
Gestational diabetes 
Others clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) 
Biochemical data 
Abnormal baseline glucose (>100mg/dL or >90mg/dL if there is atherogenic dyslipidemia) or carbohydrate intolerance (blood glucose 140–200 after OGTT) or HbA1c >5.9% 
HDL cholesterol <35mg/dL and/or triglycerides >250mg/dL 
Associated/present cardiovascular risk factors 
Abdominal obesity (BMI>25 and or waist circumference >88cm for women, >102cm for men) 
Hypertension (>140/90mmHg or treatment for hypertension) 
CVD present 

Abbreviations: BMI, body mass index; CVD, cardiovascular disease; HDL, high-density lipoprotein; OGTT, oral glucose tolerance test.

Source: Self-authored, partially based on ADA criteria.58

Treatment objectives for DM2 and prediabetes

Based on biochemical data indicating a glycemic disorder and a greater burden from other risk factors (Table 1), an individualized treatment strategy can be proposed (Fig. 3), in which age plays an essential role.

Figure 3.

Risk stratification and proposed management for prediabetes/type 2 diabetes mellitus.59

*Upper limit of normality for HbA1c (majority of laboratories 5.7%); Low risk: exclusively biochemical data indicating hyperglycemia (BQ+) (impaired fasting glucose (IFG) / impaired glucose tolerance (IGT)/HbA1c 5.7–6.5%); Medium risk: biochemical data indicating hyperglycemia (BQ+) and history of herald conditions (HC). High risk: biochemical data indicating hyperglycemia (BQ+) and cardiovascular desease risk factors (CVDRFs) or cardiovascular disease (CVD) and/or history of herald conditions (HC).

Abbreviations: LSC, lifestyle changes (see Section “Management through lifestyle changes”); DT, drug treatment (see Section “Drug treatment”).

Source: Self-authored, partially based on AACE criteria.59

Management through lifestyle changes

The main strategies for DM2 prevention appear to be maintaining a healthy weight and physical activity,60 particularly through a balanced diet and aerobic exercise. The most recently accepted carbohydrate-insulin model (CIM) of obesity recommends diets low in carbohydrates, especially reducing the intake of those with a high glycemic index, given that a high burden and glycemic index stimulate the appetite and promote obesity and the development of DM2.61

The results of large high-quality clinical trials have demonstrated that changes in diet and physical activity can reduce the incidence rate of DM2 by more than 50% in individuals with abnormal glucose regulation.62,63 However, it is still a challenge to translate these findings into clinical practice, probably due to the fact that these interventions are only effective in the long term if appropriate compliance with these programs is ensured.64 In Spain, a translation project has been implemented for the Diabetes Prevention Study (DPS)65: the Diabetes in Europe-Prevention using Lifestyle, Physical Activity and Nutritional Intervention (DE-PLAN) project, with data on efficacy, feasibility and efficiency to translate the study to actual healthcare settings.66,67


There is increasing evidence on the importance of early and intensive pharmacological management in DM2. The latest ADA guidelines68 identify a number of patient subgroups who would benefit considerably from drug treatment in preventing DM2. Specifically, therapy with metformin is recommended for patients with prediabetes, a BMI≥35kg/m2 and younger than 60years and for women with a history of gestational diabetes.69 To ensure a reduction in CVD risk, the drug treatment duration needs to be sustained in the time and a reduction in HbA1c.70 It has been shown that DM2 screening and early and intensive treatment are also cost-effective measures for individuals with a moderate to high risk.71

The use of combination therapy for patients who have high HbA1c levels at diagnosis has been tested in several controlled clinical trials. A meta-analysis conducted by Phung et al.72 in 2014 analyzed 15 clinical trials that included 6693 patients with a mean baseline HbA1c level of 7.2–9.9%, 1.6–4.1years from the diagnosis of diabetes and a mean follow-up of 6months. The study analyzed the combinations of metformin with thiazolidinediones, insulin secretagogues, dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium/glucose cotransporter-2 (SGLT-2) inhibitors. Compared with metformin treatment, the combinations achieved a significant reduction in HbA1c levels (−0.43%, 95% CI −0.56 to −0.30) and succeeded in achieving the objective of decreasing HbA1c levels below 7% and a mean reduction in preprandial fasting plasma glucose (FPG) of −14.30mg (95% CI −16.09 to −12.51), although there was a significant increase in the risk of hypoglycemia.72

Another systematic review specifically analyzed the differences between starting with metformin treatment and starting with the addition of a DPP4i. The review covered 8 clinical trials that included a total of 7778 patients. The combinations achieved significant reductions in HbA1c levels (−0.49, 95% CI −0.57 to −0.40) and preprandial glucose levels of 14.40 mg/dl (95% CI −15.66 to −13.32) but did not decrease the CVD risk factors or the risk of hypoglycemia.73

Another more recent (2018) meta-analysis by Cai et al.74 that analyzed 36 clinical trials and encompassed the previous meta-analyses was able to compare the various combinations with their respective placebos. Compared with metformin alone, its combination with other therapies achieved a significant reduction in HbA1c levels. Many of the combined therapies showed a similar risk of hypoglycemia, with the exception of the sulfonylurea/glinide combination and the thiazolidinedione and metformin combination in which the risk was higher. Compared with treatment with DPP4i in isolation, its combination recorded a significant reduction in HbA1c levels and a similar risk of hypoglycemia.74

In a recent meta-analysis, Milder et al.75 reviewed 4 studies that analyzed the combinations with SGLT-2 inhibitors in a total of 3749 patients. The combination with metformin decreased HbA1c levels by −0.55% (95% CI −0.67 to −0.43), as well as weight (−2.00kg, 95% CI −2.34 to −1.66). High doses of SGLT-2 inhibitor showed a slight benefit in reducing weight but not in glycemic control.

The VERIFY study

The advantages of an early intensive approach for DM2 and the need for addressing various therapeutic targets through combined therapies were the basis for the design of VERIFY,76 a randomized, double-blind, 5-year study (divided into 3 periods) that compared early combined therapy with vildagliptin and metformin against a standard initial therapy of metformin in monotherapy (period 1), followed by the stepped addition of a second oral antidiabetic agent (period 2). Insulin was added as rescue therapy if the glycemic control deteriorated (period 3).


The main study objective was to assess the duration of glycemic control (HbA1c <7%) with both treatment approaches. The study also assessed the changes in β-cell function and insulin sensitivity, the time to the start of insulin therapy, the effect on the diabetic complications and other aspects such as quality of life.

Design and implementation

The study included patients 18–70 years of age diagnosed with DM2 within the previous 2 years, with HbA1c levels of 48–58mmol/mol (6.5–7.5%) and a BMI of 22–40kg/m2. The patients were randomly assigned 1:1 to the early combined therapy group or to the metformin plus initial placebo group. The stable daily dose of metformin was 1000, 1500 and 2000mg for both arms, and vildagliptin was administered at 50mg twice daily. The patients and researchers were kept blinded to the treatments. Primary failure was defined as the point at which the therapy did not maintain HbA1c levels below 53mmol/mol (7.0%), confirmed in 2 consecutive scheduled visits separated by 13weeks. At that point, the patients entered period 2: in the metformin monotherapy arm, vildagliptin 50mg twice daily was added rather than placebo, while those who were taking the combination were kept the same. Therefore, during period 2, all patients underwent the combined therapy. The primary efficacy variable was the time from randomization to primary failure.

If the local diabetes protocols recommended intensification therapy with insulin during period 2, the participants started the therapy with insulin, as well as the vildagliptin-metformin combination (secondary failure and start of period 3).

Results of the study

The study included 2001 participants. HbA1c levels were consistently lower over time in the combined therapy group compared with the monotherapy group, with a larger proportion of patients with HbA1c levels below 7% (53mmol/mol), 6.5% (48mmol/mol) and 6% (42mmol/mol) for the 1000, 1500 and 2000mg metformin doses, respectively. The primary failure rate was 43.6% (429 patients) for the combined therapy group and 62.1% (614 patients) for the monotherapy group.77 The median time to primary failure in the monotherapy group was 36.1months, while the median time for those treated with early combined therapy was 61.9months. A significant reduction (49%) was observed in the relative risk in the time to primary failure for the early combination compared with the monotherapy group during the 5years of the study (hazard ratio [HR], 0.51; p<.0001). The time to secondary failure (insulinization) was also significantly reduced for the initial combined therapy group (HR, 0.74; p<.0001).78 The trial was not designed to assess the differences in cardiovascular results, but all events were subject to adjudication. During the 5years of the study, a numerical reduction was observed in the relative risk in the time to the first macrovascular event with the early combined therapy when compared with the initial monotherapy (HR, 0.71; p=.19). Both treatment approaches were safe and well tolerated, and there were no deaths related to the study treatment.78 There are various aspects of the study that are awaiting publication, such as the preservation of β-cell function and the progression of microangiopathy in the 2 study arms.


The progressive impairment in β-cell function is the key element in the current biochemical diagnosis of DM2. However, other important pathophysiological bases for DM2, including insulin resistance, atherogenic dyslipidemia, associated arterial hypertension and the proinflammatory state, start decades before DM2 and determine a marked increase in cardiovascular risk. Progress needs to be made in detecting individuals with high cardiovascular risk associated with this complex syndrome in the earliest phases by eschewing a purely glucocentric view of DM2. The use of additional parameters to the glycemic ones, mainly clinical, biochemical and (in the near future) genetic parameters, will help individualize the risk of progression, morbidity and mortality. The VERIFY study has shown that early intervention and the combined therapy of vildagliptin and metformin provides greater and longer-lasting long-term benefits than metformin in monotherapy for patients with recently diagnosed DM2.


Novartis Pharma supported medical writing of this manuscript.

Conflicts of interest

F.G.P. has received fees (personal and otherwise) from Novartis, research grants and other grants from Astra Zeneca, research grants and other grants from Sanofi, research grants and other grants from Novo Nordisk, research grants and other grants from Boehringer Ingelheim Pharmaceuticals, other grants from Lilly and other grants from Bristol-Myers Squibb Co.

C.A. has received research support from Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals and Lilly and has acted as speaker for Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals, Astra Zeneca Pharmaceuticals and Bristol-Myers Squibb.

X.C. has received subsidies and personal fees from Novartis and personal fees from Esteve.

R.G.H. has received subsidies, personal fees and others from Boehringer-Lilly, research grants, personal fees and other grants from Novo Nordisk, research grants, personal fees and other grants from Sanofi, personal fees and others from Astra Zeneca, other grants from MSD, research grants and other grants from Janssen and personal fees from Novartis.

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Please cite this article as: Gómez-Peralta F, Abreu C, Cos X, Gómez-Huelgas R. ¿Cuándo empieza la diabetes? Detección e intervención tempranas en diabetes mellitus tipo 2. Rev Clin Esp. 2020;220:305–314.

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