Guideline for management of postmeal glucose in diabetes

      1. Methodology

      This update builds on the original IDF guideline for the management of postmeal glucose published in 2007. The methodology used in the development of this guideline is not described in detail here, as it broadly follows the principles described in the IDF guide for guidelines (www.idf.org).In summary:
      • The update was overseen by a Guideline Development Group of clinicians and researchers with expertise in the topic and guideline development (see Appendix A)
      • Geographical representation included various IDF regions and countries in different states of economic development
      • The evidence used in developing this guideline included reports from key meta-analyses, evidence-based reviews, clinical trials, cohort studies, epidemiological studies, animal and basic science studies, position statements and guidelines (English language only). Evidence relating to both postmeal and postchallenge plasma glucose was considered and cited as appropriate. Members of the Guideline Development Group were asked to identify any relevant reports or publications
      • The evidence was graded according to criteria presented in Table 1
        Table 1Evidence-grading criteria.
        Source: From the Scottish Intercollegiate Guidelines Network. SIGN 50. A guideline developer's handbook. January 2008.
        LevelType of evidence
        1++• High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias
        1+• Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
        1−• Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
        2++• High-quality systematic reviews of case–control or cohort studies

        • High-quality case control or cohort studies with a very low risk of confounding bias and a high probability that the relationship is causal
        2+• Well-conducted case–control or cohort studies with a low risk of confounding bias or chance and a moderate probability that the relationship is causal

        • Well-conducted basic science with low risk of bias
        2−• Case–control or cohort studies with a high risk of confounding bias or chance and a significant risk that the relationship is not causal
        3• Non-analytic studies (for example case reports, case series)
        4• Expert opinion
      • The Guideline Development Group met at a 2-day workshop held in May 2011 to review the evidence and to update or revise the evidence statements and recommendations. A recommendation was made according to the level of scientific substantiation based on evidence ratings whenever possible. However, when there was a lack of supporting studies, the Guideline Development Group formulated a consensus recommendation
      • The final guideline is being made available in paper form and on the IDF website
      • IDF will consider the need to review and update this guideline within 3–5 years

      2. Introduction

      An estimated 366 million people worldwide had diabetes in 2011 and this number is projected to reach 552 in 2030 [
      • Whiting D.R.
      • Guariguata L.
      • Weil C.
      • Shaw J.
      IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030.
      ]. Diabetes is a leading cause of death in most developed countries, and there is substantial evidence that it is reaching epidemic proportions in many developing and newly industrialized nations.
      Poorly controlled diabetes is associated with the development of macrovascular disease, vision loss, renal failure, neuropathy and amputations [
      • Diabetes Control and Complications Trial (DCCT) Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus.
      ,
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin- dependent diabetes mellitus: a randomized prospective 6-year study.
      ,
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ,
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      ]. Macrovascular complications are the major cause of death in people with diabetes [
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      ].
      Large controlled clinical trials have demonstrated that intensive treatment of diabetes can significantly decrease the development and/or progression of micro-vascular complications of diabetes [
      • Diabetes Control and Complications Trial (DCCT) Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus.
      ,
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin- dependent diabetes mellitus: a randomized prospective 6-year study.
      ,
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ]. Furthermore, intensive glycaemic control in people with type 1 diabetes or impaired glucose tolerance (IGT) lowers the risk for cardiovascular disease [
      • Nathan D.M.
      • Cleary P.A.
      • Backlund J.Y.
      • Genuth S.M.
      • Lachin J.M.
      • Orchard T.J.
      • et al.
      Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
      ,
      • Hanefeld M.
      • Chiasson J.L.
      • Koehler C.
      • Henkel E.
      • Schaper F.
      • Temelkova-Kurktschiev T.
      Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance.
      ].
      There appears to be no glycaemic threshold for either microvascular or macrovascular complications; the lower the glycated haemoglobin (HbA1c), the lower the risk [
      • Stettler C.
      • Allemann S.
      • Juni P.
      • Cull C.A.
      • Holman R.R.
      • Egger M.
      • et al.
      Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials.
      ,
      • Diabetes Control and Complications Trial (DCCT) Research Group
      The absence of a glycemic threshold for the development of longterm complications: the perspective of the Diabetes Control and Complications Trial.
      ,
      • Stratton I.M.
      • Adler A.I.
      • Neil H.A.
      • Matthews D.R.
      • Manley S.E.
      • Cull C.A.
      • et al.
      Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
      ,
      • Khaw K.T.
      • Wareham N.
      • Luben R.
      • Bingham S.
      • Oakes S.
      • Welch A.
      • et al.
      Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk).
      ]. Many epidemiologic studies have demonstrated an association between glycaemia and cardiovascular risk [
      • Gerstein H.C.
      Dysglycemia, not just diabetes, is a continuous risk factor for cardiovascular disease.
      ,
      • Punthakee Z.
      • Werstuck G.H.
      • Gerstein H.C.
      Diabetes and cardiovascular disease: explaining the relationship.
      ]. However, the beneficial effect of lowering glucose on cardiovascular disease in type 2 diabetes is still a matter of debate. While the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated significant reductions in microvascular complication risk, there was a non-statistically significant reduction in macrovascular disease [
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ].
      In 2008, the results of several large randomized controlled trials (ACCORD, ADVANCE, VADT, UKPDS-PTM) [
      • The Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      ,
      • The ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • Duckworth W.
      • Abraira C.
      • Reda D.
      • Moritz T.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      ,
      • Holman R.R.
      • Paul S.K.
      • Bethel A.
      • Matthews D.R.
      • Neil A.W.
      10-Year follow-up of intensive glycemic control in type 2 diabetes.
      ] were published. The results of these trials have been reviewed elsewhere [
      • Cheng A.Y.
      • Leiter L.A.
      Glucose lowering and cardiovascular disease: what do we know and what should we do?.
      ]. Briefly, the ACCORD, ADVANCE, and VADT trials were all large, randomized controlled prospective studies to answer the question whether intensive glucose lowering would be associated with greater cardiovascular benefit relative to standard therapy in people with type 2 diabetes. In contrast to the UKPDS in which the subjects had newly diagnosed diabetes, the subjects included in these studies had their diabetes for a mean duration of 8–11.5 years and 32–40% of them had a prior history of macrovascular disease. In each of these studies, the primary macrovascular endpoint was reduced (by 6–12%), but in none of the studies was it reduced significantly.
      Several subsequent meta-analyses of these major trials have been conducted [
      • Turnbull F.M.
      • Abraira C.
      • Anderson R.J.
      • Byington R.P.
      • Chalmers J.P.
      • Duckworth W.C.
      • et al.
      Intensive glucose control and macrovascular outcomes in type 2 diabetes.
      ,
      • Ray K.K.
      • Seshasai S.R.
      • Wijesuriya S.
      • Sivakumaran R.
      • Nethercott S.
      • Preiss D.
      • et al.
      Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
      ,
      • Mannucci E.
      • Monami M.
      • Lamanna C.
      • Gori F.
      • Marchionni N.
      Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials.
      ]. The meta-analysis by Turnbull et al. [
      • Turnbull F.M.
      • Abraira C.
      • Anderson R.J.
      • Byington R.P.
      • Chalmers J.P.
      • Duckworth W.C.
      • et al.
      Intensive glucose control and macrovascular outcomes in type 2 diabetes.
      ] incorporated the ACCORD, ADVANCE, VADT, and UKPDS trials and demonstrated significant reductions in major cardiovascular events (HR 0.91; 95% CI 0.76–0.94) and myocardial infarctions (OR 0.85; 95% CI 0.75–0.93). There was no overall increase or decrease in all-cause mortality (HR 1.04; 95% CI 0.90–1.20). There were significantly more major hypoglycaemic episodes (HR 2.48; 95% CI 1.91–3.21). Significant heterogeneity for CV events was observed based on history of macrovascular disease. A significant 16% reduction was observed in those in whom it was absent (HR 0.84; 95% CI 0.75–0.94) while no effect (HR 1.00; 95% CI 0.89–1.13) was observed in those in whom it was present. Other subgroup analyses including age, baseline HbA1c and duration of diabetes did not show any heterogeneity.
      Of note is the fact that the ACCORD glycaemic control study was stopped prematurely after a mean follow-up of 3.5 years because of a 22% (95% CI 1.01–1.46; P = 0.04) increased mortality in the intensive group. After multiple analyses, no definitive explanation has yet been identified to explain this surprising mortality finding. Achieving a lower HbA1c was not associated with increased mortality. In fact, the mortality was higher in those subjects in the intensive group who did not achieve a lower HbA1c [
      • Riddle M.C.
      • Ambrosius W.T.
      • Brillon D.J.
      • Buse J.B.
      • Byington R.P.
      • Cohen R.M.
      • et al.
      Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Action to Control Cardiovascular Risk in Diabetes Investigators.
      ].
      The results of the UKPDS 10-year post-trial monitoring (UKPDS-PTM) study are also noteworthy [
      • Holman R.R.
      • Paul S.K.
      • Bethel A.
      • Matthews D.R.
      • Neil A.W.
      10-Year follow-up of intensive glycemic control in type 2 diabetes.
      ]. Whereas the difference in macrovascular complications between the two groups did not achieve statistical significance in the original UKPDS trial, with longer follow-up myocardial infarction risk reduction became significant with a HR of 0.85 (P = 0.01) and a number needed to treat (NNT) of 36 over 17 years. All cause mortality risk reduction also became significant with a HR of 0.87 (P = 0.007) and a NNT of 29, also over 17 years. Therefore, the results of the 10-year post-trial monitoring have demonstrated significant microvascular and macrovascular risk reduction with early intensive glycaemic control in newly diagnosed type 2 diabetes. There appears to be a “legacy effect” in that early risk reductions persist over time and, in the case of macrovascular risk reduction, may take many years to manifest.
      Thus, the preponderance of data support the view that glycaemic control plays a role in reducing cardiovascular complications, but it needs to be instituted early in the disease course and the benefit may take many years to manifest. These benefits are in addition to the reduced risk of microvascular complications.
      The relationship between hyperglycaemia and cardiovascular disease is complex with evidence suggesting that an acute increase of glycaemia, particularly after a meal, may have a direct detrimental effect on cardiovascular disease [
      • Ceriello A.
      • Hanefeld M.
      • Leiter L.
      • Monnier L.
      • Moses A.
      • Owens D.
      • et al.
      Postprandial glucose regulation and diabetic complications.
      ]. Moreover, until recently, the predominant focus of therapy has been on lowering HbA1c levels, with a strong emphasis on fasting plasma glucose [
      • Nathan D.M.
      • Buse J.B.
      • Davidson M.B.
      • Hein R.J.
      • Holman R.R.
      • Sherwin R.
      • et al.
      Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
      ]. Although control of fasting hyperglycaemia is necessary, it is usually insufficient to obtain optimal glycaemic control. A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1c goals [
      • Ceriello A.
      The glucose triad and its role in comprehensive glycaemic control: current status, future management.
      ].

      3. Objective

      The purpose of this guideline is to consider the evidence on the relationship between postmeal glucose and glycaemic control (HbA1c), and with diabetes outcomes. Based on this information, recommendations for the appropriate management and monitoring of postmeal glucose in type 1 and type 2 diabetes have been developed. Management of postmeal glucose in pregnancy has not been addressed in this guideline.
      The recommendations are intended to assist clinicians and organizations in developing strategies to consider and effectively manage postmeal glucose in people with type 1 and type 2 diabetes, taking into consideration locally available therapies and resources. Although the literature provides valuable information and evidence regarding this area of diabetes management, uncertainties remain about a causal association between postmeal plasma glucose and complications and additional research is needed to clarify our understanding in this area. Logic and clinical judgment remain critical components of diabetes care and implementation of any guideline recommendations.

      4. Summary of recommendations

      As a basis for developing the recommendations, the Guideline Development Group addressed four questions relevant to the role and importance of postmeal hyperglycaemia in diabetes management. The evidence supporting the recommendations is shown as evidence statements (with the level of evidence indicated at the end of the statement).

      4.1 Question 1

      Is postmeal hyperglycemia harmful?
      EVIDENCE STATEMENTS
      Postmeal and postchallenge hyperglycaemia are independently associated with the following in people with diabetes:
      • -
        macrovascular disease [Level 1+]
      • -
        retinopathy [Level 2+]
      • -
        cancer [Level 2+]
      • -
        impaired cognitive function in elderly people with type 2 diabetes [Level 2+]
      • -
        increased carotid intima-media thickness [Level 2+]
      • -
        decreased myocardial blood volume and myocardial blood flow [Level 2+]
      • -
        oxidative stress, inflammation and endothelial dysfunction [Level 2+]
      RECOMMENDATION
      Postmeal hyperglycaemia is harmful and should be addressed.

      4.2 Question 2

      Is the treatment of postmeal hyperglycaemia beneficial in improving clinical outcomes and glycaemic control (HbA1c)?
      EVIDENCE STATEMENTS
      • There is currently a lack of direct randomized clinical trial evidence that correcting postmeal hyperglycaemia improves clinical outcomes [Level 1−]
      • Treatment with agents which target postmeal plasma glucose reduces vascular events in primary prevention [Level 1−]
      • Targeting both postmeal plasma glucose and fasting plasma glucose is an important strategy for achieving optimal glycaemic control [Level 1+]
      RECOMMENDATION
      Implement treatment strategies to lower postmeal plasma glucose in people with postmeal hyperglycaemia.

      4.3 Question 3

      Which therapies are effective in controlling postmeal plasma glucose?
      EVIDENCE STATEMENTS
      • Diets with a low glycaemic load are beneficial in improving glycaemic control [Level 1+]
      • Several classes of pharmacologic agents preferentially lower postmeal plasma glucose [Level 1+]
      RECOMMENDATION
      A variety of both non-pharmacologic and pharmacologic therapies should be considered to target postmeal plasma glucose.

      4.4 Question 4

      What are the targets for postmeal glycaemic control and how should they be assessed?
      EVIDENCE STATEMENTS
      • Postmeal plasma glucose levels seldom rise above 7.8 mmol/l (140 mg/dl) after food ingestion in healthy non-pregnant people [Level 2++]
      • Self-monitoring of blood glucose (SMBG) is currently the optimal method for assessing plasma glucose levels [Level 2++]
      RECOMMENDATION
      • Postmeal plasma glucose should be measured 1–2 h after a meal
      • The target for postmeal glucose is 9.0 mmol/l (160 mg/dl) as long as hypoglycaemia is avoided
      • Self-monitoring of blood glucose (SMBG) should be considered because it is currently the most practical method for monitoring postmeal glycaemia

      5. Background

      5.1 Definition of postprandial glucose and contribution to overall hyperglycaemia

      In people with diabetes, the total exposure to glucose is the sum of two components [
      • Monnier L.
      • Colette C.
      • Owens D.
      Postprandial and basal glucose in Type 2 diabetes: assessment and respective impacts.
      ]:
      • (i)
        The normal physiological glucose exposure as observed in healthy individuals
      • (ii)
        The additional glucose exposure observed in hyperglycaemic individuals which has been defined as all plasma glucose values above 5.5 mmol/l (99 mg/dl). This additional glucose exposure can be further divided into its two subcomponents – basal/preprandial and postprandial hyperglycaemia
      Calculating the absolute and relative contributions of the different components of glucose exposure is best determined using methods based on data provided by continuous glucose monitoring. The overall glucose exposure in a given individual can be estimated by calculating the total area under the 24-h glycaemic profile above zero, i.e. PGAUCtotal. Postprandial glucose (PPG) is measured by calculating the AUC above the preprandial values over a 4-h period after the start of the meal, i.e. PGAUCpp. The choice of the 4-h value is dictated by the mean duration of the hydrolysis and absorption of dietary carbohydrates (the so called postprandial state) which equals 4 h both in normal individuals and in people with diabetes [
      • Dinneen S.
      • Gerich J.
      • Rizza R.
      Carbohydrate metabolism in non-insulin-dependent diabetes mellitus.
      ]. It should be noted that the postprandial state corresponds to a physiological definition although the postprandial excursions can be shorter or usually longer in type 2 diabetes [
      • Polonsky K.S.
      • Given B.D.
      • Hirsch L.
      • Tilil H.
      • Shapiro E.T.
      • Beebe C.
      • et al.
      Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus.
      ,
      • Monnier L.
      • Colette C.
      • Dunseath G.J.
      • Owens D.R.
      The loss of postprandial glycaemic control precedes stepwise deterioration of fasting with worsening diabetes.
      ]. The contribution of postprandial glucose excursions to HbA1c can be defined according to the following equation [
      • Monnier L.
      • Colette C.
      • Owens D.
      Postprandial and basal glucose in Type 2 diabetes: assessment and respective impacts.
      ]:
      HbA1c×PGAUCppPGAUCtotal%


      Using this mathematical approach, it has been demonstrated [
      • Monnier L.
      • Colette C.
      • Owens D.R.
      Type 2 diabetes: a well characterized but suboptimally controlled disease Can we bridge the divide?.
      ,
      • Monnier L.
      • Colette C.
      • Owens D.R.
      Glycaemic variability: the third component of the dysglycaemia in diabetes: is it important? How to measure it?.
      ] that the absolute impact of PPG excursions on HbA1c was constant at approximately 1% in people with non-insulin-treated type 2 diabetes with an HbA1c ≥ 6.5%. This calculation provides a simple and generalizable description of the absolute contribution by the PPG excursions to the overall glucose exposure.
      In people with non-insulin-treated type 2 diabetes, the contribution of PPG relative to fasting glycaemia is predominant when the HbA1c levels are approximately below 7.5% and the contribution decreases progressively with increasing HbA1c levels [
      • Monnier L.
      • Lapinski H.
      • Colette C.
      Contributions of fasting and postprandial plasma increments to overall diurnal hyperglycaemia of type 2 diabetic patients: variations with increasing levels of HbA1c.
      ].

      5.2 Postmeal plasma glucose in people with normal glucose tolerance

      In people with normal glucose tolerance, plasma glucose generally rises no higher than 7.8 mmol/l (140 mg/dl) in response to meals and typically returns to premeal levels within 2–3 h [
      • Polonsky K.S.
      • Given B.D.
      • Van C.E.
      Twenty-four hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.
      ,
      • Mazze R.S.
      • Strock E.
      • Wesley D.
      • Borgman S.
      • Morgan B.
      • Bergenstal R.
      • et al.
      Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis.
      ,
      • Tsujino D.
      • Nishimura R.
      • Taki K.
      • Miyashita Y.
      • Morimoto A.
      • Tajima N.
      Daily glucose profiles in Japanese people with normal glucose tolerance as assessed by continuous glucose monitoring.
      ].
      In this guideline, postmeal hyperglycaemia is defined as a plasma glucose level >7.8 mmol/l (140 mg/dl) 1–2 h after ingestion of food [
      • Monnier L.
      • Colette C.
      • Dunseath G.J.
      • Owens D.R.
      The loss of postprandial glycaemic control precedes stepwise deterioration of fasting with worsening diabetes.
      ].

      5.3 Postmeal hyperglycaemia begins prior to type 2 diabetes

      The development of type 2 diabetes is characterized by a progressive decline in insulin action and relentless deterioration of β-cell function and hence insulin secretion [
      • Weyer C.
      • Bogardus C.
      • Mott D.M.
      • Pratley R.E.
      The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.
      ,
      • Pratley R.E.
      • Weyer C.
      The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus.
      ]. Prior to clinical diabetes, these metabolic abnormalities are first evident as elevations in postmeal plasma glucose, due to the loss of first-phase insulin secretion, decreased insulin sensitivity in peripheral tissues and consequent decreased suppression of hepatic glucose output after meals due to insulin deficiency [
      • Weyer C.
      • Bogardus C.
      • Mott D.M.
      • Pratley R.E.
      The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.
      ,
      • Pratley R.E.
      • Weyer C.
      The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus.
      ,
      • Gerich J.E.
      Pathogenesis and treatment of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).
      ]. Elevated postmeal plasma glucose levels can be associated with deficiencies in glucagon-like peptide-1 (GLP-1) and glucose-dependent gastric inhibitory peptide (GIP), incretin hormones secreted by the gut [
      • Holst J.J.
      • Gromada J.
      Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
      ,
      • Toft-Nielsen M.B.
      • Damholt M.B.
      • Madsbad S.
      • Hilsted L.M.
      • Hughes T.E.
      • Michelsen B.K.
      • et al.
      Determinants of the impaired secretion of glucagon like peptide-1 in type 2 diabetic patients.
      ]. There is evidence that the gradual loss in daytime postmeal glycaemic control precedes a stepwise deterioration in nocturnal fasting periods with worsening diabetes [
      • Monnier L.
      • Colette C.
      • Dunseath G.J.
      • Owens D.R.
      The loss of postprandial glycaemic control precedes stepwise deterioration of fasting with worsening diabetes.
      ].

      5.4 Postmeal hyperglycaemia is common in diabetes

      Postmeal hyperglycaemia occurs very frequently in people with type 1 and type 2 diabetes and occur even when overall metabolic control appears to be adequate as assessed by HbA1c [
      • Maia F.F.
      • Araujo L.R.
      Efficacy of continuous glucose monitoring system (CGMS) to detect postprandial hyperglycemia and unrecognized hypoglycemia in type 1 diabetic patients.
      ,
      • Bonora E.
      • Corrao G.
      • Bagnardi V.
      • Ceriello A.
      • Comaschi M.
      • Montanari P.
      • et al.
      Prevalence and correlates of post-prandial hyperglycaemia in a large sample of patients with type 2 diabetes mellitus.
      ]. For example a study which assessed daily plasma glucose profiles from 3284 people with non-insulin-treated type 2 diabetes compiled over a 1-week period, demonstrated that a postmeal plasma glucose value >8.9 mmol/l (160 mg/dl) was recorded at least once in 84% of those studied [
      • Bonora E.
      • Corrao G.
      • Bagnardi V.
      • Ceriello A.
      • Comaschi M.
      • Montanari P.
      • et al.
      Prevalence and correlates of post-prandial hyperglycaemia in a large sample of patients with type 2 diabetes mellitus.
      ].

      6. Question 1

      Is postmeal hyperglycemia harmful?
      Epidemiological studies have shown a strong association between postmeal and postchallenge glycaemia and cardiovascular risk and outcomes [
      • DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-h diagnostic criteria.
      ,
      • Nakagami T.
      • Qiao Q.
      • Tuomilehto J.
      • Balkau B.
      • Tajima N.
      • Hu G.
      • et al.
      Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five populations of Asian origin: the DECODA study.
      ,
      • Levitan E.B.
      • Song Y.
      • Ford E.S.
      • Liu S.
      Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies.
      ,
      • Cavalot F.
      • Petrelli A.
      • Traversa M.
      • Bonomo K.
      • Fiora E.
      • Conti M.
      • et al.
      Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.
      ]. Furthermore, a large and growing body of evidence shows a relationship between postmeal hyperglycaemia and oxidative stress [
      • Ceriello A.
      • Taboga C.
      • Tonutti L.
      • Quagliaro L.
      • Piconi L.
      • Bais B.
      • et al.
      Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment.
      ], carotid IMT [
      • Hanefeld M.
      • Koehler C.
      • Schaper F.
      • Fuecker K.
      • Henkel E.
      • Temelkova-Kurktschiev T.
      Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals.
      ] and endothelial dysfunction [
      • Ceriello A.
      • Taboga C.
      • Tonutti L.
      • Quagliaro L.
      • Piconi L.
      • Bais B.
      • et al.
      Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment.
      ,
      • Kawano H.
      • Motoyama T.
      • Hirashima O.
      • Hirai N.
      • Miyao Y.
      • Sakamoto T.
      • et al.
      Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.
      ], all of which are known markers of cardiovascular disease. Postmeal hyperglycaemia is also linked to retinopathy [
      • Shiraiwa T.
      • Kaneto H.
      • Miyatsuka T.
      • Kato K.
      • Yamamoto K.
      • Kawashima A.
      • et al.
      Post-prandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.
      ,
      • Aizawa T.
      • Katakura M.
      • Naka M.
      • Kondo T.
      Postprandial hyperglycemia is an independent risk for retinopathy in elderly patients with type 2 diabetes mellitus, especially in those with near-normal glycosylated hemoglobin.
      ], cognitive dysfunction in elderly people [
      • Abbatecola A.M.
      • Rizzo M.R.
      • Barbieri M.
      • Grella R.
      • Arciello A.
      • Laieta M.T.
      • et al.
      Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.
      ], and certain cancers [
      • Gapstur S.M.
      • Gann P.H.
      • Lowe W.
      • Liu K.
      • Colangelo L.
      • Dyer A.
      Abnormal glucose metabolism and pancreatic cancer mortality.
      ,
      • Larsson S.C.
      • Bergkvist L.
      • Wolk A.
      Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study.
      ,
      • Michaud D.S.
      • Liu S.
      • Giovannucci E.
      • Willett W.C.
      • Colditz G.A.
      • Fuchs C.S.
      Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study.
      ,
      • Michaud D.S.
      • Fuchs C.S.
      • Liu S.
      • Willett W.C.
      • Colditz G.A.
      • Giovannucci E.
      Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women.
      ,
      • Lajous M.
      • Willett W.
      • Lazcano-Ponce E.
      • Sanchez-Zamorano L.M.
      • Hernandez-Avila M.
      • Romieu I.
      Glycemic load, glycemic index, and the risk of breast cancer among Mexican women.
      ].

      6.1 Postmeal and postchallenge hyperglycaemia are independent risk factors for macrovascular disease [Level 1+]

      The Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) and the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Asia (DECODA) studies [
      • DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-h diagnostic criteria.
      ,
      • Nakagami T.
      • Qiao Q.
      • Tuomilehto J.
      • Balkau B.
      • Tajima N.
      • Hu G.
      • et al.
      Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five populations of Asian origin: the DECODA study.
      ], which analysed baseline and 2-h postchallenge glucose data from prospective cohort studies including a large number of men and women of European and Asian origin, found 2-h plasma glucose to be a better predictor of cardiovascular disease and all-cause mortality than fasting plasma glucose.
      Levitan et al. [
      • Levitan E.B.
      • Song Y.
      • Ford E.S.
      • Liu S.
      Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies.
      ] performed a meta-analysis of 38 prospective studies and confirmed that hyperglycaemia in the non-diabetic range was associated with increased risk of fatal and non-fatal cardiovascular disease, with a similar relationship between events and fasting or 2-h plasma glucose. In the analysis, 12 studies reporting fasting plasma glucose levels and six studies reporting postchallenge glucose allowed for dose–response curve estimates. Cardiovascular events increased in a linear fashion without a threshold for 2-h postchallenge plasma glucose, whereas fasting plasma glucose showed a possible threshold effect at 5.5 mmol/l (99 mg/dl).
      Similarly, in the Baltimore Longitudinal Study of Aging [
      • Sorkin J.D.
      • Muller D.C.
      • Fleg J.L.
      • Andres R.
      The relation of fasting and 2-h postchallenge plasma glucose concentrations to mortality: data from the Baltimore Longitudinal Study of Aging with a critical review of the literature.
      ], which followed 1236 men for a mean of 13.4 years to determine the relationship between fasting plasma glucose and 2-h postmeal plasma glucose and all-cause mortality, all-cause mortality increased significantly above a fasting plasma glucose of 6.1 mmol/l (110 mg/dl) but not at lower fasting plasma glucose levels. However, risk increased significantly at 2-h postmeal plasma glucose levels above 7.8 mmol/l (140 mg/dl).
      The observations also extend to people with diabetes with postmeal plasma glucose being a stronger predictor of cardiovascular events than fasting plasma glucose in type 2 diabetes, particularly in women [
      • Cavalot F.
      • Petrelli A.
      • Traversa M.
      • Bonomo K.
      • Fiora E.
      • Conti M.
      • et al.
      Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.
      ], data which have been confirmed in a longer follow-up [
      • Cavalot F.
      • Pagliarino A.
      • Valle M.
      • Di Martino L.
      • Bonomo K.
      • Massucco P.
      • et al.
      Postprandial blood glucose predicts cardiovascular events and all-cause mortality in Type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study.
      ].
      However most of the epidemiological data supporting this concept are based on studies using the oral glucose tolerance test (OGTT). Since the OGTT cannot be considered a standard meal, questions have been raised about the relationship between the 2 h glucose values during an OGTT and postprandial hyperglycaemia after a meal. This concern is minimized by the demonstration of a strong relationship between the level of glycaemia during an OGTT and during a meal, particularly in terms of peak values [
      • Meier J.J.
      • Baller B.
      • Menge B.A.
      • Gallwitz B.
      • Schmidt W.E.
      • Nauck M.A.
      Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa?.
      ].

      6.2 Postmeal hyperglycaemia is associated with increased risk of retinopathy [Level 2+]

      While postchallenge and postmeal hyperglycaemia are associated with the development and progression of diabetic macrovascular disease, there are limited data on the relationship between postmeal hyperglycaemia and microvascular complications. Two observational prospective studies from Japan demonstrated that postmeal hyperglycaemia is a better predictor of diabetic retinopathy than HbA1c. A multiple regression analysis revealed that not only postmeal hyperglycaemia independently correlated with the incidence of diabetic retinopathy [
      • Shiraiwa T.
      • Kaneto H.
      • Miyatsuka T.
      • Kato K.
      • Yamamoto K.
      • Kawashima A.
      • et al.
      Post-prandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.
      ,
      • Shiraiwa T.
      • Kaneto H.
      • Miyatsuka T.
      • Kato K.
      • Yamamoto K.
      • Kawashima A.
      • et al.
      Postprandial hyperglycemia is a better predictor of the progression of diabetic retinopathy than HbA1c in Japanese type 2 diabetic patients.
      ], but also was a strong predictor of the progression of this complication [
      • Shiraiwa T.
      • Kaneto H.
      • Miyatsuka T.
      • Kato K.
      • Yamamoto K.
      • Kawashima A.
      • et al.
      Postprandial hyperglycemia is a better predictor of the progression of diabetic retinopathy than HbA1c in Japanese type 2 diabetic patients.
      ]. This finding is consistent with the evidence that at 1 and 2 h after glucose ingestion, endothelial function decreases, while retinal vascular reactivity increases, compared with baseline values [
      • Chittari M.V.
      • McTernan P.
      • Bawazeer N.
      • Constantinides K.
      • Ciotola M.
      • O’Hare J.P.
      • et al.
      Impact of acute hyperglycaemia on endothelial function and retinal vascular reactivity in patients with Type 2 diabetes.
      ]. These data highlight that acute hyperglycaemia impacts on endothelial function simultaneously at both macrovascular and microvascular levels, inducing functional change which could contribute towards explaining the clinical evidence of an association between postprandial hyperglycaemia, cardiovascular disease and retinopathy.

      6.3 Postmeal hyperglycaemia is associated with increased risk of cancer [Level 2+]

      In addition to vascular disease, diabetes is associated with premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors [
      • Emerging Risk Factors Collaboration
      • Seshasai S.R.
      • Kaptoge S.
      • Thompson A.
      • Di Angelantonio E.
      • Gao P.
      • Sarwar N.
      • et al.
      Diabetes mellitus, fasting glucose, and risk of cause-specific death.
      ].
      Postmeal hyperglycaemia and factors known to promote postmeal hyperglycaemia are implicated in the development of pancreatic cancer [
      • Gapstur S.M.
      • Gann P.H.
      • Lowe W.
      • Liu K.
      • Colangelo L.
      • Dyer A.
      Abnormal glucose metabolism and pancreatic cancer mortality.
      ,
      • Larsson S.C.
      • Bergkvist L.
      • Wolk A.
      Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study.
      ,
      • Michaud D.S.
      • Liu S.
      • Giovannucci E.
      • Willett W.C.
      • Colditz G.A.
      • Fuchs C.S.
      Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study.
      ]. A large, prospective cohort study of 35,658 adult men and women [
      • Gapstur S.M.
      • Gann P.H.
      • Lowe W.
      • Liu K.
      • Colangelo L.
      • Dyer A.
      Abnormal glucose metabolism and pancreatic cancer mortality.
      ] found a strong correlation between pancreatic cancer mortality and postload plasma glucose levels. The relative risk for developing pancreatic cancer was 2.15 in people with postload plasma glucose levels of >11.1 mmol/l (200 mg/dl) compared with people who maintained postload plasma glucose <6.7 mmol/l (121 mg/dl). This association was stronger for men than women.
      In a study in northern Sweden which included 33,293 women and 31,304 men and 2478 incident cases of cancer, relative risk of cancer over 10 years in women increased significantly by 1.26 in the highest quartile for fasting and 1.31 for postload glucose compared with the lowest quartile. No significant association was found in men [
      • Stattin P.
      • Bjor O.
      • Ferrari P.
      • Lukanova A.
      • Lenner P.
      • Lindahl B.
      • et al.
      Prospective study of hyperglycemia and cancer risk.
      ].

      6.4 Postmeal hyperglycaemia is associated with impaired cognitive function in elderly people with type 2 diabetes [Level 2+]

      Postmeal hyperglycaemia may also negatively affect cognitive function in older people with type 2 diabetes. One study [
      • Abbatecola A.M.
      • Rizzo M.R.
      • Barbieri M.
      • Grella R.
      • Arciello A.
      • Laieta M.T.
      • et al.
      Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.
      ] reported that significantly elevated postmeal plasma glucose excursions (11.1 mmol; 200 mg/dl) were associated with a disturbance of global, executive and attention functioning.

      6.5 Postmeal hyperglycaemia is associated with increased carotid intima-media thickness (IMT) [Level 2+]

      A clear correlation has been demonstrated between postmeal plasma glucose excursions and carotid IMT in 403 people without diabetes [
      • Hanefeld M.
      • Koehler C.
      • Schaper F.
      • Fuecker K.
      • Henkel E.
      • Temelkova-Kurktschiev T.
      Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals.
      ]. In multivariate analysis, age, male gender, postmeal plasma glucose, total cholesterol and HDL-cholesterol were found to be independent risk factors for increased carotid IMT.
      Interestingly, it has been recently reported that incremental glucose peak (the maximal incremental increase in blood glucose obtained at any point after the meal), is associated with a significant increase of carotid IMT in type 2 diabetes [
      • Esposito K.
      • Ciotola M.
      • Carleo D.
      • Schisano B.
      • Sardelli L.
      • Di Tommaso D.
      • et al.
      Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes.
      ] and that controlling postprandial hyperglycaemia significantly reduces IMT progression, independent of reduction in HbA1c [
      • Esposito K.
      • Giugliano D.
      • Nappo F.
      • Marfella R.
      • Campanian Postprandial Hyperglycemia Study Group
      Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.
      ]. Another study has shown a slowing of progression of carotid IMT with treatment with acarbose, an agent known to reduce postprandial glucose exercursions [
      • Hanefeld M.
      • Chiasson J.L.
      • Koehler C.
      • Henkel E.
      • Schaper F.
      • Temelkova-Kurktschiev T.
      Acarbose slows progression of intima-media thickness of the carotid Aateries in subjects with impaired glucose tolerance.
      ].

      6.6 Postmeal hyperglycaemia causes oxidative stress, inflammation and endothelial dysfunction [Level 2+]

      Acute glucose fluctuations during postmeal periods have shown a more specific triggering effect on oxidative stress [
      • Monnier L.
      • Mas E.
      • Ginet C.
      • Michel F.
      • Villon L.
      • Cristol J.P.
      • et al.
      Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.
      ,
      • Ceriello A.
      • Esposito K.
      • Piconi L.
      • Ihnat M.A.
      • Thorpe J.E.
      • Testa R.
      • et al.
      Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.
      ] and endothelial function [
      • Ceriello A.
      • Esposito K.
      • Piconi L.
      • Ihnat M.A.
      • Thorpe J.E.
      • Testa R.
      • et al.
      Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.
      ] than chronic sustained hyperglycaemia in people with type 2 diabetes compared with people without diabetes. Another study demonstrated that people with type 2 diabetes and postmeal hyperglycaemia were exposed to meal-induced periods of oxidative stress during the day [
      • Hasegawa G.
      • Yamamoto Y.
      • Zhi J.G.
      • Tanino Y.
      • Yamasaki M.
      • Yano M.
      • et al.
      Daily profile of plasma %CoQ10 level, a biomarker of oxidative stress, in patients with diabetes manifesting postprandial hyperglycaemia.
      ].
      Elevated levels of adhesion molecules, which play an important role in the initiation of atherosclerosis [
      • Ross R.
      The pathogenesis of atherosclerosis: a perspective for the 1990s.
      ], have been reported in people with diabetes [
      • Ceriello A.
      • Falleti E.
      • Motz E.
      • Taboga C.
      • Tonutti L.
      • Ezsol Z.
      • et al.
      Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus: the possible role of oxidative stress.
      ]. Ceriello et al. [
      • Ceriello A.
      • Quagliaro L.
      • Piconi L.
      • Assaloni R.
      • Da R.R.
      • Maier A.
      • et al.
      Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment.
      ] studied the effects of three different meals (high-fat meal, 75 g of glucose alone, high-fat meal plus 75 g of glucose) in 30 people with type 2 diabetes and 20 people without diabetes. The results demonstrated an independent and cumulative effect of postmeal hypertriglyceridaemia and hyperglycaemia on ICAM-1, VCAM-1 and E-selectin plasma levels.
      Acute hyperglycaemia in response to oral glucose loading in people with normal glucose tolerance, IGT, or type 2 diabetes, rapidly suppressed endothelium dependent vasodilation and impaired endothelial nitric oxide release [
      • Kawano H.
      • Motoyama T.
      • Hirashima O.
      • Hirai N.
      • Miyao Y.
      • Sakamoto T.
      • et al.
      Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.
      ]. Other studies have shown that acute hyperglycaemia in normoglycaemic people impairs endothelium-dependent vasodilation [
      • Williams S.B.
      • Goldfine A.B.
      • Timimi F.K.
      • Ting H.H.
      • Roddy M.A.
      • Simonson D.C.
      • et al.
      Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.
      ], may activate thrombosis [
      • Ceriello A.
      • Giacomello R.
      • Stel G.
      • Motz E.
      • Taboga C.
      • Tonutti L.
      • et al.
      Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress.
      ] and increases circulating levels of soluble adhesion molecules [
      • Esposito K.
      • Nappo F.
      • Marfella R.
      • Giugliano G.
      • Giugliano F.
      • Ciotola M.
      • et al.
      Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress.
      ]. Treating postprandial hyperglycaemia can improve oxidative stress [
      • Ceriello A.
      • Quagliaro L.
      • Catone B.
      • Pascon R.
      • Piazzola M.
      • Bais B.
      • et al.
      Role of hyperglycemia in nitrotyrosine postprandial generation.
      ], inflammation [
      • Beisswenger P.J.
      • Brown W.V.
      • Ceriello A.
      • Le N.A.
      • Goldberg R.B.
      • Cooke J.P.
      • et al.
      Meal-induced increases in C-reactive protein, interleukin-6 and tumour necrosis factor α are attenuated by prandial + basal insulin in patients with Type 2 diabetes.
      ], endothelial dysfunction [
      • Ceriello A.
      • Cavarape A.
      • Martinelli L.
      • Da Ros R.
      • Marra G.
      • Quagliaro L.
      • et al.
      The post-prandial state in Type 2 diabetes and endothelial dysfunction: effects of insulin aspart.
      ] and thrombosis [
      • Santilli F.
      • Formoso G.
      • Sbraccia P.
      • Averna M.
      • Miccoli R.
      • Di Fulvio P.
      • et al.
      Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus.
      ].

      6.7 Postmeal hyperglycaemia is associated with decreased myocardial blood volume and myocardial blood flow [Level 2+]

      One study evaluated the effects of a standardized mixed meal on myocardial perfusion in 20 people without diabetes and 20 people with type 2 diabetes without macrovascular or microvascular complications [
      • Scognamiglio R.
      • Negut C.
      • De Kreutzenberg S.V.
      • Tiengo A.
      • Avogaro A.
      Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients.
      ]. No difference in fasting myocardial flow velocity (MFV), myocardial blood volume (MBV) and myocardial blood flow (MBF) between the control group and people with diabetes were observed. However, in the postmeal state, MBV and MBF decreased significantly in people with diabetes. Controlling postprandial hyperglycaemia has been demonstrated to improve myocardial blood flow and function [
      • Scognamiglio R.
      • Negut C.
      • de Kreutzenberg S.V.
      • Tiengo A.
      • Avogaro A.
      Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients.
      ,
      • Bibra H.
      • Siegmund T.
      • Ceriello A.
      • Volozhyna M.
      • Schumm-Draeger P.M.
      Optimized postprandial glucose control is associated with improved cardiac/vascular function—comparison of three insulin regimens in well-controlled type 2 diabetes.
      ].

      7. Question 2

      Is the treatment of postmeal hyperglycaemia beneficial in improving clinical outcomes and glycaemic control (HbA1c)?

      7.1 There is currently a lack of direct randomized clinical trial evidence that correcting postmeal hyperglycaemia improves clinical outcomes [Level 1−]

      Two studies were specifically designed to asses the hypothesis that controlling postprandial hyperglycaemia can prevent cardiovascular complications.
      The “Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D)” is a multinational, randomized, controlled trial designed to compare the effects of prandial vs. fasting glycaemic control on risk for cardiovascular outcomes in people with type 2 diabetes after acute myocardial infarction (AMI) [
      • Raz I.
      • Wilson P.W.
      • Strojek K.
      • Kowalska I.
      • Bozikov V.
      • Gitt A.K.
      • et al.
      Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial.
      ]. People with type 2 diabetes aged 30–75 years were randomly assigned within 21 days after AMI to (1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or (2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l). A total of 1115 subjects were randomized (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation time after randomization was 963 days (range 1–1687 days). The trial was stopped for lack of efficacy. Risk of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean HbA1c did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4). The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 mmol/l vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 mmol/l vs. 1.3 mmol/l; P < 0.001) compared with the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 mmol/l vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 mmol/l vs. 7.3 mmol/l; P = 0.233) compared with the PRANDIAL group.
      Overall the HEART2D study did not show a beneficial effect of preferentially treating postprandial hyperglycaemia in reducing further cardiovascular events in people with diabetes who had had an acute myocardial infarction.
      The ability of the short-acting insulin secretagogue, nateglinide, to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance has been evaluated in the NAVIGATOR Trial [
      • Trial (NAVIGATOR Study Group)
      Effect of Nateglinide on the incidence of diabetes and cardiovascular events.
      ]. In a double-blind, randomized clinical trial, 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors were assigned to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification programme. Participants were followed for a median of 5 years for incident diabetes. The effect of nateglinide on the occurrence of three co-primary outcomes was evaluated: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. After adjustment for multiple testing, nateglinide, compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00–1.15; P = 0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI 0.82–1.09; P = 0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI 0.83–1.03; P = 0.16). Nateglinide did, however, increase the risk of hypoglycaemia.
      Unfortunately, neither the HEART2D Study [
      • Raz I.
      • Wilson P.W.
      • Strojek K.
      • Kowalska I.
      • Bozikov V.
      • Gitt A.K.
      • et al.
      Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial.
      ] nor the NAVIGATOR Study [
      • Trial (NAVIGATOR Study Group)
      Effect of Nateglinide on the incidence of diabetes and cardiovascular events.
      ] help in answering the question of whether lowering postprandial hyperglycaemia reduces cardiovascular disease. The HEART2D study failed to reach the study's prespecified difference in postprandial hyperglycaemia of 2.5 mmol/l (45 mg/dl) with the mean difference at the end of the study being only 0.8 mmol/l (14 mg/dl), less than 1/3 of the goal, even though this was statistically significantly different between the two groups. This small difference is unlikely to influence cardiovascular outcomes, particularly in such a short period [
      • Ceriello A.
      Postprandial hyperglycemia and cardiovascular disease: is the HEART2D study the answer?.
      ]. Moreover, the study was under-powered as confirmed by the low rate of the events [
      • Ceriello A.
      Postprandial hyperglycemia and cardiovascular disease: is the HEART2D study the answer?.
      ]. Despite the overall negative result, a recent post hoc analysis suggested that older type 2 diabetes AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial vs. fasting/premeal glycaemia [
      • Raz I.
      • Ceriello A.
      • Wilson P.W.
      • Battioui C.
      • Su E.W.
      • Kerr L.
      • et al.
      Post hoc subgroup analysis of the HEART2D Trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia.
      ]. The results of the NAVIGATOR study are difficult to reconcile. Nateglinide not only failed to improve glucose levels 2 h after the glucose challenge in the annual OGTT, but glucose levels were actually higher in the nateglinide compared with the placebo group [
      • Ceriello A.
      Postprandial hyperglycemia and cardiovascular disease: is the HEART2D study the answer?.
      ]. Furthermore the drop-out rate was very high [
      • Ceriello A.
      Postprandial hyperglycemia and cardiovascular disease: is the HEART2D study the answer?.
      ].
      The Kumamoto study [
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin- dependent diabetes mellitus: a randomized prospective 6-year study.
      ], which used multiple daily insulin injections to control both fasting and postmeal glycaemia in people with type 2 diabetes, reported a curvilinear relationship between retinopathy and microalbuminuria with both fasting and 2-h postmeal plasma glucose control. The study showed no development or progression of retinopathy or nephropathy with fasting blood plasma glucose <6.1 mmol/l (110 mg/dl) and 2-h postmeal blood plasma glucose <10 mmol/l (180 mg/dl). The Kumamoto study suggests that both reduced postmeal plasma glucose and reduced fasting plasma glucose are strongly associated with reductions in retinopathy and nephropathy.
      Other consideration in interpreting these findings is the level of risk of study participants and their duration of diabetes [
      • Ceriello A.
      Point: postprandial glucose levels are a clinically important treatment target.
      ]. As reviewed above, recent studies have suggested that control of hyperglycemia may have a different impact in primary and secondary prevention of cardiovascular disease in type 2 diabetes and that the timing of initiation of more intensive glucose control may also be important. Starting too late may attenuate any possible beneficial effect of treating hyperglycaemia at an early stage of the disease.
      At this time the impact of treating postprandial hyperglycaemia on cardiovascular disease is still a matter of debate.

      7.2 Treatment with agents which target postmeal plasma glucose reduces vascular events in primary prevention [Level 1−]

      A meta-analysis by Hanefeld et al. [
      • Hanefeld M.
      • Cagatay M.
      • Petrowitsch T.
      • Neuser D.
      • Petzinna D.
      • Rupp M.
      Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies.
      ] showed significant positive trends in risk reduction for all selected cardiovascular event categories with treatment with acarbose, an α-glucosidase inhibitor that specifically reduces postmeal plasma glucose excursions by delaying the breakdown of disaccharides and polysaccharides (starches) into glucose in the upper small intestine. In all of the seven studies of at least one year's duration, people treated with acarbose showed reduced 2-h postmeal levels compared with controls. Treatment with acarbose was significantly associated with a reduced risk for myocardial infarction and other cardiovascular events. These findings are consistent with findings from the STOP-NIDDM trial [
      • Chiasson J.L.
      • Josse R.G.
      • Gomis R.
      • Hanefeld M.
      • Karasik A.
      • Laakso M.
      Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOPNIDDM trial.
      ], which showed that treating people with IGT with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension, although postmeal glucose was not routinely monitored. The ACE (Acarbose Cardiovascular Evaluation) study (www.clinicaltrials.gov NCT00829660) will provide further information on this question.

      7.3 Targeting both postmeal plasma glucose and fasting plasma glucose is an important strategy for achieving optimal glycaemic control [Level 1+]

      The relative contribution of postmeal plasma glucose to overall glycaemia increases as the HbA1c level decreases. Monnier et al. [
      • Monnier L.
      • Lapinski H.
      • Colette C.
      Contributions of fasting and postprandial plasma increments to overall diurnal hyperglycaemia of type 2 diabetic patients: variations with increasing levels of HbA1c.
      ] showed that in people with HbA1c levels <7.3%, the contribution of postmeal plasma glucose to HbA1c was ∼70%, whereas the postmeal contribution was ∼40% when HbA1c levels were above 9.3%. Also nocturnal fasting plasma glucose levels remain at near-normal levels as long as the HbA1c level remains <8% [
      • Monnier L.
      • Colette C.
      • Dunseath G.J.
      • Owens D.R.
      The loss of postprandial glycaemic control precedes stepwise deterioration of fasting with worsening diabetes.
      ]. However, postmeal plasma glucose control deteriorates earlier, occurring when HbA1c levels rise above 6.5%, indicating that people with relatively normal fasting plasma glucose values can exhibit abnormal elevations of glucose levels after meals. The same study also reported that the rate of deterioration of postmeal plasma glucose excursions after breakfast, lunch and dinner differs with postbreakfast plasma glucose being negatively affected first.
      These findings are supported by interventions demonstrating that achieving target fasting plasma glucose alone is still associated with HbA1c levels >7%. Woerle et al. [
      • Woerle H.J.
      • Neumann C.
      • Zschau S.
      • Tenner S.
      • Irsigler A.
      • Schirra J.
      • et al.
      Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes importance of postprandial glycemia to achieve target HbA1c levels.
      ] assessed the relative contribution of controlling fasting and postmeal plasma glucose in people with type 2 diabetes and HbA1c ≥ 7.5%. Only 64% of people achieving a fasting plasma glucose <5.6 mmol/l (100 mg/dl) achieved an HbA1c < 7% whereas 94% who achieved the postmeal target of <7.8 mmol/l (140 mg/dl) did. Decreases in postmeal plasma glucose accounted for nearly twice the decrease in HbA1c compared with decreases in fasting plasma glucose. Postmeal plasma glucose accounted for 80% of HbA1c when HbA1c was <6.2% and about 40% when HbA1c was above 9.0%.
      These studies support the view that control of fasting hyperglycaemia is necessary but usually insufficient for achieving HbA1c goals <7% and that control of postmeal hyperglycaemia is an important consideration for achieving recommended HbA1c goals.
      The efficacy of achieving HbA1c target with different approaches to insulin therapy targeting or not targeting postprandial hyperglycaemia has also recently been evaluated in two metaanalyses [
      • Lasserson D.S.
      • Glasziou P.
      • Perera R.
      • Holman R.R.
      • Farmer A.J.
      Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses.
      ,
      • Giugliano D.
      • Maiorino M.I.
      • Bellastella G.
      • Chiodini P.
      • Ceriello A.
      • Esposito K.
      Efficacy of insulin analogs in achieving the hemoglobin A1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials.
      ]. The overall conclusions were that a greater HbA1c reduction may be obtained in type 2 diabetes using biphasic or prandial insulin rather than a basal regimen, but with increased risk of hypoglycaemia.
      Rates of hypoglycaemia may different depending on whether treatment attempting to lower HbA1c levels to <7% targets fasting or postprandial hyperglycaemia. In the “treat-to-target” study [
      • Riddle M.C.
      • Rosenstock J.
      • Gerich J.
      The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.
      ], which used long-acting and intermediate-acting insulins to control fasting plasma glucose, only 25% of once-daily glargine-treated people achieved an HbA1c of <7% without documented nocturnal hypoglycaemia. Conversely, Bastyr et al. [
      • Bastyr III, E.J.
      • Stuart C.A.
      • Brodows R.G.
      • Schwartz S.
      • Graf C.J.
      • Zagar A.
      • et al.
      Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group.
      ], demonstrated that targeting postmeal plasma glucose vs. fasting plasma glucose was associated with lower levels of HbA1c. Also no severe hypoglycaemia was observed in the study by Woerle et al. in which a reduction of mean HbA1c from 8.7% to 6.5% was achieved, including targeting of postmeal plasma glucose [
      • Woerle H.J.
      • Neumann C.
      • Zschau S.
      • Tenner S.
      • Irsigler A.
      • Schirra J.
      • et al.
      Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes importance of postprandial glycemia to achieve target HbA1c levels.
      ].

      8. Question 3

      Which therapies are effective in controlling postmeal plasma glucose?

      8.1 Diets with a low glycaemic load are beneficial in improving glycaemic control [Level 1+]

      Nutritional interventions, physical activity and weight control remain the cornerstones of effective diabetes management. Although few would dispute the importance and benefits of regular physical activity and maintenance of desirable body weight, there is considerable debate regarding optimum diet composition. Some forms of carbohydrate may exacerbate postmeal glycaemia. The glycaemic index (GI) is an approach to classifying carbohydrate foods by comparing the glycaemic effect (expressed as the postmeal incremental area under the curve) of carbohydrate weight in individual foods. Most modern starchy foods have a relatively high GI, including potatoes, white and brown bread, rice and breakfast cereals [
      • Foster-Powell K.
      • Holt S.H.
      • Brand-Miller J.C.
      International table of glycemic index and glycemic load values: 2002.
      ]. Foods with a lower GI (e.g. legumes, pasta and most fruits) contain starches and sugars that are more slowly digested and absorbed, or less glycaemic by nature (e.g. fructose, lactose). Dietary glycaemic load (GL), the product of the carbohydrate content of the diet and its average GI, has been applied as a “global” estimate of postmeal glycaemia and insulin demand. Despite early controversy, the GI and GL of single foods have been shown to reliably predict the relative ranking of postmeal glycaemic and insulinemic responses to mixed meals [
      • McMillan-Price J.
      • Petocz P.
      • Atkinson F.
      • O’neill K.
      • Samman S.
      • Steinbeck K.
      • et al.
      Comparison of 4 diets of varying glycemic load on weight loss and cardiovascular risk reduction in overweight and obese young adults: a randomized controlled trial.
      ,
      • Wolever T.M.
      • Yang M.
      • Zeng X.Y.
      • Atkinson F.
      • Brand-Miller J.C.
      Food glycemic index, as given in glycemic index tables, is a significant determinant of glycemic responses elicited by composite breakfast meals.
      ]. The use of GI can provide an additional benefit for diabetes control beyond that of carbohydrate counting [
      • Sheard N.F.
      • Clark N.G.
      • Brand-Miller J.C.
      • Franz M.J.
      • Pi-Sunyer F.X.
      • Mayer-Davis E.
      • et al.
      Dietary carbohydrate (amount and type) in the prevention and management of diabetes: a statement by the American diabetes association.
      ].
      Meta-analyses of randomized controlled trials have shown that diets with a lower GI result in improvements in HbA1c in the order of 0.5% [
      • Brand-Miller J.C.
      • Petocz P.
      • Colagiuri S.
      Meta-analysis of low-glycemic index diets in the management of diabetes: response to Franz.
      ,
      • Thomas D.
      • Elliott E.J.
      Low glycaemic index, or low glycaemic load, diets for diabetes mellitus.
      ,
      • Thomas D.E.
      • Elliott E.J.
      The use of low-glycaemic index diets in diabetes control.
      ]. A recent study compared a low GL with a low-fat diet in a randomized trial in 79 obese adults with type 2 diabetes over a 40-week period and found that HbA1c reduction was 0.7% greater with the low GL diet [
      • Fabricatore A.N.
      • Wadden T.A.
      • Ebbeling C.B.
      • Thomas J.G.
      • Stallings V.A.
      • Schwartz S.
      • et al.
      Targeting dietary fat or glycemic load in the treatment of obesity and type 2 diabetes: a randomized controlled trial.
      ]. Another 6 month study in people with type 2 diabetes compared a low GI diet with a high cereal fibre diet and showed an HbA1c decreased of 0.5% with the low GI diet and a 0.18% decrease with the high cereal fibre diet (P < 0.001) [
      • Jenkins D.J.
      • Kendall C.W.
      • McKeown-Eyssen G.
      • Josse R.G.
      • Silverberg J.
      • Booth G.L.
      • et al.
      Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes: a randomized trial.
      ].

      8.2 Several classes of pharmacologic agents preferentially lower postmeal plasma glucose [Level 1+]

      Although many agents improve overall glycaemic control, including postmeal plasma glucose levels, several pharmacologic therapies specifically target postmeal plasma glucose.
      Therapies which have been available for some time include α-glucosidase inhibitors, glinides (rapid-acting insulin secretagogues), short-acting sulphonylureas, and insulins (rapid-acting human insulins/insulin analogues and biphasic [premixed] human insulins/insulin analogues).
      In addition, new classes of therapies for managing postmeal plasma glucose in people with diabetes (glucagon-like peptide-1 [GLP-1] derivatives, dipeptidyl peptidase-4 [DPP-4] inhibitors) have shown significant benefits in reducing postmeal plasma glucose excursions and lowering HbA1c. These therapies address deficiencies in pancreatic and gut hormones that affect insulin and glucagon secretion, satiety and gastric emptying.
      This section presents a description of the pharmacologic agents preferentially lowering postmeal plasma glucose, listed alphabetically. Specific combinations of therapies are not included in this summary.

      8.2.1 α-Glucosidase inhibitors

      α-Glucosidase inhibitors (AGIs) delay the absorption of carbohydrates from the gastrointestinal tract, thereby limiting postmeal plasma glucose excursions. Specifically, they inhibit α-glucosidases located in the brush border of the proximal small intestine that breaks down disaccharides and more complex carbohydrates. Through competitive inhibition of these enzyme, AGIs delay intestinal carbohydrate absorption and attenuate postmeal plasma glucose excursions [
      • Van de Laar F.A.
      • Lucassen P.L.B.J.
      • Akkermans R.P.
      • Van de Lisdonk E.H.
      • Rutten G.E.H.M.
      • Van Weel C.
      Alpha-glucosidase inhibitors for type 2 diabetes mellitus.
      ]. Acarbose, miglitol and voglibose are commercially available AGIs.

      8.2.2 Dipeptidyl peptidase-4 (DPP-4) inhibitors

      DPP-4 inhibitors act by inhibiting the DPP-4 enzyme which degrades GLP-1, thereby increasing the active form of the hormone. This in turn stimulates glucose-dependent insulin secretion and suppresses glucagon release [
      • Holst J.J.
      • Gromada J.
      Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
      ]. DPP-4 inhibitors decrease postmeal glucose and improve HbA1c without causing hypoglycaemia [
      • Richter B.
      • Bandeira-Echtler E.
      • Bergerhoff K.
      • Lerch C.
      Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus.
      ]. Currently, alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin are commercially available DPP-4 inhibitors.

      8.2.3 Glinides

      Glinides have a mechanism of action similar to sulphonylureas, but they act through a separate receptor and have a much shorter metabolic half-life. They stimulate a rapid but short-lived release of insulin from pancreatic β-cells that lasts 1–2 h [
      • Wolffenbuttel B.H.
      • Nijst L.
      • Sels J.P.
      • Menheere P.P.
      • Muller P.G.
      • Kruseman A.C.
      Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM.
      ]. When taken at mealtimes, these agents attenuate postmeal plasma glucose excursions and decrease the risk of hypoglycaemia during the late postmeal phase because less insulin is secreted several hours after the meal [
      • Nattrass M.
      • Lauritzen T.
      Review of prandial glucose regulation with repaglinide: a solution to the problem of hypoglycaemia in the treatment of Type 2 diabetes?.
      ]. Two agents are commercially available: nateglinide and repaglinide.

      8.2.4 Glucagon-like peptide-1 (GLP-1) derivatives

      GLP-1 is an incretin hormone secreted from the gut that lowers glucose through its ability to stimulate insulin secretion, inhibit glucagon secretion, decelerate gastric emptying and induce satiety [
      • Ritzel R.
      • Orskov C.
      • Holst J.J.
      • Nauck M.A.
      Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose–response relationships.
      ]. In people with type 2 diabetes, the incretin effect, i.e. the ability of an orally injected meal to stimulate insulin secretion, is diminished [
      • Nauck M.A.
      • Vardarli I.
      • Deacon C.F.
      • Holst J.J.
      • Meier J.J.
      Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?.
      ]. This defect can be overcome by the administration of exogenous GLP-1 analogues or GLP-1 receptor agonists [
      • Holst J.J.
      • Gromada J.
      Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
      ] GLP-1 derivatives diminish postmeal glucose excursions with a low risk of hypoglycaemic episodes, which is an advantage of the glucose dependent effect of GLP-1 [
      • Amori R.E.
      • Lau J.
      • Pittas A.G.
      Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.
      • Amori R.E.
      • Lau J.
      • Pittas A.G.
      2 years as monotherapy compared with glimepiride in patients with type 2 diabetes.
      ]. Exenatide and liraglutide are currently commercially available GLP-1 derivatives.

      8.2.5 Insulins

      • Rapid-acting human insulins/insulin analogues
      Rapid-acting human insulins have been used for decades with the main goal of decreasing postmeal glucose excursions and thereby preventing postmeal hyperglycemia. Rapid-acting insulin analogues were developed in order to better mimic the normal physiologic insulin response. The rapid-acting insulin analogues achieve a rapid onset, peak activity and a short duration of action [
      • DeWitt D.E.
      • Hirsch I.B.
      Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review.
      ]
      • Biphasic (premixed) human insulins/insulin analogues
      Biphasic (premixed) insulins combine a rapid-acting with an intermediate acting insulin component, which is an alternative to addressing postmeal in addition to overall glucose control in people with type 2 diabetes [
      • Halimi S.
      • Raskin P.
      • Liebl A.
      • Kawamori R.
      • Fulcher G.
      • Yan G.
      Efficacy of biphasic insulin aspart in patients with type 2 diabetes.
      ]. Biphasic insulin analogues are associated with advantages compared with biphasic human insulin preparations in controlling postmeal glucose [
      • Garber A.J.
      • Ligthelm R.
      • Christiansen J.S.
      • Liebl A.
      Premixed insulin treatment for type 2 diabetes: analogue or human?.
      ,
      • Christiansen J.S.
      • Liebl A.
      • Davidson A.J.
      • Ligthelm R.J.
      • Halimi S.
      Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose control.
      ]. Currently, there are several rapid-acting biphasic insulin formulations commercially available throughout the world, with different ratios of rapid and intermediate insulins, including 25/75, 30/70, 40/60 and 50/50 mixtures.

      8.2.6 Short-acting sulphonylureas

      Of the sulphonylureas, glipizide is short-acting and is occasionally used specifically for postmeal hyperglycaemia [
      • Carroll M.F.
      • Gutierrez A.
      • Castro M.
      • Tsewang D.
      • Schade D.S.
      Targeting postprandial hyperglycemia: a comparative study of insulinotropic agents in type 2 diabetes.
      ].

      9. Question 4

      What are the targets for postmeal glycaemic control and how should they be assessed?

      9.1 Postmeal plasma glucose levels seldom rise above 7.8 mmol/l (140 mg/dl) in people with normal glucose tolerance and typically return to basal levels 2–3 h after food ingestion [Level 2++].

      Several studies using continuous glucose monitoring have shown that postmeal plasma glucose levels seldom rise above 7.8 mmol/l (140 mg/dl) in healthy people with normal glucose tolerance and typically return to basal levels 2–3 h after food ingestion [
      • Polonsky K.S.
      • Given B.D.
      • Van C.E.
      Twenty-four hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.
      ,
      • Mazze R.S.
      • Strock E.
      • Wesley D.
      • Borgman S.
      • Morgan B.
      • Bergenstal R.
      • et al.
      Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis.
      ,
      • Tsujino D.
      • Nishimura R.
      • Taki K.
      • Miyashita Y.
      • Morimoto A.
      • Tajima N.
      Daily glucose profiles in Japanese people with normal glucose tolerance as assessed by continuous glucose monitoring.
      ].
      Despite the postmeal plasma glucose levels being below 7.8 mmol/l (140 mg/dl) in people with normal glucose tolerance, glucose levels in healthy people are often difficult to achieve in people with diabetes without an undue risk of hypoglycaemia. Therefore, for reasons of safety, the IDF sets a glycaemic target slightly above the normal levels and for postmeal glucose this target is 9.0 mmol/l (162 mg/dl).

      9.2 Self-monitoring of blood glucose (SMBG) is currently the optimal method for assessing plasma glucose levels [Level 2++]

      SMBG allows people with diabetes to obtain and use information about “real-time” plasma glucose levels and facilitates timely intervention to achieve and maintain glycaemic control. SMBG in accepted as an integral part of diabetes management in people with diabetes requiring insulin therapy. Recently the IDF has published guidance on the use of SMBG in people with non-insulin treated diabetes and emphasized the need to ensure that there is an agreed purpose for using SMBG and that specific action should be linked to SMBG [

      IDF guideline on self-monitoring of blood glucose in non-insulin treated type 2 diabetes. www.idf.org/guidelines/smbg-t2d.

      ]. Recent studies have confirmed that structured SMBG followed by therapeutic interventions result in greater HbA1c reduction in people with non-insulin-requiring type 2 diabetes compared with programmes without structured SMBG [
      • Polonsky W.H.
      • Fisher L.
      • Schikman C.H.
      • Hinnen D.A.
      • Parkin C.G.
      • Jeisovsky Z.
      • et al.
      Structured self-monitoring blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the Structured Testing Program study.
      ,
      • Franciosi M.
      • Lucisano G.
      • Pellegrini F.
      • Cantarello A.
      • Consoli A.
      • Cucco L.
      • et al.
      ROSES: role of self-monitoring of blood glucose and intensive education in patients with Type 2 diabetes not receiving insulin. A pilot randomized clinical trial.
      ,
      • Durán A.
      • Martín P.
      • Runkle I.
      • Perez N.
      • Abad R.
      • Fernandez M.
      • et al.
      Benefits of self-monitoring blood glucose in the management of new-onset Type 2 diabetes mellitus: the St Carlos Study, a prospective randomized clinic-based interventional study with parallel groups.
      ].
      SMBG is only one component of diabetes management. Its potential benefits require training of people to perform SMBG, interpret their test results and appropriately adjust their treatment regimens to achieve glycaemic control. Moreover, clinicians must be versed in interpreting SMBG data, prescribing appropriate medications and closely monitoring people in order to make timely adjustments to their regimens as needed.
      The timing and frequency of SMBG must be individualized to each person's treatment regimen and level of glycaemic control [

      IDF guideline on self-monitoring of blood glucose in non-insulin treated type 2 diabetes. www.idf.org/guidelines/smbg-t2d.

      ].

      10. Emerging technologies

      10.1 Continuous glucose monitoring

      The use of continuous glucose monitoring (CGM) for monitoring diabetes is increasing [
      • Hoeks L.B.
      • Greven W.L.
      • de Valk H.W.
      Real-time continuous glucose monitoring system for treatment of diabetes: a systematic review.
      ]. CGM employs a sensor, a data storage device and a monitor. The sensor measures glucose every 1–10 min and transmits this reading to a data storage device. Results can be either downloaded retrospectively by the physician, or displayed in “real time” in the monitor. CGM provides information on glucose levels, patterns and trends, thereby reflecting the effects of medication, meals, stress, exercise and other factors that affect glucose levels. Because CGM devices measure interstitial glucose, test values lag behind single “point in-time” measurements by several minutes.

      10.2 1,5-Anhydroglucitol

      Plasma 1,5-anhydroglucitol (1,5-AG), a naturally occurring dietary polyol, has been proposed as a marker for postmeal hyperglycaemia. Because 1,5-AG is sensitive and responds rapidly to changes in serum glucose, it accurately reflects transient elevations of glucose within a few days [
      • Yamanouchi T.
      • Ogata N.
      • Tagaya T.
      • Kawasaki T.
      • Sekino N.
      • Funato H.
      • et al.
      Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycaemic control.
      ]. An automated assay for 1,5-AG has been used in Japan for over a decade [
      • Fukumura Y.
      • Tajima S.
      • Oshitani S.
      • Ushijima Y.
      • Kobayashi I.
      • Hara F.
      • et al.
      Fully enzymatic method for determining 1,5-anhydro-d-glucitol in serum.
      ]. A recent study suggests that 1,5-AG best reflects 2-h postprandial glucose values of the 2 previous weeks [
      • Stettler C.
      • Stahl M.
      • Allemann S.
      • et al.
      Association of 1,5-anhydroglucitol and 2-h postprandial blood glucose in type 2 diabetic patients.
      ]. However there is no outcome studies using this measure of glycaemic control.

      11. Clinical implications

      Most guidelines, including the updated IDF Global Guideline for Type 2 Diabetes, recommend a general HbA1c target of <7.0% while emphasizing the need to take into account patient factors in determining the appropriate target for an individual.
      The data reviewed in this guideline support the concept that postmeal glucose makes a significant contribution to overall glycaemia reflected in the HbA1c level and that the relative contribution increases at lower levels of HbA1c, especially below 8.0%. Therefore efforts to reach the HbA1c target from lower HbA1c levels will often require specific attention to correcting postmeal glucose.
      Consequently particularly in people with HbA1c levels between 7.0 and 8.0% in whom it is considered clinically appropriate to improve glycaemic control, assessing postmeal glucose is warranted and if found to be elevated, blood glucose lowering therapy should preferentially choose an agent which specifically lowers postmeal glucose. Similarly dietary interventions which lower postmeal glucose should be emphasized.
      This approach compliments the IDF Treatment Algorithm for people with type 2 diabetes.

      Conflict of interest

      Members of the Guideline Development Group have declared relevant dualities of interest in the topic and in relationships with commercial enterprises, governments and non-governmental organizations. No fees were paid to the Guideline Development Group members in connection with the current activity. Members of the Guideline Development Group (except for Antonio Ceriello and Stephen Colagiuri) were not aware of the identity of the sponsors during the entire development of this guideline. The authors declare that they have no conflict of interest.

      Acknowledgements

      This update of the 2007 PostMeal Glucose was supported by unrestricted educational grants from Bristol-Myers Squibb , Lilly Diabetes , Novo Nordisk A/S , Nutricia , Roche Diabetes Care . These companies did not take part in any aspect of the development of this guideline.

      Appendix A. Members of the Guideline Development Group

      • Antonio Ceriello, Chair, Barcelona, Spain
      • Maha Barakat, Abudabi, United Arab Emirates
      • Silver Bahendeka, Kampala, Uganda
      • Stephen Colagiuri, Sydney, Australia
      • John Gerich, Rochester, United States
      • Markolf Hanefeld, Dresden, Germany
      • Linong Ji, Beijing, China
      • Nebojsa Lalic, Belgrade, Serbia
      • Lawrence A. Leiter, Toronto, Canada
      • Louis Monnier, Montpellier, France
      • David Owens, Cardiff, United Kingdom
      • Naoko Tajima, Tokyo, Japan
      • Jaakko Tuomilehto, Helsinki, Finland

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