Studies have shown that high PPG levels increases the risk of micro- and macrovascular risk in both T2DM and type 1 diabetes (T1DM). The link between post-prandial hyperglycaemia and markers of CVD such as oxidative stress, inflammation, endothelial dysfunction, and carotid intima-media thickness have been shown in numerous studies. In addition, post-prandial hyperglycaemia has also been connected with the incidence of carcinomas and cognitive dysfunction in elderly patients with T2DM.³

Tight glycaemic control reduces the risk of hyperglycaemia, which in turn has been shown to reduce the chances of CVD in patients with diabetes. The Diabetes Control and Complications Trial showed that people with T1DM, who kept their blood glucose levels as close to normal (<7%) as safely possible and as early as possible in their disease, had fewer diabetes-related health problems after 6.5 years:⁴

• The risk of diabetic eye disease decreased by 76%, and advancement of eye disease by 54% in people with some eye disease at the beginning of the study
• The risk of diabetic kidney disease by 50%
• The risk of diabetic nerve disease by 60%.

Similarly, the United Kingdom Prospective Diabetes Study (UKPDS) showed tight glycaemic control prevents microvascular complications. The UKPDS showed that reducing glucose exposure (HbA_1c 7% versus 7.9% over a median of 10 years) in patients with T2DM, reduced the risk of:⁵

• Any diabetes-related complications by 12%
• Microvascular disease by 25%
• Myocardial infarction by 16%.

How does FPG and PPG affect HbA_1c?

HbA_1c is the gold-standard in providing an average of an individual's long‐term glucose exposure (two to three months). However, in order to achieve recommended HbA_1c goals (<7%), it is essential to manage both FPG  and PPG to reduce the risk of glucose variability.⁶

Studies investigating the contributions of FPG and PPG to HbA_1c found that these contributions change, depending on whether a patient’s diabetes is well controlled or not.⁷

In what many consider a ground-breaking study, Monnier and Colette showed that PPG excursions predominate at lower HbA_1c levels, while FPG predominated at higher HbA_1c levels. They calculated that the relative contribution of PPG is 70% in patients with HbA_1c <7.3%, reducing to 30% in patients with HbA_1c>10.2%.⁸

More recently, a study by Liao et al, which included patients with T2DM, showed that a 1mmol/L increase in FPG was associated with a 2.7mmol/mol (0.25%) increase in HbA_1c, while a 1mmol/L increase in PPG was associated with 1.8mmol/mol (0.16%) increase in HbA_1c.⁹

According to the authors, this should reinforce the importance of daily glucose management of both FPG and PPG in order to achieve long‐term glycaemic goals in patients with T2DM.⁹

Ketema et al concur, stressing that a clear understanding of the relationship between different plasma glucose measurements and HbA_1c is necessary for setting appropriate day-to-day plasma glucose testing goals with the expectation of achieving specific HbA_1c targets.⁶

Recommended targets

Most treatment guidelines now include specific PPG targets alongside HbA_1c and FPG targets. The American Diabetes Association (ADA)/European Association for the Study of Diabetes guidelines recommend targets of HbA_1c <7%, FPG 4.4mmol/L, and PPG <10mmol/L.¹⁰

The International Diabetes Federation recommends targets of HbA_1c <7%, FPG 6.4mmol/L, and PPG <8.9mmol/L. The American Association of Clinical Endocrinology recommends targets of HbA_1c <7%, FPG 6.1mmol/L, and PPG ≤7.8mmol/L.¹⁰

Current strategies and therapies

Lifestyle modification and metformin are the mainstays of T2DM treatment. The 2021 ADA guideline recommends early initiation of insulin if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycaemia are present, or when HbA_1c (>10%) or FPG (16.7mmol/L) levels are very high.¹²

The preferred regimen for insulin initiation in T2DM is once-daily basal insulin. Starting doses can be estimated based on body weight (0.1–0.2 units/kg/day) and the degree of hyperglycaemia, with individualised titration over days to weeks as needed.¹²

Despite the availability of effective treatment, the majority of patients (between 40%–60%) living with T2DM does not reach glycaemic targets.¹⁷

According to Elizarova et al, a possible reason for this is that current strategies and therapies are only effective in controlling FPG, while the importance of PPG - particularly in maintaining long-term glycaemic control - receives less attention.¹¹

Basal insulin, which consists of multiple daily injections of rapid-acting insulin pre-prandially, only controls high FPG levels (by suppressing hepatic gluconeogenesis) but does not address high PPG levels, which can contribute significantly to overall HbA_1c and daily glycaemic variability, leading to an increased risk of diabetic complications.¹⁴

Managing PPG excursions

Managing PPG is one of the most challenging aspects of diabetes care, write Leahy et al. According to the authors, faster-acting insulins, new non-insulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve PPG management and overall care for people with insulin-treated diabetes, as well as new opportunities to understand and target PPG excursions specifically.¹³

The key determinants of overall PPG control are insulin secretion, insulin action in stimulating glucose uptake and suppressing glucose production, glucagon suppression,  glucose effectiveness in stimulating its own uptake and production, as well as gastric emptying and incretin hormones.¹³

How to manage PPG excursions

Leahy and colleagues stress the importance of effective lifestyle modification. Below are some of their suggestions:¹³

• Eating carbohydrates last in a meal may more effectively regulate PPG and lower glucose excursions
• Eating protein and/or vegetables first, followed 10 minutes later by carbohydrates, significantly reduced both glucose and incremental glucose peaks compared with eating carbohydrates first or eating all components together
• A study in children with T1DM found that eating protein and fat 15 minutes before carbohydrates lowered PPG and GV significantly more than standard meals
• Circadian rhythms studies suggest that exclusively limiting food intake to a six- to eight-hour daily window (a common recommendation is 10h00 to 18h00) may have a benefit on body weight and CV health regardless of macronutrients or portion sizes
• Several nutritional supplements, including viscous fibre, ascorbic acid (vitamin C), and apple cider vinegar also appear to reduce post-meal glucose levels
• Timing of exercise may be equally if not more important than its amount or vigour. A study showed that in non–insulin-using people with T2DM, 10 minutes or more of postprandial walking may lower the glycaemic effect of evening meals more than premeal exercise, effectively blunting PPG excursions. Other studies have shown similar benefits from moderate or high-intensity exercise 30 minutes to an hour after eating.

In terms of pharmaceutical management, Miyoshi et al write that basal-bolus and premixed insulin regimens that provide basal and prandial insulins may lower PPG as well as FPG levels.¹⁴

Premixed insulin regimens consist of a fixed ratio of rapid-acting insulin and intermediate insulin combined, thus eliminating the need for patients to mix or adjust the insulin, themselves whilst also reducing the number of required daily injections.¹¹

According to the ADA guideline, if basal insulin has been titrated to an acceptable FBG level (or if the dose is >0.5 units/kg/day with indications of need for other therapy) and HbA_1c remains above target, intensification should be considered.¹²

Intensification of insulin treatment can be done by adding a prandial dose to basal insulin. Starting with a single prandial dose with the largest meal of the day is simple and effective, and it can be advanced to a regimen with multiple prandial doses if necessary.¹²

Alternatively, in a patient on basal insulin in whom additional prandial coverage is desired, the regimen can be converted to two doses of a premixed insulin.¹²

Two doses of premixed insulin are a simple, convenient means of spreading insulin across the day. Moreover, human insulins, separately, self-mixed, or as premixed neutral protamine Hagedorn/regular (70/30) formulations, are less costly alternatives to insulin analogues.¹²

Efficacy of a premixed regimen vs insulin alone

Malone et al compared the glycaemic control of a premixed insulin regimen used twice daily in combination with metformin to that of a once daily insulin plus metformin in patients with T2DM inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. At endpoint, HbA_1c was lower with the premixed insulin regimen plus metformin compared with insulin plus metformin (7.54% vs 8.14%).¹⁶

Change in HbA_1c from baseline to endpoint was greater with the premix regimen plus metformin (-1.00% vs -0.42%). Two-hour PPG was lower after morning, midday, and evening meals during treatment with the premixed regimen plus metformin.¹⁶

The FBG values were lower in the insulin and metformin arm. Despite lower BG at three hours, patients treated with the premix regimen plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 vs 0.34 episodes/patient/30 days). Overall hypoglycaemia rate was not different between treatments (0.61 vs 0.44 episodes/patient/30 days).¹⁶

The authors conclude that in patients with T2DM and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily regimen plus metformin, which targets both PPG and FBG, provided clinically significant improvements in HbA_1c, significantly reducing PPG after each meal, and reducing nocturnal hypoglycaemia as compared with once-daily insulin plus metformin, a treatment that targets FBG.¹⁶

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