Despite type 2 diabetes being a condition of relative insulin deficiency, people with newly diagnosed diabetes usually have near-normal or even elevated fasting plasma insulin values. This apparent conundrum is explained by hepatic glucose efflux being increased to raise fasting plasma glucose values sufficiently to stimulate β-cells with a reduced insulin secretory capacity to maintain “normal” fasting plasma insulin values. Teleologically this ensures that insulin-related metabolic processes are not impaired and ketoacidosis is avoided. The downstream cost is chronic fasting and postprandial hyperglycemia that leads in the longer term to glucose-specific microvascular complications such as diabetic retinopathy and diabetic kidney disease, and substantial increase in the risk of macrovascular complications. The 20-year UK Prospective Diabetes Study (UKPDS) showed that type 2 diabetes–related complications are not inevitable, as was widely believed, but, rather, could be mitigated to a great extent by achievement of good glycemic control from the time type 2 diabetes was diagnosed. Extended posttrial follow-up of UKPDS participants identified that there are near-lifelong beneficial glycemic and metformin “legacy” effects whereby within-trial risk reductions persist virtually unchanged for up to 24 years. Achieving near-normoglycemia immediately following diagnosis appears to be essential to minimize the lifetime risk of diabetes-related complications to the greatest extent possible.

Serendipity is a happy and unexpected event that apparently occurs due to chance. Such opportunities need to be recognized and consciously acted on, particularly where research is concerned, as serendipity often points in different directions. I have been fortunate to have many serendipity moments during my career, even if only apparent in hindsight.

As a newly qualified physician in 1973 I was perplexed by my clinical colleagues’ somewhat cavalier attitude to hyperglycemia in people living with diabetes. At that time there were no universally accepted guidelines for blood glucose targets (1), with treatment focused on controlling symptoms such as excessive thirst and polyuria, rather than striving for near-normal glucose levels. As a result, blood glucose levels often remained in the 10–15 mmol/L range or even higher. I found this lack of concern remarkable, as other biochemical parameters found to be even marginally out of range were investigated and remedial therapy was instigated where feasible. It was widely believed, by Martin Siperstein and others, that the complications of type 2 diabetes were inevitable and genetic in origin (2), although some proponents, such as George Cahill, were convinced that microvascular complications were hyperglycemia related (3). Following studies I performed in 1975 and 1976 as the late Robert Turner’s first research fellow, we published a hypothesis in The Lancet to explain persistent hyperglycemia, proposing that insulin rather than glucose homeostasis underpinned the pathophysiology of type 2 diabetes (4). We proposed that basal plasma insulin levels were maintained preferentially to support essential metabolic functions and to avoid ketoacidosis at the expense of often marked hyperglycemia. This hypothesis provided an explanation for the apparently “normal” basal plasma insulin concentrations found in people with type 2 diabetes despite their impaired β-cell function. Indeed, when we reduced fasting plasma glucose levels to normal by means of a fish insulin infusion, mean endogenous human insulin levels were halved (5). It is inadequate functional β-cell mass that underlies the pathogenesis of type 2 diabetes (6).

I became convinced that fasting glucose values should be restored to the normal range with a consequent reduction in postprandial hyperglycemia and that doing so may impact favorably on the development of the complications of type 2 diabetes. This was the start of my quest for basal normoglycemia, having concluded that type 2 diabetes was an endocrine deficiency disease, a logical treatment of which would be hormone replacement therapy (7). To rectify the relative endogenous insulin deficiency seen in people with diet-treated type 2 diabetes, I used subcutaneous beef ultralente, an exogenous long-acting insulin, to successfully achieve normal fasting plasma glucose values in all study participants. Postprandial glucose excursions were unchanged but frameshifted to occur from a normal baseline (Fig. 1) (7). I then used chlorpropamide, a long-acting sulfonylurea, to increase endogenous insulin levels and again successfully restored fasting normoglycemia. This time there was a small reduction in the frameshifted postprandial excursions (Fig. 1) (8). Hypoglycemia did not occur with either intervention.

Figure 1

Mean 24-h plasma glucose values in eight individuals with normal weight and five individuals with obesity with mild type 2 diabetes when treated with diet alone (▴––––▴), with basal insulin supplements (△––––△), and with chlorpropamide (△- - - -△). Eight age-matched individuals without diabetes are shown with data as a mean (–––––). The horizontal dotted line represents 80 mg/dL (4.4 mmol/L) (7,8). hrs., hours. Reprinted with permission from Holman et al. (8).

Figure 1

Mean 24-h plasma glucose values in eight individuals with normal weight and five individuals with obesity with mild type 2 diabetes when treated with diet alone (▴––––▴), with basal insulin supplements (△––––△), and with chlorpropamide (△- - - -△). Eight age-matched individuals without diabetes are shown with data as a mean (–––––). The horizontal dotted line represents 80 mg/dL (4.4 mmol/L) (7,8). hrs., hours. Reprinted with permission from Holman et al. (8).

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In November 1976, just 14 months after starting these two studies, I presented the findings at the ninth International Diabetes Federation congress, in New Delhi, India. The suggestion that a basal insulin or a long-acting sulfonylurea could be used as first-line therapy to restore normal fasting plasma glucose levels was poorly received. Hyperglycemia was still not regarded as an important issue, and there were concerns about the risks of hypoglycemia. Robert Turner and I concluded that a large randomized controlled trial would be needed to determine 1) the benefits of restoring normoglycemia and 2) the relative merits of available glucose-lowering therapies. This was the birth of the UK Prospective Diabetes Study (UKPDS) (9).

To better understand the dynamics of hyperglycemia in type 2 diabetes I performed 24-h plasma glucose and insulin profiles in triplicate in individuals with diet-treated type 2 diabetes and individuals without diabetes (10). These profiles showed that fasting plasma glucose levels were tightly controlled, with each person maintaining their own set value (Fig. 2). I hypothesized that plasma glucose and insulin levels were controlled in the basal state by a feedback loop between the liver and β-cells, with the height of the fasting plasma glucose value being a bioassay of the reduction in β-cell function and the height of the fasting plasma insulin value being a function of the degree of insulin resistance. In 1978 I wrote a computer feedback model program that used paired fasting plasma glucose and insulin values to estimate β-cell function and insulin resistance levels for people with or without diet-treated type 2 diabetes. Subsequently a more comprehensive model was developed that incorporated glucose and insulin fluxes in brain, muscle, and fat (11). In 1985, David Matthews et al. (12) published an expanded and more detailed structural model, known as homeostasis model assessment (HOMA), that took greater account of peripheral glucose uptake and could use fasting values of specific insulin or C-peptide in addition to radioimmunoassay-measured insulin. The HOMA2 Calculator, for estimating β-cell function (HOMA2_%B), insulin sensitivity (HOMA2_%S), and insulin resistance (HOMA2_IR), is freely available from the University of Oxford Diabetes Trials Unit website (13).

Figure 2

The 7:00 a.m. basal plasma glucose values of nine individuals of normal weight with diet-treated type 2 diabetes and six without diabetes, with measurements on three separate nights. The individuals are ranked in order of the height of their basal plasma glucose values (10).

Figure 2

The 7:00 a.m. basal plasma glucose values of nine individuals of normal weight with diet-treated type 2 diabetes and six without diabetes, with measurements on three separate nights. The individuals are ranked in order of the height of their basal plasma glucose values (10).

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To titrate glucose-lowering therapies to achieve normoglycemia safely it was clear that routine urine glucose testing would need to be replaced by more informative home blood glucose monitoring (14). Reflomat point-of-care glucose meters, first available in 1974, were too expensive for home use. However, we showed that home-performed seven-point glucose profiles could give stable readings for up to a week if the glucose oxidase strips were stored in a desiccant container (15). Money could also be saved by cutting the strips lengthways in two. To enable HbA1c levels to be measured prior to clinic visits, we invented a capillary blood sampling bottle that collected exactly 50 µL blood into a protective diluent at home (16). Using this liquid sample collector device in a 1-year study of 200 outpatients with type 2 diabetes meant therapy adjustment advice could be given at the time of clinic visits, which led to a mean reduction in HbA1c levels of 0.8% (17). People were understandably reluctant to prick their fingers manually. It was painful if the needle went too deep and had to be repeated if too shallow. Accordingly, we invented the first automated lancet, which pricked the finger to a precise depth at the touch of a button, before instantly withdrawing the needle (18). The Autolet was manufactured and marketed by a local plastic injection molding firm (Fig. 3). Well received by patients and health care providers worldwide, it won the UK Design Council award in 1980. Many people, especially the elderly, found drawing up insulin from vials with a syringe to be a difficult and error-prone task, so we designed the world’s first automated insulin pen (19). Doses are selected accurately by turning the dial, and the insulin dose chosen is delivered simply by pushing the button. The Autopen, launched in 1982, continues to be used widely (Fig. 4).

Figure 3

First automated lancet (Autolet) (18).

Figure 3

First automated lancet (Autolet) (18).

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Figure 4

First automated insulin pen (Autopen) (19). Image reproduced with permission from Owen Mumford.

Figure 4

First automated insulin pen (Autopen) (19). Image reproduced with permission from Owen Mumford.

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Many people with type 2 diabetes have insulin resistance and need substantially larger insulin doses than individuals with type 1 diabetes, with people with overweight requiring even higher doses. Using data from my earlier studies I devised an algorithm, based on weight and fasting plasma glucose, to help estimate the larger starting doses needed to achieve normoglycemia more rapidly (20). I designed a slide rule dose guide to simplify the dose calculation and also programmed a Sharp PC-1360 pocket computer to make dose estimation even easier. The basal insulin dose calculator was validated subsequently in my Treating To Target in Type 2 Diabetes (4-T) trial (21) in which basal insulin was added to maximally tolerated doses of metformin and sulfonylurea in 708 people with type 2 diabetes whose blood glucose levels were inadequately controlled. No major episodes of hypoglycemia occurred despite advised starting doses ranging from 2 to 76 IU/day.

To assist people with type 1 diabetes to more confidently adjust their basal and insulin doses I implemented a self-adaptive hybrid algorithm on an EHT-10 touch screen handheld computer called the Patient-Oriented Insulin Regimen Optimizer (POIRO). Information on meal size, planned exercise, state of health, and recent hypoglycemic episodes was entered simply by tapping appropriate on-screen options. POIRO then suggested the most appropriate insulin dose, which patients could “nudge” up or down if they wished to take a higher or lower dose. Additional screens provided overviews of glucose profiles and trends. Our pilot study showed that use of POIRO improved preprandial glucose levels with no increased risk of hypoglycemia (22).

Interventional Trial

The UKPDS was launched in December 1977, just 13 months after my International Diabetes Federation presentation. This landmark trial recruited 5,102 individuals with newly diagnosed type 2 diabetes, median age 53 years (range 25–65), in 23 U.K. centers and ran for 20 years (23). Unusually, the UKPDS included people <40 years of age and those with confirmed fasting plasma glucose values >6.0 mmol/L rather than the then diagnostic criterion of ≥7.8 mmol/L, allowing for a wider range of individuals to be studied. In the UKPDS glycemic control study a conventional glycemic control strategy, aiming for the lowest attainable fasting plasma glucose with diet alone, was compared with an intensive glycemic control strategy, aiming for fasting plasma glucose values <6.0 mmol/L with insulin or sulfonylurea monotherapy. Only participants with overweight could be randomized to metformin, as ethics committees were reluctant to allow its use off-label in people of normal weight following the adverse biguanide findings of the University Group Diabetes Program (UGDP) (24). The UKPDS was primarily a monotherapy trial, as ethics committees were also reluctant to approve combination therapies in light of the UGDP results.

While the UKPDS was ongoing it provided a number of major new insights into the pathophysiology and progression of type 2 diabetes. Firstly, at the time of diagnosis ∼50% of those enrolled had clinically evident significant tissue damage, with one in five having retinopathy or an abnormal electrocardiogram, 7% impaired reflexes or diminished vibration sense, and 1%–3% angina pectoris, intermittent claudication, myocardial infarction, stroke, or transient ischemic attack (23). This finding helped change the view that type 2 diabetes was a “mild” disease and emphasized the need for early detection. Secondly, the UKPDS showed unequivocally that elevated HbA1c was an independent potentially modifiable risk factor for coronary heart disease that could be added to the deadly quartet of increased LDL cholesterol, reduced HDL cholesterol, increased systolic blood pressure, and smoking to become the deadly quintet (25). Thirdly, the UKPDS showed that progressive hyperglycemia was a key pathophysiological feature of type 2 diabetes (26). Following the ∼2% drop in mean HbA1c values during the dietary run-in period, mean values rose steadily over the next 10 years in participants randomized to the diet arm, suggesting this was the natural history of the condition. Surprisingly, after a further initial drop in mean HbA1c values in participants randomized to insulin, sulfonylurea, or metformin when these therapies were initiated, mean values rose over time in an identical fashion. Fourthly, the mechanism driving progressive hyperglycemia was shown to be declining β-cell function over time (27). In those allocated to the diet arm, β-cell function declined by ∼4% per year, regardless of whether they were overweight. Those allocated to sulfonylurea or metformin had identical downward trajectories, after an initial boost of β-cell function. Importantly, β-cell function decline with sulfonylurea therapy was no quicker than with diet or metformin, suggesting that sulfonylureas do not hasten the loss of β-cell function as some have suggested (28). Fifthly, concerns that the early introduction of glucose-lowering therapies would promote substantial weight gain were unfounded. Over 10 years, mean weight was ∼2.5 kg below baseline in participants assigned to diet or metformin, unchanged in those assigned to chlorpropamide or glibenclamide, and ∼2.5 kg higher in those assigned to basal insulin therapy (26). Sixthly, a critical UKPDS finding was that type 2 diabetes in conjunction with hypertension constitutes “double jeopardy.” Participants who were hypertensive at baseline were at an 82% greater risk of a diabetes-related death over 10 years, compared with those who were normotensive (29). For mitigation of the potential risk of hypertension-related treatment bias in light of this finding, the 1,148 hypertensive UKPDS participants were randomized in the Hypertension in Diabetes Study (HDS) in a two-by-two factorial design to a tight blood pressure control strategy with an ACE inhibitor or β-blocker, or to a less tight blood pressure control strategy avoiding these agents (23,30).

Primary Results

The primary results of the UKPDS were presented at the 1998 European Association for the Study of Diabetes meeting in Barcelona. They showed that diabetes complications were not inevitable and their incidence could be reduced by improved glycemic control. A median 0.9% lower HbA1c over median 10.0 years in the sulfonylurea or insulin arm, compared with the diet arm, resulted in a 12% significantly lower risk for any diabetes-related end point (P = 0.029), 25% for microvascular disease (P = 0.0099), and 21% for retinopathy (P = 0.015). The 16% lower risk for myocardial infarction did not achieve statistical significance (31). In the metformin arm in participants with overweight, a median 0.6% lower HbA1c over median 10.7 years, compared with the diet arm, resulted in risk reductions of 32% for any diabetes-related end point (P = 0.0023), 39% for myocardial infarction (P = 0.010), and 36% for all-cause mortality (P = 0.011) but no significant reduction in microvascular disease (26). In the HDS, a mean 10/5 mmHg lower blood pressure over median 8.0 years in the tight control arm, compared with the less tight control arm, resulted in a 24% risk reduction for any diabetes-related end point (P = 0.0046), 44% for stroke (P = 0.013), and 37% for microvascular disease (P = 0.0092) (32). Captopril and atenolol were equally effective in lowering blood pressure and in reducing the risks of complications (33). In a record unbroken to date, five articles were published simultaneously, including an HDS cost-effectiveness analysis showing that tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, with a cost-effectiveness ratio that compared favorably with many accepted health care programs (26,31–34). Following publication of the UKPDS and HDS results, a question frequently asked was whether blood glucose control or blood pressure control was the more important intervention. Accordingly, we assessed the interactive effects of glycemia and systolic blood pressure exposure on the risk of diabetes complications over time and showed that the risk of complications was associated independently and additively with hyperglycemia and with hypertension. We concluded that intensive treatment of both of these risk factors is required to minimize the incidence of complications to the fullest extent possible (35).

The landmark UKPDS results led rapidly to the updating of type 2 diabetes management guidelines worldwide to emphasize the need to prevent complications through early intensive glycemic and tight blood pressure control. One year later, in 1999, the UKPDS group was awarded the Charles H. Best Medal for Distinguished Service in the Cause of Diabetes by the American Diabetes Association at their 59th Scientific Sessions.

When the UKPDS interventional trial ended on 30 September 1997, all 3,277 surviving trial participants consented to be followed and were entered into a 10-year posttrial monitoring (PTM) study that ran until 30 September 2007. Participants were returned to usual care with no attempt made to maintain their randomized treatment strategies or targets. It was assumed that the within-trial differences in the risk of complications between the intensive and conventional groups would soon disappear, as mean HbA1c values became virtually identical within the first year, and the glucose-lowering therapies rapidly became similar between groups (36).

The PTM study yielded remarkable results showing that the benefits observed at the end of the interventional trial did not wane as anticipated but persisted—a phenomenon I described as a “legacy” effect (36). In the sulfonylurea-insulin group at 10 years the relative risk reductions were 9% for any diabetes-related end point (P = 0.040) and 24% for microvascular disease (P = 0.001), with emerging benefits of 15% for myocardial infarction (P = 0.01) and 13% for all-cause mortality (P = 0.007) (Fig. 5). The glycemic legacy effect is akin to “metabolic memory,” first described in the Epidemiology of Diabetes Interventions and Complications (EDIC) study in individuals with type 1 diabetes (37).

Figure 5

Hazard ratios for UKPDS participants who had any diabetes-related end point (A and B), myocardial infarction (C and D), or microvascular disease (E and F) or who died from any cause (G and H) are shown for the sulfonylurea-insulin group and for the metformin group, respectively, vs. their corresponding conventional therapy groups. Hazard ratios at the end of the interventional trial in 1997, the 10-year PTM period in 2007, and the posttrial record linkage study in 2021 are shown as red squares, with intervening annual values as blue diamonds. Hazard ratios below unity indicate a favorable outcome from sulfonylurea-insulin or metformin therapy. Numbers of first events for aggregate outcomes that accumulated in each group are shown under the year at 4-year intervals. The vertical bars represent 95% CIs. P values are shown for 1997, 2007, and 2021.

Figure 5

Hazard ratios for UKPDS participants who had any diabetes-related end point (A and B), myocardial infarction (C and D), or microvascular disease (E and F) or who died from any cause (G and H) are shown for the sulfonylurea-insulin group and for the metformin group, respectively, vs. their corresponding conventional therapy groups. Hazard ratios at the end of the interventional trial in 1997, the 10-year PTM period in 2007, and the posttrial record linkage study in 2021 are shown as red squares, with intervening annual values as blue diamonds. Hazard ratios below unity indicate a favorable outcome from sulfonylurea-insulin or metformin therapy. Numbers of first events for aggregate outcomes that accumulated in each group are shown under the year at 4-year intervals. The vertical bars represent 95% CIs. P values are shown for 1997, 2007, and 2021.

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In the metformin group, significant risk reductions also persisted: 21% for any diabetes-related end point (P = 0.013), 33% for myocardial infarction (P = 0.005), and 7% for all-cause mortality (P = 0.002) (Fig. 5). No legacy effects were seen, however, for early tight blood pressure control (38).

Posttrial Record Linkage Study

When the PTM study ended, participants were followed up for a further 14 years to 30 September 2021 to see how long the glycemic and metformin legacy effects might persist. Of the 1,561 PTM study survivors, 1,525 could be linked to their routinely collected U.K. National Health Service data with their clinical outcomes derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendance (39). Extraordinarily, the results demonstrated near-lifelong legacy effects of early intensive glycemic control with sulfonylurea or insulin and with metformin. After 44 years from randomization early intensive glycemic control with sulfonylurea or insulin led overall to 10% fewer of any diabetes-related end points (P = 0.015), 17% fewer first myocardial infarctions (P = 0.002), 26% fewer microvascular complications (P < 0.0001), and 10% fewer deaths (P = 0.015) (Fig. 5), as well as 16% fewer diabetes-related deaths (P = 0.003) (Fig. 6). Early intensive glycemic control with metformin led overall to 18% fewer of any diabetes-related end points (P = 0.025), 31% fewer first myocardial infarctions (P = 0.003), and 20% fewer deaths (P = 0.010) (Fig. 5), as well as 25% fewer diabetes-related deaths (P = 0.016) (Fig. 6).

Figure 6

Hazard ratios for participants in the UKPDS for the occurrence of diabetes-related deaths (A and B), stroke (C and D), or peripheral vascular disease (E and F) are shown for the sulfonylurea-insulin group and for the metformin group, respectively, vs. their corresponding conventional therapy groups. Hazard ratios at the end of the interventional trial in 1997, the 10-year PTM period in 2007, and the posttrial record linkage study in 2021 are shown as red squares, with intervening annual values as blue diamonds. Hazard ratios below unity indicate a favorable outcome from sulfonylurea-insulin or metformin therapy. Numbers of first events for aggregate outcomes that accumulated in each group are shown under the year at 4-year intervals. The vertical bars represent 95% CIs. P values are shown for 1997, 2007, and 2021.

Figure 6

Hazard ratios for participants in the UKPDS for the occurrence of diabetes-related deaths (A and B), stroke (C and D), or peripheral vascular disease (E and F) are shown for the sulfonylurea-insulin group and for the metformin group, respectively, vs. their corresponding conventional therapy groups. Hazard ratios at the end of the interventional trial in 1997, the 10-year PTM period in 2007, and the posttrial record linkage study in 2021 are shown as red squares, with intervening annual values as blue diamonds. Hazard ratios below unity indicate a favorable outcome from sulfonylurea-insulin or metformin therapy. Numbers of first events for aggregate outcomes that accumulated in each group are shown under the year at 4-year intervals. The vertical bars represent 95% CIs. P values are shown for 1997, 2007, and 2021.

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In reality I believe the glycemic legacy effect is a hyperglycemic legacy effect. Early inadequate control of hyperglycemia appears to induce irreversible pathophysiological changes, likely epigenetic in nature, that permanently increase the risk of diabetes complications and of premature death. Establishing and maintaining near-normoglycemia from diagnosis of type 2 diabetes can minimize the risk of complications and prolong life. The use of newer glucose-lowering agents, such as glucagon-like peptide 1 (GLP-1) receptor agonists (40) and sodium–glucose cotransporter 2 inhibitors (41), in the modern management of type 2 diabetes has been shown to reduce the risk of diabetes-related complications. Their glucose-lowering properties, however, appear to explain only part of their ability to prevent or delay cardiovascular and kidney disease, suggesting that nonglycemic mechanisms might largely be responsible (42–45). Accordingly, achieving and maintaining near-normoglycemia is essential if the lifetime risk of complications is to be reduced to the greatest extent possible. The numerically greater legacy effect seen with metformin suggests that additional protective mechanisms might exist, such as inhibition of inflammatory pathways (46).

I founded the Diabetes Trials Unit (DTU) when I became a consultant physician in 1985 and ran it for more than three decades (47). As a fully registered UK Clinical Research Collaboration Clinical Trials Unit it specialized in facilitating studies from early-phase translational trials to multinational phase III and IV trials, that have involved >150,000 people.

Cardiovascular Outcome Trials

When the primary results of the UKPDS did not show a statistically significant reduction in macrovascular complications with intensive glycemic control, attention focused on postprandial hyperglycemia as a new therapeutic target, given that epidemiologically postprandial glucose values were more strongly associated with coronary heart disease risk than were fasting plasma glucose values (48). Accordingly, Robert Califf and I designed and co-chaired the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial with randomization of 9,306 participants in 40 countries who had documented cardiovascular disease or were at high cardiovascular risk and who had impaired glucose tolerance (IGT). Our aim was to see whether enhancing postprandial insulin levels with a meglitinide (nateglinide up to 60 mg three times daily) to reduce postprandial glucose excursions in this population would reduce the risk of cardiovascular disease or new-onset type 2 diabetes, as well as the impact of valsartan (up to 160 mg daily), in a two-by-two factorial design (49). Assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes (50). The use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes (P < 0.001) but did not reduce the rate of cardiovascular events (51). The suggestion that endogenous hyperinsulinemia might predict death from coronary heart disease in patients with type 2 diabetes led some to say that any beneficial effects of nateglinide might have been offset by increasing postprandial plasma insulin excursions (52). To explore matters further I designed and chaired the Acarbose Cardiovascular Evaluation (ACE) trial, with co-chairs Pang ChangYu and Hu DaYi, to see whether reducing postprandial glucose excursions with an insulin-sparing α-glucosidase inhibitor, acarbose, would reduce cardiovascular risk or the incidence of type 2 diabetes (53). In ACE 6,522 participants, with established coronary heart disease and IGT in 176 hospital centers in the People’s Republic of China and Hong Kong, were randomized to acarbose (50 mg three times a day) or placebo. Acarbose did not reduce the risk of major adverse cardiovascular events but did reduce the incidence of diabetes by 18% (P = 0.005) (54). NAVIGATOR and ACE clearly indicate that reducing postprandial glucose excursions in isolation does not reduce cardiovascular risk.

Before the 2008 U.S. Food and Drug Administration guidance was issued on evaluating cardiovascular risk in new antidiabetes therapies to treat type 2 diabetes (55), Robert Califf and I designed and launched two more cardiovascular outcome trials. The first was the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS), where 14,671 participants with type 2 diabetes in 35 countries were randomized to add either sitagliptin, the first-in-class dipeptidyl peptidase 4 inhibitor, at a dose of 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate was ≥30 and <50 mL/min per 1.73 m2) or placebo to their existing therapy (56). During a median follow-up of 3.0 years, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events or other adverse events and, crucially, had no impact on the risk of hospitalization for heart failure as had been observed for alogliptin and saxagliptin (57). The second was the EXenatide Study of Cardiovascular Event Lowering (EXSCEL), with randomization of 14,752 participants with type 2 diabetes (73.1% with previous cardiovascular disease) in 35 countries to receive subcutaneous injections of a GLP-1 receptor agonist, once-weekly exenatide (EQW), at a dose of 2 mg, or matching placebo in addition to usual care (58). We felt that the early-phase studies showing reductions in HbA1c, blood pressure, LDL cholesterol, and weight with EQW indicated a potential to reduce cardiovascular risk. With the novel statistical design EQW was tested for superiority for efficacy and for noninferiority for safety. Over a median 3.2 years of follow-up, the incidence of major adverse cardiovascular events did not differ significantly between participants receiving EQW and those receiving placebo (59), although the results were in line with those of other GLP-1 receptor agonist cardiovascular outcome studies (60).

In light of our experiences with cardiovascular outcome trials, Robert Califf and I published a Lancet Series article summarizing randomized controlled cardiovascular outcome trials in type 2 diabetes, where we provided an overview of ongoing trials and their limitations and speculated on how future trials could be made more efficient and effective (61). A major concern I shared with John McMurray and others was the universal absence of hospital admission for heart failure as a prespecified component of primary composite cardiovascular outcomes in large-scale type 2 diabetes trials of new glucose-lowering drugs. In our 2014 article we recommended that heart failure should be systematically evaluated in all such trials (62).

One of my major interests was the possibility of delaying or preventing the onset of type 2 diabetes to further reduce the risk of diabetes complications. I co-chaired, with Hertzel Gerstein and Salim Yusuf, the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial, run jointly by the DTU and the Population Health Research Institute. A total of 5,269 participants with IGT in 21 countries were randomized to ramipril (15 mg/day) or placebo and to rosiglitazone (8 mg/day) or placebo in a two-by-two factorial design (63). Over median 3.0 years follow-up, rosiglitazone reduced incident diabetes by 60% (P < 0.0001) (64), but no reduction was seen with ramipril (65). The substantial risk reduction seen with rosiglitazone, however, did not translate into clinical practice, given Steve Nissen’s adverse findings on its effects on myocardial infarction cardiovascular death (66).

DTU Translational Research Group

The DTU Translational Research Group (TRG) undertook early-phase research on potential future therapies, new medical devices, and complex interventions with a successful track record of synergistic collaborations with industry and other academic groups. In 2003 I was appointed the founding Academic Chairman of the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) and between 2012 and 2017 was the Diabetes Theme leader for the National Institute for Health and Care Research Oxford Biomedical Research Centre. Notable studies performed by the TRG include the development of a standardized oral triglyceride tolerance test (67); evaluation of a disposable, self-administered, electronic oral glucose tolerance test device in a community setting (68); the EMpagliflozin in patients with acute MYocardial infarction (EMMY) trial (69); and using an 11β-HSD1 inhibitor to mitigate adverse prednisolone-induced effects (70).

Personal Fat Threshold

T2D risk is increased by obesity but also occurs in people who do not have obesity. Indeed, 36% of UKPDS participants were normal weight at entry (23). Roy Taylor and I hypothesized that individuals have a personal fat threshold the exceeding of which makes likely the development of diabetes (71). This hypothesis was confirmed by our 1-year Reversal of Type 2 diabetes Upon Normalization of Energy intake in the non-obese (ReTUNE) study (72). With dietary weight loss 70% of people with T2D and BMI <27 kg/m2 achieved remission, as shown previously in the Diabetes Remission Clinical Trial (DiRECT) in individuals with overweight or obesity (73). Raised liver fat, de novo lipogenesis, and hepatic fat export parameters all returned to normal, resulting in improved β-cell function and remission of diabetes lasting for at least 12 months. We concluded that the etiology of type 2 diabetes is the same in people with either normal weight or obesity, meaning that the same glucose-lowering modalities can be used irrespective of body weight.

I have been fortunate to have led many trials that have done so much to help improve the care, management, and outcomes for people living with diabetes. Regularly embedding key research questions within clinical trials has generated greater understanding of the pathophysiology of diabetes and new insights into the mechanistic impacts of the interventions evaluated. Routinely collecting biomarker samples and conducting post hoc analyses of rigorously collected trial data have provided a wealth of new information, often at minimal cost. My take-home message for all young researchers is to be sure to follow your vision and to look out for serendipity. Going forward one of the greatest research challenges is to identify treatments that can preserve or indeed restore β-cell function in type 1 and type 2 diabetes.

The 2024 Banting Medal for Scientific Achievement Award Lecture was presented at the American Diabetes Association’s 84th Scientific Sessions, 24 June 2024.

Acknowledgments. The Banting Medal for Scientific Achievement Award lecture title was taken from the 2021 profile of R.R.H. in The Lancet by Geoff Watts (74). The author gives grateful thanks to all study participants and staff, especially Robert Turner, his mentor, colleague, and friend. The author is indebted to the many research fellows who have worked with him over the years and thanks them for their excellent contributions. The ultimate thanks go to the author’s family. The author thanks them for their unstinting support of his work and encouragement in all of his endeavors. R.R.H. is a National Institute for Health and Care Research Emeritus Senior Investigator.

Duality of Interest. R.R.H. reports personal fees from AstraZeneca, Lilly, Merck KGaA, and Novartis. No other potential conflicts of interest relevant to this article were reported.

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