How treatment developed
11 and 23 January 1922
The first insulin injections
At Toronto General Hospital, 14 year old Leonard Thompson receives the first insulin injection on 11 January 1922. The extract is impure and he has an allergic reaction. Biochemist James Collip refines it over the next 12 days, and the second injection, on 23 January, works. Banting and Macleod share the 1923 Nobel Prize in Physiology or Medicine. Before insulin, people with type 1 diabetes did not survive more than weeks or months.
27 July 2000 and 28 September 2006
Islet transplants: insulin independence, but not for long
A team in Edmonton led by James Shapiro reports in the New England Journal of Medicine that seven people with type 1 diabetes were free of insulin injections after receiving donor islet cells. A multicentre trial published in 2006 found that 44% of recipients no longer needed insulin a year after their final infusion and another 28% had partial islet function, but insulin independence did not last for most of them.
What conventional treatment has not solved
A century on, insulin keeps people with type 1 diabetes alive, and newer drugs have improved control in type 2. What they have not done is stop the immune attack in type 1, or reliably prevent the complications. The International Diabetes Federation lists heart disease, kidney failure, nerve damage and loss of vision among the serious complications of diabetes. Much of the peptide research below is an attempt to reach those problems.
The peptide research, by what it was trying to do
Trying to stop or reverse type 1 diabetes
2011 to 2015
DiaPep277: a positive phase 3, then an allegation, then a failed second trial
DiaPep277 is a peptide from the human heat shock protein 60, designed to calm the immune attack on insulin cells. In 2011 Andromeda Biotech reported that its first phase 3 trial, DIA-AID 1 in 457 people with newly diagnosed type 1 diabetes, met its main goal, with 23.4% more C-peptide preserved than on placebo. C-peptide is a marker of the body's own insulin production. The results were published in Diabetes Care in 2014.
After buying Andromeda, Hyperion Therapeutics stopped development and said some Andromeda employees had improperly obtained unblinded DIA-AID 1 data from a third-party statistics firm, adding that the apparent treatment effect was lost when the data were examined. The second phase 3 trial, DIA-AID 2, in about 475 people aged 20 to 45, missed its main goal in September 2015.
17 November 2022
Not a peptide: teplizumab delays type 1 diabetes in people at risk
The US Food and Drug Administration approves teplizumab, an antibody, to delay stage 3 type 1 diabetes in people aged 8 and over who are already at stage 2. In a trial of 76 people, 45% of those given teplizumab were later diagnosed with stage 3 disease, against 72% on placebo, over a median 51 months of follow up. It is listed here because it is the one immune therapy in this field that reached approval.
Controlling blood sugar, weight and the heart
1992 to 2005
A peptide from Gila monster venom becomes the first GLP-1 drug
In 1992 endocrinologist John Eng, working at a Veterans Affairs hospital in the Bronx, isolates exendin-4 from Gila monster venom. It acts on the same receptor as the gut hormone GLP-1 but lasts far longer in the body. Its synthetic version, exenatide, is approved by the FDA in 2005, the first drug of the GLP-1 class.
2016
LEADER and SUSTAIN-6: GLP-1 drugs reduce heart events
In LEADER, 9,340 people with type 2 diabetes and high cardiovascular risk were followed for a median 3.8 years. Heart attack, stroke or cardiovascular death occurred in 13.0% on liraglutide and 14.9% on placebo (hazard ratio 0.87, 95% confidence interval 0.78 to 0.97). In SUSTAIN-6, 3,297 people on semaglutide or placebo for 104 weeks had those events in 6.6% and 8.9% (hazard ratio 0.74, 0.58 to 0.95). SUSTAIN-6 also raised a concern about the eyes, covered below.
June 2021
SURPASS-2: tirzepatide beats semaglutide on HbA1c and weight
Tirzepatide acts on both the GIP and GLP-1 receptors. In an open label, 40 week trial of 1,879 people with type 2 diabetes on metformin, HbA1c fell by 2.01, 2.24 and 2.30 percentage points on tirzepatide 5, 10 and 15 mg, against 1.86 on semaglutide 1 mg. Weight loss was greater by 1.9, 3.6 and 5.5 kg. Nausea, diarrhoea and vomiting were the most common side effects.
Nerve damage
2012 to 2015
Ersatta, a C-peptide replacement, fails in a 250 person trial
Cebix developed Ersatta, a long acting form of C-peptide, for nerve damage in type 1 diabetes. A phase 1 and 2 study reported in 2012 showed a favourable signal over 12 weeks. The phase 2b trial that followed, in roughly 250 people over a year, finished in December 2014. Chief executive Joel Martin said Ersatta and placebo were indistinguishable. Cebix, which had raised close to 50 million dollars, wound down.
Eye disease and sight loss
1999 to 2006
Octreotide: two phase 3 trials, mixed results, no approval
In 1999 Novartis began two phase 3 trials of monthly octreotide, a somatostatin peptide, in people with moderate to severe or early proliferative diabetic retinopathy. In one study, octreotide delayed progression of retinopathy but not macular oedema. In the other, it had no significant effect on progression, though loss of visual acuity was delayed at the 30 mg dose. Side effects included diarrhoea, gallstones and mild hypoglycaemia. A 2006 review in Review of Ophthalmology concluded that because the studies did not meet their endpoints, approval for diabetic retinopathy was not expected.
2016
SUSTAIN-6 raises an eye signal for semaglutide
In SUSTAIN-6, retinopathy complications, meaning vitreous haemorrhage, blindness or a condition needing treatment, occurred in 50 people (3.0%) on semaglutide and 29 (1.8%) on placebo (hazard ratio 1.76, 95% confidence interval 1.11 to 2.78). Of the 79 people affected, 83.5% already had retinopathy at the start. Retinopathy was not the trial's main question, and it can worsen early when blood sugar falls fast. Novo Nordisk is running a dedicated trial, FOCUS, covered below.
Foot ulcers and wound healing
1997 to 2018
Becaplermin: a growth factor gel with a cancer warning that was later removed
Becaplermin (Regranex) is a recombinant platelet derived growth factor gel approved in the US in 1997 for diabetic foot ulcers. A boxed warning about cancer mortality was added in 2008 after a retrospective claims study. In November 2018 the FDA removed it. Smith and Nephew's petition included a Veterans Affairs database study of 6,429 gel users and 6,429 non-users over 11 years, which found no increase in cancer or cancer deaths.
October 2016
Pexiganan, an antimicrobial peptide cream, fails two phase 3 trials
Dipexium's Locilex (pexiganan cream 0.8%) was tested for mild infections of diabetic foot ulcers in two identical trials, OneStep-1 and OneStep-2, covering 389 people at 59 US centres. It did not beat the same cream without the active peptide on clinical cure, wound closure or bacterial clearance. The company reported higher than expected rates of serious osteomyelitis and cellulitis and its shares fell about 83%. An earlier phase 3 had reported it was non-inferior to an oral antibiotic. The trial chair said some mild infections may not need an antibacterial at all.
Used in Cuba and elsewhere
Heberprot-P: injected epidermal growth factor, with mostly uncontrolled evidence
Heberprot-P is a recombinant human epidermal growth factor injected into and around diabetic foot ulcers. It is an innovation of Cuba's Center for Genetic Engineering and Biotechnology and has been used there for years, with about 4,000 people covered in post-marketing surveillance according to a trial registry description. Most reports we found are uncontrolled. One 2022 study of 58 people in Turkey reported healing in 93.1% and amputation in 3.4%, with tremor and fainting the commonest adverse events. Such figures cannot be compared with a placebo group.
Stomach, and the brain
2016 to 2021
Relamorelin: a diabetic gastroparesis drug ends in four phase 3 trials
Relamorelin, a ghrelin receptor peptide agonist, was tested by Allergan for diabetic gastroparesis, a condition in which the stomach empties slowly. After a phase 2b trial, Allergan ran four phase 3 studies and an extension from 2017 to 2020. The registry records the reason the programme ended as solely a business decision, and gives no efficacy explanation.