Review
Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus

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Summary

Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin—this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual β-cell function are populations of interest for future trials.

Introduction

Type 1 diabetes is characterised by destruction of the pancreatic β cells,1 resulting in severely impaired or absent insulin secretion combined with abnormal α-cell function, with excess glucagon in the fasting and postprandial state.2, 3, 4 Hence, type 1 diabetes is regarded as a bihormonal disease.5 Tight glycaemic control reduces the risk of development and progression of late diabetic microvascular complications,6 and also has long-term positive effects on the development and progression of nephropathy, hypertension,7 cardiovascular disease, and atherosclerosis.8 However, intensified insulin therapy to achieve such tight control simultaneously increases the risk of hypoglycaemia.6 Additionally, despite the availability of new insulin analogues with more physiological absorption profiles and less day-to-day variation in bioavailability than older insulin preparations, erratic blood glucose profiles, which also raise the risk of hypoglycaemia, remain a major problem.9, 10

Insulin treatment in type 1 diabetes also has several other limitations. First, insulin treatment only partly addresses the paradoxical and pathophysiological excess of glucagon. Second, in individuals with type 1 diabetes the gastric emptying rate is altered,11 and even the most rapid-acting mealtime insulin peaks too late to match the postprandial glucose absorption, resulting in large postprandial glucose excursions. Third, intensive insulin treatment is associated with weight gain, adversely affecting the cardiovascular risk profile,10, 12 and might reduce treatment compliance by patients missing insulin injections or reducing the dose, resulting in hyperglycaemia. Obesity is an increasing problem in type 1 diabetes, with an estimated prevalence of about 50% in some high-income countries.13 Accordingly, the exploration of novel non-insulin adjunct therapies in patients with type 1 diabetes seems pertinent.

The ideal treatment for type 1 diabetes should address the abnormal α-cell function, improve HbA1c without increasing the risk of hypoglycaemia, induce weight loss in overweight individuals, and reduce the risk of cardiovascular disease. To achieve treatment targets, combination therapy using drugs with actions complementary to insulin could be appropriate. Pramlintide and glucagon-like peptide-1 (GLP-1) receptor agonists induce satiety, inhibit glucagon secretion, and delay gastric emptying.14, 15, 16 Further, GLP-1 receptor agonists have the potential to improve residual β-cell function, which has clear beneficial metabolic effects.17 GLP-1 receptor agonists also lower blood pressure by 2–4 mm Hg.18 Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the concentration of endogenous GLP-1 by two to three times, potentiating glucose-dependent insulin secretion and glucagon inhibition, but have no effect on bodyweight.19, 20 Metformin mainly decreases hepatic glucose production and induces a minor weight loss. Thiazolidinediones mainly improve insulin sensitivity, but this effect is often associated with weight gain, whereas sulfonylureas solely potentiate insulin secretion.21

Sodium-glucose co-transporter-2 (SGLT2) inhibitors impair renal glucose reabsorption, causing a substantial excretion of glucose in urine. Since the mechanism of action of SGLT2 inhibitors is insulin independent, a significant effect of these drugs on glucose control should be expected if used in patients with type 1 diabetes.22 The glucosuria and osmotic diuresis induced by these drugs are associated with weight loss and blood pressure lowering of 2–4 mm Hg.23 Sodium-glucose co-transporter-1 (SGLT1) inhibitors impair intestinal absorption of glucose; they have been combined with SGLT2 inhibitors and are in phase 3 development for treatment of type 2 diabetes.24

In theory, future treatment regimens for type 1 diabetes might be improved by combining one or more of these drugs with insulin. This Review aims to discuss the mechanisms of action, efficacy, and adverse effects of pramlintide, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT1 inhibitors, and SGLT2 inhibitors when used in combination with insulin in type 1 diabetes, and will also briefly discuss the use of metformin, sulfonylureas, and thiazolidinediones as add-on therapies in this disease.

Section snippets

Amylin (pramlintide)

The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is a 37-aminoacid peptide that is synthesised in the pancreatic β cells, stored in the pancreas with insulin (1:100), and is co-secreted with insulin in a high-frequency, pulsatile manner every 4 to 6 min.25 Amylin seemingly exerts its actions centrally by activating receptors in the area postrema, stimulating satiety centres and triggering efferent nervous impulses that inhibit glucagon secretion, and thereby reduce

GLP-1 receptor agonists

Endogenous GLP-1 is secreted from L cells distributed throughout the small and large intestine in response to food ingestion,37, 38 and has pleiotropic effects such as enhancement of glucose-induced insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, and induced satiety resulting in weight loss (figure 2).39, 40, 41, 42 In patients with type 1 diabetes, the amount of meal-induced GLP-1 secretion is similar to that of healthy individuals, but for therapeutical use

DPP-4 inhibitors

DPP-4 inhibitors lower blood glucose by extending the half-life of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).57, 58 After secretion from L cells, GLP-1 is degraded by DDP-4 within 2–3 min,59 thus DPP-4 inhibition increases the concentration of endogenous secreted GLP-1 by two to three times. In patients with type 2 diabetes, DPP-4 inhibitors potentiate glucose-dependent insulin secretion and inhibit glucagon release without any clinically relevant effect on gastric

SGLT2 inhibitors and dual inhibitors of SGLT1 and SGLT2

SGLT2 mainly causes renal glucose reabsorption and SGLT1 is pivotal in the intestinal absorption of glucose.22 Thus, inhibition of SGLT1 and SGLT2 results in decreased blood glucose through a reduction of glucose absorption in the gastrointestinal tract and increased renal glucose excretion. SGLT1 inhibition also increases postprandial release of the gastrointestinal hormones GLP-1 and polypeptide YY (PYY), probably by increasing delivery of glucose to the distal small intestine, thereby

Metformin

Metformin is a first-line therapy in patients with type 2 diabetes. Metformin mainly decreases hepatic glucose production, and also induces minor weight loss in individuals with type 2 diabetes (figure 4).74, 75, 76 Efficacy of metformin therapy in type 1 diabetes has been comprehensively described in a systematic review and meta-analysis by Vella and colleagues.77 Findings from five randomised clinical trials provided appropriate data for the meta-analysis, suggesting that metformin

Thiazolidinediones

Insulin resistance exists even in lean patients with type 1 diabetes.80, 81 Thiazolidinediones improve insulin sensitivity (figure 4) and were investigated in a double-blind randomised study,82 in which 50 overweight patients with type 1 diabetes were assigned to either placebo or 4 mg rosiglitazone twice per day. After 8 months of follow-up, both groups had an equal reduction in HbA1c and increase in bodyweight. Daily insulin dose rose by 11% in placebo-treated patients and decreased by 3% in

Sulfonylureas

Potentiation of insulin secretion is the entire mechanism of action of sulfonylureas (figure 4); consequently, no significant effect on glycaemic control or insulin dose would be expected with these drugs in patients with type 1 diabetes without β-cell function. Accordingly, in small studies including patients with long duration of diabetes, no effect on glycaemic control, insulin requirements, or glucose metabolism was noted.88, 89 Improvement in glycaemic control and higher rates of remission

Discussion and future studies

Several barriers interfere with achieving target HbA1c in patients with type 1 diabetes.93 Monnier and colleagues94 showed that when HbA1c values are less than 7·8%, postprandial blood glucose has a greater effect on overall glucose control, suggesting the need for more aggressive management of postprandial hyperglycaemia. Additionally, patients with type 1 diabetes show a paradoxical increase in glucagon that contributes to increased hepatic glucose output, resulting in worsening of

Search strategy and selection criteria

We searched the Cochrane Library, MEDLINE, and Embase for studies published from 2005 to 2016 using the terms “glucagon-like peptide-1” or “GLP-1” or “GLP-1RA” or “pramlintide” or “SGLT-2 inhibitors” or “DPP-4 inhibitors” or “metformin” or “sulfonylurea” or “thiazolidinedione” combined with the terms “type 1 diabetes” or “IDDM” or “T1D” or “T1DM”. We favoured publications from 2011 to 2016, but did not exclude widely referenced and highly regarded older publications. We also searched the

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