Introduction
Many guidelines on type 2 diabetes recommend a glycosylated haemoglobin A1c (HbA1c) level below 7%. HbA1c levels in the blood express glucose or glycaemic control over a longer time period (two to three months). During the course of type 2 diabetes it will get more difficult to reach these levels with 'lifestyle' modification (diet, exercise or both) and oral glucose-lowering agents alone. Finally, a substantial number of people will need insulin therapy for better glycaemic control. Insulin therapy can be initiated as insulin alone, called monotherapy (which means that oral glucose-lowering medication will be stopped) or in combination with oral glucose-lowering agents. In the former case, oral blood glucose-lowering agents can be added at a later stage, if insulin monotherapy fails to achieve a good HbA1c level. Hypoglycaemia and weight gain are the most common and well known side effects of insulin therapy. Adding oral agents to insulin could reduce the required insulin dose and thus decrease these insulin-related side effects. However, there could be other side effects specific to the various oral blood glucose-lowering drugs.
Review question
To assess the effects of insulin monotherapy and the addition of an oral antidiabetic drug in people with type 2 diabetes already treated with insulin but not having good glycaemic control.
Background
It is unclear whether people with type 2 diabetes mellitus on insulin alone who do not achieve good glucose levels should continue with insulin alone or can benefit from adding an oral antidiabetic drug to their insulin therapy.
Study characteristics
All 37 included studies were randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups). Their duration ranged from 2 to 12 months. The total number of participants was 3227. Several types of insulin monotherapy (once-daily long- or intermediate-acting insulin, twice-daily premixed insulin, multiple injection therapy with short-acting insulin) were compared with different types of additional antidiabetic tablets: sulphonylureas (such as glibenclamide/glyburide), metformin, alpha-glucosidase inhibitors (such as acarbose), pioglitazone and DPP-4 inhibitors (such as saxagliptin).
Key results
The addition of oral agents to insulin monotherapy reduced HbA1c by 0.4% to 1%. Most combinations of oral antidiabetic agents with insulin resulted in a reduction in the necessary insulin dose per day whereas the insulin dose per day had to be increased or remained stable in participants with insulin monotherapy. In studies reporting hypoglycaemic episodes severe events were rare and mild to moderate hypoglycaemia was observed in similar numbers when comparing insulin monotherapy to the addition of oral antidiabetic agents to insulin. However, most studies adding sulphonylureas to insulin reported more hypoglycaemic episodes. Moreover, the addition of sulphonylureas to insulin resulted in an additional weight gain of 0.4 kg to 1.9 kg compared with -0.8 kg to 2.1 kg in the insulin monotherapy groups. Pioglitazone insulin combination therapy caused on average an increase in weight of 3.8 kg compared with insulin monotherapy. The difference in average weight gain with metformin insulin combination therapy compared with insulin monotherapy was 2.1 kg less in favour of the combination therapy. Gastro-intestinal side effects such as flatulence and diarrhoea were mostly reported with metformin and alpha-glucosidase inhibitors. Addition of pioglitazone to insulin compared with insulin monotherapy resulted in more cases of oedema (fluid retention in the body) and heart failure. Only one study assessed participants' treatment satisfaction and showed no substantial differences between the addition of glimepiride or metformin and glimepiride to insulin compared with insulin monotherapy. No study assessed all-cause mortality, diabetes-related morbidity or health-related quality of life.
This evidence is up to date as of November 2015.
Quality of the evidence
Almost a third of the studies had 30 or fewer participants. A lot of studies seemed to be underpowered and thus were probably not able to answer their own research question. This could mean that potentially important differences between intervention and control groups were not detected. Only five studies had a follow-up of 12 months.
The addition of all oral glucose-lowering agents in people with type 2 diabetes and inadequate glycaemic control who are on insulin therapy has positive effects on glycaemic control and insulin requirements. The addition of sulphonylureas results in more hypoglycaemic events. Additional weight gain can only be avoided by adding metformin to insulin. Other well-known adverse effects of oral glucose-lowering agents have to be taken into account when prescribing oral glucose-lowering agents in addition to insulin therapy.
It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or can benefit from adding oral glucose-lowering agents to the insulin therapy.
To assess the effects of insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin monotherapy for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and reference lists of articles. The date of the last search was November 2015 for all databases.
Randomised controlled clinical trials of at least two months' duration comparing insulin monotherapy with combinations of insulin with one or more oral glucose-lowering agent in people with type 2 diabetes.
Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated overall quality of the evidence using GRADE. We summarised data statistically if they were available, sufficiently similar and of sufficient quality. We performed statistical analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.
We included 37 trials with 40 treatment comparisons involving 3227 participants. The duration of the interventions ranged from 2 to 12 months for parallel trials and two to four months for cross-over trials.
The majority of trials had an unclear risk of bias in several risk of bias domains. Fourteen trials showed a high risk of bias, mainly for performance and detection bias. Insulin monotherapy, including once-daily long-acting, once-daily intermediate-acting, twice-daily premixed insulin, and basal-bolus regimens (multiple injections), was compared to insulin in combination with sulphonylureas (17 comparisons: glibenclamide = 11, glipizide = 2, tolazamide = 2, gliclazide = 1, glimepiride = 1), metformin (11 comparisons), pioglitazone (four comparisons), alpha-glucosidase inhibitors (four comparisons: acarbose = 3, miglitol = 1), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) (three comparisons: vildagliptin = 1, sitagliptin = 1, saxagliptin = 1) and the combination of metformin and glimepiride (one comparison). No trials assessed all-cause mortality, diabetes-related morbidity or health-related quality of life. Only one trial assessed patients' treatment satisfaction and showed no substantial differences between the addition of either glimepiride or metformin and glimepiride to insulin compared with insulin monotherapy.
Insulin-sulphonylurea combination therapy (CT) compared with insulin monotherapy (IM) showed a MD in glycosylated haemoglobin A1c (HbA1c) of -1% (95% confidence interval (CI) -1.6 to -0.5); P < 0.01; 316 participants; 9 trials; low-quality evidence. Insulin-metformin CT compared with IM showed a MD in HbA1c of -0.9% (95% CI -1.2 to -0.5); P < 0.01; 698 participants; 9 trials; low-quality evidence. We could not pool the results of adding pioglitazone to insulin. Insulin combined with alpha-glucosidase inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.2); P < 0.01; 448 participants; 3 trials; low-quality evidence). Insulin combined with DPP-4 inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.4); P < 0.01; 265 participants; 2 trials; low quality evidence. In most trials the participants with CT needed less insulin, whereas insulin requirements increased or remained stable in participants with IM.
We did not perform a meta-analysis for hypoglycaemic events because the included studies used different definitions.. In most trials the insulin-sulphonylurea combination resulted in a higher number of mild episodes of hypoglycaemia, compared to the IM group (range: 2.2 to 6.1 episodes per participant in CT versus 2.0 to 2.6 episodes per participant in IM; low-quality evidence). Pioglitazone CT also resulted in more mild to moderate hypoglycaemic episodes compared with IM (range 15 to 90 episodes versus 9 to 75 episodes, respectively; low-quality evidence. The trials that reported hypoglycaemic episodes in the other combinations found comparable numbers of mild to moderate hypoglycaemic events (low-quality evidence).
The addition of sulphonylureas resulted in an additional weight gain of 0.4 kg to 1.9 kg versus -0.8 kg to 2.1 kg in the IM group (220 participants; 7 trials; low-quality evidence). Pioglitazone CT caused more weight gain compared to IM: MD 3.8 kg (95% CI 3.0 to 4.6); P < 0.01; 288 participants; 2 trials; low-quality evidence. Metformin CT was associated with weight loss: MD -2.1 kg (95% CI -3.2 to -1.1), P < 0.01; 615 participants; 7 trials; low-quality evidence). DPP-4 inhibitors CT showed weight gain of -0.7 to 1.3 kg versus 0.6 to 1.1 kg in the IM group (362 participants; 2 trials; low-quality evidence). Alpha-glucosidase CT compared to IM showed a MD of -0.5 kg (95% CI -1.2 to 0.3); P = 0.26; 241 participants; 2 trials; low-quality evidence.
Users of metformin CT (range 7% to 67% versus 5% to 16%), and alpha-glucosidase inhibitors CT (14% to 75% versus 4% to 35%) experienced more gastro-intestinal adverse effects compared to participants on IM. Two trials reported a higher frequency of oedema with the use of pioglitazone CT (range: 16% to 18% versus 4% to 7% IM).