There were a total of 69 674 people included in the analysis (). The most common initial drug therapy was metformin (66.3% of patients), with insulin secretagogue monotherapy being less common (29.3%) (). The mean initial dose was equivalent to 0.5 (standard deviation 0.4) defined daily doses. Almost one-third of the study population was admitted to hospital at least once in the year before the index date, and about 60% of patients consulted a physician more than 10 times in that period.
Selection of the study population. *Patients who received an oral antidiabetes drug between Jan. 1, 1998, and Dec. 24, 2004, and who had not taken an oral antidiabetes drug in the 1 year before the date of the first prescription.
Characteristics of elderly patients (n = 69 674) who initiated oral antidiabetes therapy during the study period
In this cohort, the rate of initiation of insulin therapy was 9.7 cases per 1000 patient-years. In total, 1955 (2.8%) patients who initially used oral antidiabetes drugs began insulin therapy during a median follow-up time of 2.9 years ().
Initiation of insulin among patients who started to take an oral antidiabetes drug during the study period.
Of the 17 potential determinants of insulin initiation that we evaluated, 7 were statistically significant at p < 0.01 (). Patients who received initial treatment with an insulin secretagogue (v. metformin), who had their oral antidiabetes drug prescribed by an endocrinologist or an internist (v. general practitioner), who used higher initial doses of an oral antidiabetes drug, who used oral corticosteroids, who used glucometer strips, who were admitted to hospital in the year before initiation of oral antidiabetes therapy, or who were prescribed 16 or more medications were more likely than those without these characteristics to initiate insulin therapy. Patients who received thiazides or who used up to 12 medications (v. none) had a decreased risk of insulin initiation. The year of initiation of oral antidiabetes therapy was not associated with initiation of insulin therapy.
Factors associated with the initiation of insulin therapy in elderly patients (n = 69 674) who initiated oral antidiabetes therapy during the study period
Among new elderly users of oral antidiabetes drugs, the rate of insulin initiation was 9.7 cases per 1000 patient-years. In other words, for every 1000 new users of oral antidiabetes drugs observed for 1 year, about 10 would be expected to initiate insulin therapy.
This rate of insulin initiation seems low. It is, however, difficult to interpret because it may either indicate a low rate of secondary failure of oral antidiabetes therapy in this population or that diabetes is not being treated aggressively enough. The incidence rate is helpful because it allows comparisons with different populations or in the same population over time. The incidence rate also provides the opportunity to examine factors associated with the initiation of insulin therapy.
Several of the factors that we observed to be associated with initiation of insulin therapy may reflect the effects of insulin resistance. First, in contrast with metformin, sulfonylureas do not have a stabilizing effect on weight and do not enhance insulin sensitivity.15
Second, patients receiving high initial doses of oral antidiabetes drugs are likely to have high blood glucose levels at diagnosis because of inadequate pancreatic β-cell function to keep pace with higher insulin resistance levels. These patients may require insulin earlier. Third, it is well established that corticosteroids can significantly increase glucose levels.16
Patients admitted to hospital in the year before starting an oral antidiabetes drug were more likely than those not admitted to be prescribed insulin. Past hospital admission may indicate patients who were more ill. Also, because the diagnosis of type 2 diabetes is often delayed,6,17
the probability of being diagnosed with type 2 diabetes might increase during a hospital stay, especially if patients have microvascular and macrovascular complications. Similarly, patients taking 16 or more drugs in the year before initiation were more likely than those taking 15 or fewer medications to be sicker, because the number of different drugs prescribed is an indicator of comorbidities.14
These patients are also more likely to consult a physician on a regular basis and, therefore, are more likely to be offered insulin. In contrast, patients who took up to 12 medications had a decreased risk compared to patients who took no medications. This result is difficult to explain.
Evidence is lacking about the relation between prior use of self-administered glycemic tests and subsequent initiation of insulin therapy. Patients who monitor their own blood glucose are used to manipulating needles and, therefore, might be less fearful of self-administering insulin injections. Also, their behaviour demonstrates that they are already taking their condition seriously.18
We found that patients taking thiazide diuretics in the year before initiation of oral antidiabetes drugs were less likely than those not taking thiazide to initiate insulin therapy. Since the early 1980s, studies of drug therapy for hypertension have documented an unfavourable effect of thiazides on plasma lipid levels.19
Thiazides are also known to induce a mild form of glucose intolerance.20
Although the development of clinically important diabetes may be unusual, it is clear that some degree of insulin resistance may be seen in many patients receiving thiazides. However, this effect is mainly seen at high doses.21
Because lower doses of thiazide, which may be metabolically neutral, are currently used,22,23
we no longer expect thiazides to predispose patients to dysglycemia.
Other researchers have examined the factors associated with insulin initiation among new users of oral antidiabetes drugs. A younger age,7
a low body mass index,7
being a woman,24
taking more than 1 oral antidiabetes drug,24
an increase in daily dosage frequency or in the number of comedications,24
and having a history of myocardial infarction, dyslipidemia, depression and atrial fibrillation25
have all been reported to be predictors of insulin initiation. Researchers in these studies7,24,25
did not observe factors similar to those that we have identified. These discrepencies may be explained by differences in methodology. First, except for age and sex, the variables that we tested were different from those evaluated in these 3 studies.7,24,25
Second, our study population, on average, was older than the populations in those studies. Next, in 2 studies,7,25
the length of exposure to oral antidiabetes drugs was not the same for all participants, which makes the interpretation of cumulative incidence difficult. In the third,24
individuals who discontinued oral antidiabetes drugs in the 18-month period before insulin initiation were excluded. This exclusion criterion may be a potential source of bias because people who discontinued oral antidiabetes therapy during the first 18 months may have been switched to insulin therapy. Therefore, in these studies, factors reported as being associated with insulin initiation should be interpreted with caution.
Our study provides “real-world” insight from a population-based cohort of elderly people taking oral diabetes medications; however, several limitations should be considered when interpreting the results. First, studies have reported that thiazolidinediones may delay the onset of insulin initiation.26
Because we excluded patients initially taking a thiazolidinedione, we were not able to confirm this finding in our population. Second, analysis of medications was based on pharmacy refills; however, refilling may not represent the actual use of drugs. Third, we were not able to assess whether insulin initiation by new users of oral antidiabetes drugs was because of a higher body mass index, severity of diabetes or failure to achieve glycemic control because these clinical data are not captured in the Régie de l’assurance maladie du Québec database. Lastly, patient preferences, perception of health or beliefs about their disease and its treatment were not available in the administrative databases. Thus, the associations that we reported were limited to the examination of an incomplete set of variables.
This study was based on information gathered between 1998 and 2004. Although during that period, insulin initiation was mainly considered to represent secondary failure of oral antidiabetes drug therapy, insulin is now recommended as the initial treatment for patients with type 2 diabetes and marked hyperglycemia.2,4
It is therefore unclear whether the factors associated with insulin initiation indicate secondary failure of oral antidiabetes drug therapy or simply better management of type 2 diabetes. Indeed, recent improvements in the organization of care have made it easier and safer to care for older patients with diabetes.
The main disadvantage of insulin therapy is hypoglycemia. Reported benefits for patients with type 2 diabetes include improved well-being and possibly quality of life,27,28
as well as improved cognitive function,29
partly because of improved glycemic control. However, others have found lower treatment satisfaction in patients taking insulin.30
Although the advantages of better metabolic control in patients with type 2 diabetes have been advocated for a long time, in particular for patients aged 40–55 years,31,32
this has recently been challenged by a study showing that intensive glucose therapy may be beneficial only in patients aged 65 or fewer years.33
The clinical decision to initiate insulin requires that the benefits should outweigh the risks.2