Insulins NPH, glargine, and detemir, and risk of severe hypoglycemia among working-age adults*

Abstract

Introduction: The longer acting basal insulin analogs glargine and detemir have shown a lower incidence of hypoglycemia compared to insulin NPH in clinical studies. We evaluated the real-life risk of severe hypoglycemia among new users of insulins in the working-age population in Finland.

Methods: All persons aged 18–65 years with diabetes mellitus who were newly prescribed with insulins NPH, glargine, or detemir during 2006–2009, were identified from national registers. Risk of severe hypoglycemia requiring hospital care was compared between insulin types.

Results: A total of 16,985 persons initiated basal insulin treatment (5586, 7499, and 3900 patients started NPH, glargine, and detemir, respectively) during follow-up. Five hundred and thirty-six persons were hospitalized because of severe hypoglycemia. Absolute rate (per 1000 patient-years) was 20.6 (95% CI 17.9, 23.8), 17.8 (15.6, 20.3), and 12.4 (9.9, 15.5) for NPH, glargine, and detemir initiators, respectively. With NPH as reference, the adjusted hazard ratio (HR) was 0.92 (95% CI 0.74, 1.15, p = 0.47) for glargine, and 0.70 (0.51, 0.94, p= 0.018) for detemir. The HR for detemir compared to glargine was 0.76 (0.58, 0.99, p = 0.040).

Conclusions: Initiating insulin treatment with detemir, but not with glargine, was associated with a significantly lower risk of severe hypoglycemia compared to NPH, among working-age adults.

KEY MESSAGES

• The comparative safety of modern basal insulins regarding hypoglycemia among the working-age population is unclear.

• Large reductions in the incidence of severe hypoglycemia were seen among real-life patients who started insulin detemir, as compared to patients who initiated glargine or especially NPH insulin.

• Given the large amount of patients using insulin, these findings may have considerable clinical consequences at the population level.

Keywords:

• Hypoglycemia
• basal insulin therapy
• NPH insulin
• insulin glargine
• insulin detemir
• working-age population

Introduction

Hypoglycemia is a common and costly side effect of insulin treatment, both for patients with type-1 or type-2 diabetes. Serious hypoglycemia is associated with elevated mortality and risk of cardiovascular events, hospitalization, and subsequent costs (1,2). In the United States, there were almost 100,000 yearly visits of insulin-related hypoglycemia to the emergency department according to a report in 2014 (3). The risk increases further with advancing age due to reduced counter-regulatory responses and impaired awareness of warning symptoms (4,5). This has led to a re-evaluation of the benefits of stringent glucose lowering, especially among older people with cardiovascular risk. On the other hand, avoiding hypoglycemic incidents may lead to worsening of glycemic control among insulin treated patients, and increase subsequent risk of complications in the long term.

The intermediate-acting basal insulin NPH has been the conventional choice to initiate insulin treatment. Modern long-acting analogs, insulin glargine (since 2003) and insulin detemir (since 2005) have gained popularity as they permit once daily injections and have provoked less hypoglycemia in randomized controlled trials (RCTs) (6–8). However, the various inclusion criteria for the participants in clinical trials constrains the generalizability of these findings for the general population. Thus studies with real-life patients are needed to fully demonstrate the potential benefits of newer basal insulins. However, real-life studies on the association of choice of insulin and hypoglycemia are sparse, and they typically include older patients, who may have a greater susceptibility for hypoglycemia.

The aim of this nationwide, register-based longitudinal study was to evaluate the risk of severe hypoglycemia among insulin-treated patients with diabetes aged 18–65 and compare this outcome between new users of NPH, glargine, and detemir.

Methods

Study population and design

All persons aged 18–65 years, who were newly prescribed with basal insulin (NPH, glargine, or detemir) between 1 January 2006 and 31 December 2009 were identified from the Finnish Prescription Register (N = 17,483). Of these, patients with diabetes types other than type 1 or 2 (N= 485), and patients with less than one day of follow-up (N =13) were excluded. The final study cohort consisted of 16,985 patients.

The cost of all types of insulins is fully reimbursed for the patients in Finland. Because of unique personal identity codes and comprehensive and reliable national registers, we were able to retrieve both insulin use and episodes of severe hypoglycemia which required hospital care, for virtually all the patients who initiated insulin treatment during the study period.

The index date for cohort entry was defined as the date of the first purchase of one of the insulins. The subjects were followed until the first severe hypoglycemic event, death, or through 2009. During the study period, all three basal insulins were available for prescription, and 100% reimbursed for patients with diabetes.

Diabetes reimbursement status (type 1, type 2, other specified type, or undefined), and use of insulin (ATC code A10A) and sulfonylurea (A10BB) were obtained from the Finnish registry for reimbursed medications.

The study endpoint was the first severe hypoglycemic event resulting in hospital admission with the ICD-10 diagnosis code E10.00 or E11.00 as the main or secondary reason. Records of hospital visits due to severe hypoglycemia were obtained from the Finnish Hospital Care Register, which contains data concerning all hospitalization periods.

Exposure variable

Time-dependent exposure was defined “as treated” based on the date of purchase and the amount purchased. Exposure started at the time of purchase, and the duration of the purchase was based on the estimated average daily dose of the patient, which was estimated from the cumulative amount purchased and the time between the first and last purchase. In the case of overlapping basal insulins, we assumed the most recent purchased insulin to be in use. Periods with unknown exposure were assigned to exposure group “unknown”.

Statistical analysis

The Poisson regression model and the Cox’s proportional hazards (PH) model were used to estimate the absolute rates of severe hypoglycemia with 95% confidence intervals (CIs) and the adjusted HRs for the insulins with NPH as reference. The time scale adopted in the Cox’s PH model was time since index date accounting for any changes in the baseline risk with respect to time in study cohort. Use of sulfonylurea, use of other than basal insulin (this consisted mostly of brief use of a short acting insulin during periods of ill health or pregnancy), prior hospitalizations due to severe hypoglycemia, age at index date, gender, type of diabetes, and switch of basal insulin were used as adjusting covariates. The PH assumption was checked visually by the Kaplan–Meier curves, and several sensitivity analyses including propensity score (PS) (9) weighted analysis were performed to confirm the robustness of the results. The statistical significance of the HRs was evaluated using p-values with p-values under 0.05 considered as significant. Data management and data analysis were performed using the R software (http://www.r-project.org) (10).

Ethical statement

This is a register-based study with anonymous data and no patient contact was performed. The study protocol was approved by the Ethical Review Board of the Hjelt Institute, University of Helsinki Medical Faculty. The research permission numbers to use the data were obtained from the Social Insurance Institute (Kela 14/522/2011), the National Institute for Health and Welfare (Dnro THL/408/5.05.00/2011), and the Statistics Finland (TK-53-367-11).

Results

Baseline characteristics

We identified 16,985 type-1 or type-2 diabetes patients who had started treatment with newly prescribed basal insulin. Of these 3900 initiated detemir, 7499 glargine, and 5586 started NPH. The mean follow-up time was 1.8 years. Two-thirds of the patients were male. The proportion of type-2 diabetes patients was higher in the NPH insulin group compared to initiators of glargine and detemir. The number of prescriptions for NPH declined during the follow-up, whereas there was a rising trend for prescriptions for detemir and glargine with time. The mean age of the NPH initiators was 54 years, versus 52 and 51 years for the glargine and detemir initiators, respectively. The proportion of persons with an episode of hospitalization due to severe hypoglycemia prior to the index date was significantly lower among those starting detemir (6,6%) compared to among those who initiated glargine (8,6%) or NPH (8,4%). Otherwise the baseline characteristics between the three insulin groups were broadly similar (Table 1).

Table 1. Baseline characteristics of the study population stratified by type of basal insulin (n = 16,985).

Baseline	Patients who initiated detemir n = 3900 (23.0%)		Patients who initiated glargine n = 7499 (44.2%)		Patients who initiated NPH n = 5586 (32.9%)
Variables^a	n	%	n	%	n	%	p value^b
Age, years
18–29	324	8.3%	471	6.3%	140	2.5%	<0.001
30–49	1016	26.1%	1865	24.9%	1275	22.8%
50-	2560	65.6%	5163	68.9%	4171	74.7%
mean (SD)	51.1 (11.9)	52.0 (11.0)	53.9 (9.3)
Gender
Female	1373	35.2%	2369	31.6%	1863	33.4%	<0.001
Type of diabetes
Type 1	755	19.4%	1333	17.9%	516	9.2%	<0.001
Type 2	2940	75.4%	5672	75.6%	4642	83.1%
Undefined	205	5.3%	494	6.6%	428	7.7%
Time since diabetes diagnosis, years
≤1	1548	39.7%	2959	39.5%	2221	39.8%	0.25
>1–≤5	1034	26.5%	1862	24.8%	1436	25.7%
>5–≤10	895	23.0%	1766	23.6%	1271	22.8%
>10	423	10.9%	912	12.2%	658	11.8%
Mean (SD)	4.3 (5.7)	4.4 (5.8)	4.2 (5.3)
Calendar year at start of follow-up
2006	234	6.0%	595	7.9%	2492	44.6%	<0.001
2007	766	9.6%	2091	27.9%	1745	31.2%
2008	1295	33.2%	2437	32.5%	846	15.2%
2009	1605	41.2%	2376	31.7%	503	9.0%
Prior use of nonbasal insulin^c
Yes	396	10.2%	671	9.0%	329	5.9%	<0.001
Prior use of sulfonylurea
Yes	1823	46.7%	3639	48.5%	2863	51.3%	<0.001
Prior hospitalizations due to severe hypoglycemia
Yes	257	6.6%	645	8.6%	468	8.4%	<0.001

^a Baseline is the date of purchase of first basal insulin.

^b p value based on Pearson’s Chi-square test.

^c “Prior use of nonbasal insulin” denotes a prescription for a nonbasal insulin. This consisted mostly of brief use of a short acting insulin during periods of ill health or pregnancy.

Risk of severe hypoglycemic events according to insulin type

A total of 536 (3.2%) persons were hospitalized due to severe hypoglycemia during follow-up. Of these, 190 (35.4%), 222 (41.4%), and 76 (14.2%) persons were users of NPH, glargine, and detemir at the time of hospitalization, respectively. The type of insulin in use at that time was not available for 48 (9.0%) persons. The crude rates (per 1000 person-years) for severe hypoglycemic events were 20.6 (95% CI 17.9, 23.8) for NPH insulin, 17.8 (15.6, 20.3) for glargine, and 12.4 (9.9, 15.5) for detemir. The HR estimates were adjusted for the type of diabetes, gender, age, time since diagnosis, concurrent use of sulfonylureas, concurrent use of other insulin, prior use of sulfonylurea or other insulins at index date, the year of index date, prior hospitalizations due to severe hypoglycemia, and switch of basal insulin type during follow-up (Table 2). With NPH insulin as the comparator, the adjusted HR (95% CI) was 0.92 (0.74, 1.15, p= 0.47) for glargine and 0.70 (0.51, 0.94, p= 0.018) for detemir. For detemir compared to glargine, the HR was 0.76 with (0.58, 0.99, p= 0.040).

Table 2. Factors associated with risk of a severe hypoglycemic event.

Variables (Reference category)	Categories	HR	95% CI	p value
Basal insulin (NPH)	Detemir	0.70	0.52, 0.94	0.018
	Glargine	0.92	0.74, 1.15	0.47
	Unknown	0.96	0.69, 1.33	0.82
Basal insulin (glargine)^a	Detemir	0.76	0.58, 0.99	0.040
Age, years (18–29)	30–49	1.25	0.79, 1.97	0.35
	50-	1.51	0.95, 2.39	0.082
Gender (Male)	Female	0.87	0.72, 1.05	0.13
Type of diabetes (Type 1)	Type 2	1.39	1.02,1.89	0.035
	Undefined	1.21	0.73, 2.03	0.46
Time since diagnosis of diabetes, years (≤1)	>1–≤5	0.86	0.66, 1.13	0.28
	>5–≤10	0.83	0.61, 1.11	0.21
	>10-	0.85	0.56, 1.28	0.43
Calendar year at start of follow-up (2006)	2007	0.83	0.67, 1.04	0.10
	2008	0.71	0.54, 0.92	0.011
	2009	0.56	0.38, 0.81	0.002
Prior use of non-basal insulin at baseline^b (No)	Yes	0.98	0.71, 1.35	0.88
Prior use of sulfonylurea at baseline (No)	Yes	0.93	0.72, 1.20	0.58
Prior hospitalizations due to severe hypoglycemia (No)	Yes	5.71	4.75, 6.87	<0.001
Switch of basal insulin (No)	Yes	1.39	1.00, 1.93	0.052
Concurrent use of sulfonylureas (No)	Yes	1.00	0.78, 1.28
Concurrent use of other insulin (No)	Yes	1.30	1.05, 1.62	0.017

^a Alternative parameterization.

^b Denotes a prescription for a nonbasal insulin. This consisted mostly of brief use of a short acting insulin during periods of ill health or pregnancy.

Neither the declining trend for severe hypoglycemia during follow-up, nor the differences in the number of annual prescriptions of the insulins essentially affected the results.

In most of the sensitivity analyses, the risk of severe hypoglycemia remained largely unaltered and significantly lower for detemir, but did not reach significance for glargine initiators (Table 3). In a per-protocol type of analysis, where the follow-up period was censored if the initial basal insulin was switched, the risk of severe hypoglycemia was 0.69 (0.50, 0.95, p = 0.024) for detemir and 0.94 (0.74, 1.18, p= 0.57) for glargine compared to initiators of NPH (Model 5 in Table 3). In the PS-weighted analysis (Table 4), the results remained essentially unchanged with HR 0.74 (0.63, 0.86, p< 0.001) for detemir and 0.94 (0.82, 1.07, p = 0.34) for glargine compared to NPH, respectively.

Table 3. Sensitivity analyses for risk of severe hypoglycemia for the users of insulins detemir and glargine with NPH as reference.

	Detemir		Glargine
Model	Hazard ratio	95% CI, p value	Hazard ratio	95% CI, p value
Model 1: Base model. Follow-up periods with unknown exposure of basal insulin form an unknown exposure category.	0.70	0.52, 0.94, p = 0.018	0.92	0.74, 1.15, p = 0.47
Model 2: Periods with unknown insulin exposure are censored.	0.73	0.55, 0.99, p = 0.041	0.96	0.77, 1.20, p = 0.70
Model 3: Assume use of last purchased basal insulin during periods of unknown insulin exposure.	0.76	0.57, 1.01, p = 0.054	0.97	0.78, 1.20, p = 0.77
Model 4: Time periods with overlapping use of basal insulins are censored.	0.70	0.52, 0.95, p = 0.020	0.94	0.76, 1.18, p = 0.61
Model 5: The follow-up period is censored at the purchase of a basal insulin different to the initial basal insulin (switch).	0.69	0.50, 0.95, p = 0.024	0.94	0.74, 1.18, p = 0.57
Model 6: Analysis using the inverse of the propensity scores as weights (1% of the lowest and highest weights are truncated). Baseline summary table for the PS weighted population is presented in Table 4.	0.74	0.63, 0.86, p < 0.001	0.94	0.82, 1.07, p = 0.34
Model 7a: Stratified analysis: Patients with no prior hypoglycemic hospitalization at baseline.	0.77	0.53,1.11, p = 0.16	0.99	0.74, 1.31, p = 0.92
Model 7b: Stratified analysis: Patients with prior hypoglycemic hospitalization at baseline.	0.52	0.31,0.89, p = 0.017	0.77	0.53, 1.12, p = 0.17

Propensity score weighted analysis:

Propensity scores (PS), the probabilities of initiating each of the basal insulins at the start of follow-up conditional on measured potential confounders (i.e. age, gender, type of diabetes, calendar year on initiation, prior use of sulfonylurea, prior use of other insulin, prior severe hypoglycemic events, and the time since the diagnosis of diabetes), were calculated using multinomial logistic regression. Weighting each subject with the inverse of the PS results in a “pseudo”population where the distributions of the potential confounders (covariates included in PS model) are balanced between exposure groups (17). Utilizing the PS weights corresponds to performing an unweighted analysis on the pseudo population. The distribution of the baseline variables used as covariates in the PS model is presented for the pseudopopulation in Table 4. The risk of severe hypoglycemia for the PS-weighted population is given in sensitivity model 6 in Table 3.

Table 4. The distribution of baseline variables among the inverse propensity score (PS) weighted population stratified by type of insulin.

	Patients who initiated detemir n = 14,527 (31.4%)		Patients who initiated glargine n = 16,603 (35.9%)		Patients who initiated NPH n = 15,099 (32.7%)
Baseline variables^a	n	%	N	%	n	%
Age, years
18–29	1017	7.0%	949	5.7%	630	4.2%
30–49	3770	26.0%	4237	25.5%	3794	25.1%
50-	9740	67.0%	11417	68.8%	10675	70.7%
mean (SD)	51.54 (11.41)	52.11 (10.85)	52.91 (10.15)
Gender
Female	4939	34.0%	5402	32.5%	5040	33.4%
Type of diabetes
Type 1	2946	20.3%	3230	19.5%	1506	10.0%
Type 2	10,722	73.8%	12,235	73.7%	12,590	83.4%
Undefined	859	5.9%	1138	6.9%	1004	6.7%
Time since diabetes diagnosis, years
≤1	5926	40.8%	6671	40.2%	6348	42.0%
>1–≤5	3660	25.2%	4187	25.2%	3745	24.8%
>5–≤10	3272	22.5%	3801	22.9%	3289	21.8%
>10-	1669	11.5%	1944	11.7%	1717	11.4%
mean (SD)	4.35 (6.00)	4.37 (5.90)	4.08 (5.40)
Calendar year at start of follow-up
2006	1327	9.1%	2920	17.6%	3303	21.9%
2007	4109	28.3%	4615	27.8%	4585	30.4%
2008	4566	31.4%	4581	27.6%	4231	28.0%
2009	4525	31.2%	4486	27.0%	2980	19.7%
Prior use of other insulins than basal insulin^a
Yes	1378	9.5%	1432	8.6%	1153	7.6%
Prior use of sulfonylurea
Yes	6795	46.8%	7966	48.0%	7105	47.0%
Prior hospitalizations due to severe hypoglycemia
Yes	1098	7.6%	1329	8.0%	1248	8.3%

A reasonable balance in the distributions between groups is obtained for all baseline variables except for the variable “calendar year at initiation”.

Note all sample sizes result from weighting the original population with the inverse of the PS.

^a Denotes a prescription for a nonbasal insulin. This consisted mostly of brief use of a short acting insulin during periods of ill health or pregnancy.

Discussion

In a large, nationwide, real-world follow-up study of up to 4 years among diabetic patients aged 18–65, we compared the risk of severe hypoglycemia among new basal insulin users. Compared to the treatment with conventional NPH insulin, the adjusted risk of severe hypoglycemia was 8% lower among users of glargine, and 30% lower for detemir users. Furthermore, detemir was associated with a significant risk reduction of 24% in comparison to glargine.

Strengths and limitations

Our study has several strengths. We used a representative national database of 30,955 patient-years and accurate prescription data. We employed a hard endpoint of severe hypoglycemia established by comprehensive and reliable hospital records. At the start of follow-up, all participants were basal insulin-naïve. Furthermore, the large database allowed adjustment for potential confounding factors. For detemir users, the lower magnitudes of the adjusted HRs for severe hypoglycemia were consistent, as demonstrated by the sensitivity analyses.

Since the risk of severe hypoglycemia is pronounced in older persons, it must be noted that those initiating NPH were on average 2 years and 3 years older than those starting glargine or detemir, respectively. This may then favor the newer analogues in our study, albeit age was accounted for in the analysis. On the other hand, it is also a strength that the scope of our study is in the 18–65 age group omitting the old, thus reducing the number of persons with comorbidities or who are at the end of life where an episode of hypoglycemia may be a marker of serious illness. The risk may be different in the working-age population also because younger patients with insulin treatment typically have type-1 diabetes mellitus, and they are also guided for stricter glycemic control than older patients.

There are also limitations; especially a possible treatment selection bias must be considered. Firstly, we do not have information on glucose or HbA1c levels during the study. This may be important, because it is conceivable that if detemir or glargine would have been the preferred choice for patients with higher glucose values at baseline, they could also have higher glucose values during the study and subsequently experience less hypoglycemia. However, since this is a study of real-life patients, it is not presumable that the attending physicians would have had different glycemic targets for users of different basal insulins. In addition, the Finnish population is rather homogeneous in regard to ethnicity and socioeconomic factors. Nevertheless, the possibility remains that the choice of basal insulin type could depend on the glucose levels at baseline. Additionally, it must be noted that the number of patients who had experienced an episode of severe hypoglycemia before baseline, that is, before initiating basal insulin treatment, was up to 23% lower among the detemir group compared to those who started glargine or NPH. However, the history of previous hospitalizations due to severe hypoglycemia was taken into account in the adjusted analyses.

Also information on lifestyle, BMI, as well as comorbidities among the cohort is lacking. All these could affect the choice of basal insulin by the prescribing physician. For instance, the lower risk of hypoglycemia shown in clinical trials could have favored the initiation of glargine or detemir for persons with cardiovascular disease, for whom hypoglycemia could be anticipated to be more harmful. However, in our study, this would benefit the NPH group, and rather lead our results toward null.

Secondly, persons with type-1 and type-2 diabetes are analyzed together. They may constitute different patient profiles and risk of hypoglycemia, and thus, the choice for the type of insulin prescribed for them may be different. However, there were no guidelines for prescribers regarding insulin preference, and there was no difference in the availability or costs between the three insulins for the patients during the study period. Although accounted for in the analysis, the proportion of type-1 diabetes was somewhat larger among the initiators of glargine and detemir, leaving room for residual confounding.

Thirdly, changes in treatment pattern are not constricted among real-life patients as is usually the case in RCTs. In our study, 16% of the patients switched their insulin type during the follow-up. By comparison, this is a much lower figure than in a previous study of patients in primary care in the United Kingdom (11).. Nevertheless, the sensitivity analyses indicate that taking gaps and switches in insulin treatment into account does not alter our conclusions (Table 4).

Finally, the decline in the number of NPH initiators, and conversely, the rise in the number of glargine and especially detemir initiators during the study period may produce a bias. However, this reflects the real-life evolvement of insulin treatment in Finland and elsewhere: In 2006, NPH was globally the most widely used basal insulin, but the longer-acting glargine and detemir have since been gradually replacing NPH (12).

Interpretation

Hypoglycemia increases cardiovascular risk and all-cause mortality. In a study in the United Kingdom, hypoglycemia was experienced by 18% and 14% of type-1 and type-2 diabetic patients, respectively, during a follow-up of 5 years. Among these patients, there was a 50–60% increase in cardiovascular events, while total mortality was roughly doubled compared with patients who did not experience hypoglycemia (1). Another recent study demonstrated an estimated loss of life expectancy of over 10 years for persons with type-1 diabetes compared with the general Scottish population (13). Hypoglycemic coma was an important contributor to the reduced life-expectancy especially among younger patients. Additionally, intensified glycemic control is associated with a 2–2.5-fold increased risk of severe hypoglycemia in RCTs (14). Hypoglycemia may explain the conflicting results of studies such as the ACCORD study, where targeting stricter control on glucose in patients with type-2 diabetes resulted in higher mortality (15). We have recently reported significant differences in mortality among new users of NPH, glargine and detemir among real-life patients with type-2 diabetes (16).

Compared to NPH, both longer-acting insulins, glargine, and detemir have in RCTs been shown to provoke less hypoglycemia (7,8). How these outcomes translate to advantages in real-life populations is not clear. As detemir was not launched until 2005, it has not been extensively analyzed as a comparator with glargine. A recent systematic review of 28 RTCs found only four studies where detemir and glargine had been compared head to head among type-2 patients (17). No difference in risk of hypoglycemia was found in these studies. However, patients participating in clinical trials may be highly selected, and they are not necessarily representative of those in clinical practice. Observational studies in real-life setting comparing basal insulins for hypoglycemia are scarce. In a previous study using Finnish national registers (N = 75,000), new initiators of detemir and glargine had a 31% and 16% lower risk of a severe hypoglycemic episode, respectively, during a follow-up of 4 years (6). However, that study also included older adults who may have a greater susceptibility to hypoglycemia. On the other hand, a 1-year follow-up of 500 working-age adults with type-2 diabetes newly initiating NPH or glargine showed no difference in hypoglycemia frequency. However, the overall rates of hypoglycemia in this study were low (18). Furthermore, another real-life study of type-2 patients newly initiating glargine or detemir did not find a difference in hypoglycemia incidence (19). Contrary to this, we found a significant and clinically meaningful difference between detemir and glargine users for severe hypoglycemia incidence in adjusted analyses. Follow-up studies are warranted to confirm our findings.

The incidence of severe hypoglycemia in our study may seem low compared to previous studies. One explanation is that the definition of severe hypoglycemia varies among studies. We collected only hospital verified severe hypoglycemic events, and not, for instance, those where hypoglycemia was treated with assistance at home, or as recalled by the patient. Secondly, only the first episode of severe hypoglycemia was an endpoint in our study; that is, we did not analyze subsequent incidents for the same patient. This is important, because a history of severe hypoglycemia is a significant risk factor for subsequent episodes (20). And thirdly, most studies include older patients, which is likely to increase the hypoglycemia incidence.

Although the risk of serious hypoglycemia was rather low, it must be noted that hypoglycemia requiring hospital care is only the tip of the iceberg. The rate of total hypoglycemic events (including nonsevere) may be over 40-fold compared to severe hypoglycemia in insulin-treated patients (21). In addition to the acute complications and increased risk of cardiovascular events and mortality, also psychological reactions may be deleterious to the patient, to the family, or for example at the workplace. Furthermore, the fear of hypoglycemia may lead to lower adherence, and subsequently to higher glucose levels and complications later in the course of diabetes.

In conclusion, in a longitudinal study of adults of working age, the risk of severe hypoglycemia requiring hospital care was lower among new users of insulin glargine, and significantly lower among users of detemir, compared to initiators of NPH insulin. Our study of a real-life population is in line with previous findings of similar benefits found in randomized controlled trials. In all, regarding the large number of patients globally with insulin therapy, hypoglycemia is a major public health issue. Our findings implicate that it can be significantly affected by the choice of basal insulin. Because in many countries NPH is advocated as the first-line insulin over human analogs, our results may contribute to a change in clinical practice.

Disclosure statement

The authors declare that there is no conflict of interest associated with this manuscript. F. Hoti and K. Houssem are employed by EPID Research, which is a contract research organization that performs commissioned pharmacoepidemiological studies and thus its employees have been and currently are working in collaboration with several pharmaceutical companies. T. E. Strandberg has had research, educational and consultative cooperation with several pharmaceutical companies (including Novo Nordisk and Sanofi) and owns a minor amount of stock in Orion Pharma. A. Y. Strandberg has had research, educational and consultative cooperation with several pharmaceutical companies (including Novo Nordisk and Sanofi), and owns a minor amount of stock in Orion Pharma. S. Mäkimattila and T. Saukkonen are employees of Novo Nordisk A/S, the manufacturer of insulin detemir.

Funding

Retrieve and analysis of national register data by EPID Research was financially supported by Novo Nordisk Pharma. Dr T. Strandberg’s research is supported by the Gustaf V and Queen Victoria Frimurarestiftelse.