Long-Term Effectiveness and Safety of Once Weekly Dulaglutide as Add-on to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes

Abstract Aim of this monocentric retrospective observational study was to evaluate the 18-month effectiveness and safety of once weekly 1.5 mg GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) as add-on to metformin (MET) or MET plus conventional insulin secretagogues (SFU/glinide) in a study cohort with excess body weight (BW) and type 2 diabetes (T2D). Comparative efficacy versus once daily 1.2/1.8 mg liraglutide (LIRA) in a study sample naïve to GLP-1 RAs, matching for age, gender, BMI, T2D duration, cardiovascular comorbidities and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate-severe gastrointestinal AEs after a median follow-up of 6 (3 to 8) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant median HbA1c reduction of -0.9 (-1.50 to -0.20) % with respect to baseline values (p<0.001), which remained stable during 18 months of follow-up. These results were accompanied by a moderate BW loss sustained over time, with a median reduction of -1.16 (-4,29 to 0.45) % at 6 months and -1.47 (-4.2 to 0.72) % at 18 months (p=0.048). At univariate Spearman analysis, a negative correlation between baseline BMI and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity (BMI ≥ 30kg/m2) against drug discontinuation was confirmed by an exploratory logistic regression analysis, while adjusting for confounders [OR 0.211 (95%CI 0.058–0.771), p=0.019]. Neither gender, nor age, nor T2D duration, nor concomitant SUF/glinide use, nor shifting to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in form of HbA1c reduction ≥ 0.5% [OR 2.961 (95%CI 1.394–6.290), p=0.005] or BW loss ≥ 5% [OR 2.571 (95%CI 1.171–5.644), p=0.019]. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and BW in real word scenarios (1). With the advantage of once weekly administration, at 18-month follow-up, a significant larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p=0.033). Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial glycometabolic responses to DU on a background of MET or MET plus SFU/glinide are durable, especially in presence of obesity and greater HbA1c impairment. (1) Ref: Mirabelli et al. IJERPH. 2019;17(1):207.

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Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes

Journal of Clinical Medicine ◽

10.3390/jcm10050985 ◽

2021 ◽

Vol 10 (5) ◽

pp. 985

Author(s):

Maria Mirabelli ◽

Eusebio Chiefari ◽

Vera Tocci ◽

Patrizia Caroleo ◽

Stefania Giuliano ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Body Weight ◽

Receptor Agonist ◽

Drug Discontinuation ◽

Baseline Body Mass Index ◽

Study Cohort ◽

Insulin Secretagogues

Aims and methods: The aim of this monocentric retrospective observational study was to evaluate the 18-month safety and effectiveness of GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) 1.5 mg/once weekly as an add-on to metformin (MET) or MET plus conventional insulin secretagogues in a study cohort with excess body weight and type 2 diabetes (T2D). Comparative efficacy versus liraglutide (LIRA) 1.2–1.8 mg/once daily in a study sample naïve to GLP-1 RAs, frequency matching for age, gender, T2D duration, degree of glycemic impairment, cardiovascular comorbidities, and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Results: Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate–severe gastrointestinal AEs after a mean follow-up of 6 (4 standard deviations (SD)) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant mean HbA1c reduction of −0.85% (1.17 SD) with respect to baseline values (p < 0.001), which remained stable during 18 months follow-up. These results were accompanied by a moderate weight loss sustained over time, with a mean reduction of −2.0% (4.3 SD) at 6 months and −1.3% (4.8 SD) at 18 months (p = 0.091). At univariate analysis, a negative correlation between baseline body mass index (BMI) and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity against drug discontinuation was confirmed by logistic regression analysis. Neither gender, nor age, nor T2D duration, nor concomitant conventional insulin secretagogue use, nor switching to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in terms of HbA1c reduction ≥ 0.5% or body weight loss ≥ 5%. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and body weight in real-world experiences. With the advantage of once-weekly administration, at 18-month follow-up, a significantly larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p = 0.033). Conclusions: Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial responses to DU on a background of MET or MET plus insulin secretagogues are durable, especially in the presence of obesity and greater HbA1c impairment.

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Risk of lower extremity amputations in patients with type 2 diabetes using sodium-glucose co-transporter 2 inhibitors

Acta Diabetologica ◽

10.1007/s00592-021-01805-8 ◽

2021 ◽

Author(s):

Spela Zerovnik ◽

Mitja Kos ◽

Igor Locatelli

Keyword(s):

Type 2 Diabetes ◽

Lower Extremity ◽

Study Cohort ◽

Dipeptidyl Peptidase 4 ◽

Intention To Treat ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

History Of

Abstract Aims To compare the influence of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of lower extremity amputations in patients with type 2 diabetes in Slovenia. Methods This retrospective cohort study included patients aged 40 years or more who were administered a newly introduced SGLT2i or DPP-4i between June 2014 and June 2018. Patients treated with insulin at baseline and patients with a history of amputation were excluded. Patients were matched in a 1:1 ratio using propensity score matching. Survival analysis was performed; hazard ratio (HR) and ratios of cumulative hazards at 1, 2, 3, and 4 years were estimated. On-treatment and intention-to-treat approaches were used. Results The study cohort (mean age: 64 years) consisted of 2,939 new users of SGLT2i (empagliflozin, 59%; dapagliflozin, 41%) matched to 2,939 new users of DPP-4i. In the on-treatment analysis (median follow-up of 2 years), the incidence of amputations was higher in SGLT2i than in DPP-4i users (4.2 vs. 2.7 per 1,000 patient years), resulting in a HR of 1.58 (95% CI 0.85–2.92; p = 0.145). An intention-to-treat analysis yielded to similar HR of 1.86 (95% CI: 1.10–3.14; p = 0.020). There was no difference in amputation rates in the first two years, but SGLT2i users had a 2.81-fold higher (95% CI: 1.63–4.84; p = 0.007) cumulative hazard of amputation at 4 years than did DPP-4i users. Conclusions Compared with DPP-4i use, SGLT2i use did not result in a statistically significant higher overall risk of lower extremity amputations. However, the results suggest that SGLT2i may increase the risk of amputation with long-term use.

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How Family Physicians Practice the Principle of Remission Along the Glycemic Continuum

Journal of Primary Care & Community Health ◽

10.1177/2150132720977744 ◽

2020 ◽

Vol 11 ◽

pp. 215013272097774

Author(s):

Stephanie T. Fulleborn ◽

Paul F. Crawford ◽

Jeremy T. Jackson ◽

Christy J.W. Ledford

Keyword(s):

Type 2 Diabetes ◽

Medical Record ◽

The United States ◽

Case Scenario ◽

Cross Sectional ◽

Normal Glucose ◽

Normal Glucose Regulation

Introduction Recent evidence reveals that diabetes and prediabetes (preDM) can be reversed to normal glucose regulation (NGR) through significant weight loss, but how physicians clinically identify the principles of partial and complete remission of diabetes is largely unknown. Methods As part of the cross-sectional omnibus survey conducted in March 2019 at a professional annual meeting in the United States, physician participants answered case scenario questions about the diagnosis and documentation of patients with preDM and type 2 diabetes (T2DM). Results Of the registered conference attendees, 387 (72.7%) responded. When presented with the initial case of preDM, 201 physicians (70.8%) selected R73.03 Prediabetes. In a follow-up encounter with improved lab results, 118 physicians (58.7%) indicated that they would not chart any diabetes-related code and 62 (30.8%) would chart preDM again. When presented with the case of T2DM, 256 physicians (90.1%) indicated E11.0–E11.9 Type 2 Diabetes. In the follow-up encounter, only 38 (14.8%) coded a diagnosis reflecting remission from T2DM to prediabetes and 211 (82.4%) charted T2DM. Conclusion Physicians may be reluctant to document diabetes regression as there is little evidence for long-term outcomes and “downgrading” the diagnosis in the medical record may cause screenings to be missed. Documenting this regression in the medical record should communicate the accurate point on the continuum of glucose intolerance with both the patient and the care team.

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564-P: Long-Term Follow-up of Glycemic Excursion Minimization (GEM) Compared with Weight Loss in Management of Type 2 Diabetes (T2D)

Diabetes ◽

10.2337/db21-564-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 564-P

Author(s):

DANIEL COX ◽

MATTHEW A. MONCRIEF ◽

ANTHONY L. MCCALL

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Long Term Follow Up

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Association of Bariatric Surgery With Cancer Incidence in Patients With Obesity and Diabetes: Long-term Results From the Swedish Obese Subjects Study

10.2337/figshare.16903630 ◽

2021 ◽

Author(s):

Kajsa Sjöholm ◽

Lena MS Carlsson ◽

Per-Arne Svensson ◽

Johanna C. Andersson-Assarsson ◽

Felipe Kristensson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bariatric Surgery ◽

Cancer Risk ◽

Cancer Incidence ◽

Diabetes Remission ◽

Obesity And Diabetes ◽

Obese Subjects

OBJECTIVE Obesity and type 2 diabetes are associated with serious, adverse health effects, including cancer. Although bariatric surgery has been shown to reduce cancer risk in patients with obesity, the effect of bariatric surgery on cancer risk in patients with obesity and diabetes is less studied. We therefore examined the long-term incidence of cancer after bariatric surgery and usual care in patients with obesity and diabetes in the matched prospective Swedish Obese Subjects (SOS) study. RESEARCH DESIGN AND METHODS The SOS study examines long-term outcomes following bariatric surgery or usual care. The current analysis includes 701 patients with obesity and type 2 diabetes at baseline, 393 of which underwent bariatric surgery, and 308 who received conventional obesity treatment. Information on cancer events was obtained from the Swedish National Cancer Register. Median follow-up time was 21.3 years (interquartile range 17.6-24.8 years, maximum 30.7 years). RESULTS During follow-up, the incidence rate for first-time cancer was 9.1 per 1000-person-years (95% CI, 7.2-11.5) in patients with obesity and diabetes treated with bariatric surgery and 14.1 per 1000-person-years (95% CI, 11.2-17.7) in patients treated with usual obesity care (HRadj=0.63; 95% CI 0.44-0.89, p=0.008). Moreover, surgery was associated with reduced cancer incidence in women (HRadj=0.58; 0.38-0.90, p=0.016), although the sex-treatment interaction was non-significant (p=0.630). In addition, diabetes remission at the 10-year follow-up was associated with reduced cancer incidence (HRadj=0.40; 95% CI 0.22-0.74, p=0.003). CONCLUSIONS These results suggest that bariatric surgery prevents cancer in patients with obesity and diabetes, and that durable diabetes remission is associated with reduced cancer risk.

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Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes

Acta Endocrinologica ◽

10.1530/eje-13-0321 ◽

2013 ◽

Vol 169 (6) ◽

pp. 725-733 ◽

Cited By ~ 219

Author(s):

Vakkat Muraleedharan ◽

Hazel Marsh ◽

Dheeraj Kapoor ◽

Kevin S Channer ◽

T Hugh Jones

Keyword(s):

Type 2 Diabetes ◽

Untreated Group ◽

Testosterone Replacement ◽

Testosterone Deficiency ◽

Testosterone Levels ◽

All Cause Mortality ◽

Low Testosterone

ObjectiveMen with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone.Research design and methodsA total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.8±1.3 s.d. years. Mortality rates were compared between total testosterone >10.4 nmol/l (300 ng/dl; n=343) and testosterone ≤10.4 nmol/l (n=238). The effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group.ResultsMortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2–3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3–3.9, P=0.004).ConclusionsLow testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

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Long-term BMI change trajectories in Chinese adults and its association with the hazard of type 2 diabetes: evidence from a 20-year China Health and Nutrition Survey

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000879 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000879

Author(s):

Baibing Mi ◽

Chenlu Wu ◽

Xiangyu Gao ◽

Wentao Wu ◽

Jiaoyang Du ◽

...

Keyword(s):

Type 2 Diabetes ◽

Latent Class ◽

Chinese Adults ◽

Change Trajectories ◽

Nutrition Survey ◽

Health And Nutrition ◽

Increased Risk

IntroductionTo investigate the relationship between long-term change trajectory in body mass index (BMI) and the hazard of type 2 diabetes among Chinese adults.Research design and methodsData were obtained from the China Health and Nutrition Survey (CHNS). Type 2 diabetes was reported by participants themselves in each survey wave. The duration of follow-up was defined as the period from the first visit to the first time self-reported type 2 diabetes, death, or other loss to follow-up from CHNS. The patterns of change trajectories in BMI were derived by latent class trajectory analysis method. The Fine and Gray regression model was used to estimate HRs with corresponding 95% CIs for type 2 diabetes.ResultsFour patterns of the trajectories of change in BMI were identified among Chinese adults, 42.7% of participants had stable BMI change, 40.8% for moderate BMI gain, 8.9% for substantial BMI gain and 7.7% for weight loss. During the follow-up with mean 11.2 years (158 637 person-years contributed by 14 185 participants), 498 people with type 2 diabetes (3.7%) occurred. Risk of type 2 diabetes was increased by 47% among people who gained BMI more substantially and rapidly (HR: 1.47, 95% CI 1.08 to 2.02, p=0.016) and increased by 20% among those in people with the moderate BMI gain (HR: 1.20, 95% CI 0.98 to 1.48, p=0.078), compared with those with stable BMI change.ConclusionsLong-term substantial gain of BMI was significantly associated with an increased risk of type 2 diabetes in the Chinese adults.

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