Björn Eliasson

One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients: A randomized, controlled trial

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Effects of Exenatide on Measures of β-Cell Function After 3 Years in Metformin-Treated Patients With Type 2 Diabetes

OBJECTIVE We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI). RESULTS At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (−7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and −0.99 ± 0.65, respectively; P = 0.028). CONCLUSIONS EXE and GLAR sustained HbA1c over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

The insulin resistance syndrome in smokers is related to smoking habits.

The relationship between smoking habits, insulin resistance, and related risk factors for cardiovascular disease was examined in 57 middle-aged male smokers whose degree of insulin resistance was quantified by using the euglycemic clamp technique. Smoking habits correlated with degree of insulin resistance and consequently with various manifestations of the insulin resistance syndrome including levels of insulin, high-density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 (PAI-1) activity. Smoking habits, independent of degree of insulin resistance, were also related to levels of total cholesterol and low-density lipoprotein cholesterol as well as triglycerides. Stepwise regression analyses considering the effects of age, lean body mass, body fat, body mass index, waist/hip ratio, and alcohol consumption showed that only smoking habits and percent body fat were independently related to degree of insulin resistance. This study shows that insulin resistance and the insulin resistance syndrome are important but not unique contributors to the strong risk profile for cardiovascular disease in middle-aged men who smoke.

Smoking cessation improves insulin sensitivity in healthy middle‐aged men

Cigarette smokers have recently been shown to exhibit insulin resistance, dyslipidaemia and markers of the insulin resistance syndrome (IRS). The aim of this study was to examine the effects of smoking cessation on insulin sensitivity and IRS. Forty male, non‐obese healthy smokers participated in this open parallel study with 8 weeks of follow‐up. Seventeen subjects were able to stop smoking, while 23 subjects continued to smoke and served as a controls group. Anthropometric and metabolic data were measured. Degree of insulin sensitivity was determined with the euglycaemic hyperinsulinaemic clamp technique. Smoking cessation increased insulin sensitivity and improved the lipoprotein profile in spite of a modest increase in body weight. Initial smoking habits correlated positively with the increase in BMI as well as the improvements in the metabolic variables after smoking cessation. These data support the view that smoking causes insulin resistance and IRS, and also demonstrate that the beneficial metabolic effects of smoking cessation override the effects of an accompanying modest increase in body weight.

The insulin resistance syndrome and postprandial lipid intolerance in smokers

BACKGROUND The effects of cigarette smoking on insulin resistance, postprandial lipemia following a mixed meal, lipoproteins and other aspects of the insulin resistance syndrome (IRS) were investigated in healthy middle-aged men. METHODS 36 smoking and 25 age- and body mass index (BMI)-matched non-smoking men participated. They were non-obese (BMI < 27), healthy and without any medication. The smokers had been smoking more than 10 cigarettes per day for more than 20 years; the non-smokers had never been habitual smokers. Body composition and several metabolic and cardiovascular risk factors were studied, including the prevalence of small dense LDL-particles, lipoprotein and hepatic lipase activity and triglyceride levels after a mixed test meal. For determination of degree of insulin sensitivity the euglycemic hyperinsulinemic clamp technique was used. RESULTS The smokers had lower HDL-cholesterol and lipoprotein A-I levels but higher fasting triglycerides, as well as an increased proportion of small dense LDL-particles and higher postheparin hepatic lipase activity. They also had higher levels of fibrinogen, plasminogen activator inhibitor 1 (PAI-1) activity and fasting and steady-state C-peptide levels during the clamp. The smokers were insulin resistant and lipid intolerant with an impaired triglyceride clearance after a mixed test meal. This lipid intolerance was not mirrored by fasting hypertriglyceridemia. CONCLUSIONS This study, using the euglycemic hyperinsulinemic clamp technique, shows that smokers are both insulin resistant and lipid intolerant. The postprandial lipid intolerance is also seen in individuals with normal fasting triglyceride levels and is related to an increased prevalence of atherogenic small dense LDL. IRS is likely to be an important reason for the increased cardiovascular morbidity in smokers.

The gap between guidelines and reality: Type 2 diabetes in a national diabetes register 1996–2003

Guidelines for the treatment of risk factors in diabetes care have been updated recently, due to indisputable results from clinical end‐point trials. This study evaluates risk factor control compared with current national and international targets during the period 1996–2003 in Type 2 diabetes (DM2). Patients were registered in primary‐care and hospital outpatient clinics using computer software, or via the Internet. The clinical characteristics of the patients, treatment, HbA1c, and risk factors were reported after screening by local methods. The numbers of cases of DM2 reported were 17547 in 1996 and 57119 in 2003. The mean HbA1c decreased from 7.8 to 7.2%, while blood pressure decreased from 150/82 to 143/78 mmHg during the same period. Longitudinal analysis of results was performed in 5356 patients repeatedly reported, showing slightly lower effects. The new European treatment targets of HbA1c≤ 6.1%, blood pressure < 130/80 mmHg and total cholesterol < 4.5 mmol/l were attained by 16, 13 and 28% of the patients in 2003, respectively. The prevalence of the metabolic syndrome in 2003 was 77%. Aspirin was prescribed in 36% of cases. Lipid‐lowering, anti‐hypertensive drugs, and treatment with oral hypoglycaemic agents in combination with insulin were increasingly employed during the period studied. Risk factor control in DM2 reported to the National Diabetes Register (NDR) is slowly improving, although multiple risk factors and the metabolic syndrome are found in most patients. The majority of subjects do not achieve current target levels for HbA1c, blood pressure and blood lipids. Thus, giving up smoking and increased use of aspirin are called for, as well as more aggressive treatment of hyperglycaemia, elevated blood pressure and blood lipid levels, in accordance with updated international guidelines.

Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register

Objective To evaluate the effectiveness and safety of metformin use in clinical practice in a large sample of pharmacologically treated patients with type 2 diabetes and different levels of renal function. Design Observational study between July 2004 and December 2010, mean follow-up 3.9 years. Setting Hospital outpatient clinics and primary care in Sweden. Participants 51 675 men and women with type 2 diabetes, registered in the Swedish National Diabetes Register, and on continuous glucose-lowering treatment with oral hypoglycaemic agents (OHAs) or insulin. Main outcome measures Risks of cardiovascular disease (CVD), all-cause mortality and acidosis/serious infection, associated with each treatment regimens, were analysed in all patients and in subgroups with different estimated glomerular filtration rate (eGFR) intervals. Covariance adjustment and propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression. Results Compared with metformin in monotherapy, HRs for fatal/non-fatal CVD and all-cause mortality with all other OHAs combined (approximately 80% sulphonylureas) in monotherapy were 1.02 (95% CI 0.93 to 1.12) and 1.13 (1.01 to 1.27), while 1.18 (1.07 to 1.29) and 1.34 (1.19 to 1.50) with insulin in monotherapy, adjusting using propensity scores. Metformin, compared with any other treatment, showed reduced risks of acidosis/serious infection (adjusted HR 0.85, 95% CI 0.74 to 0.97) and all-cause mortality (HR 0.87, 95% CI 0.77 to 0.99), in patients with eGFR 45–60 ml/min/1.73 m2, and no increased risks of all-cause mortality, acidosis/serious infection or CVD were found in patients with eGFR 30–45 ml/min/1.73 m2. Conclusions Metformin showed lower risk than insulin for CVD and all-cause mortality and slightly lower risk for all-cause mortality compared with other OHA, in these 51 675 patients followed for 4 years. Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. In clinical practice, the benefits of metformin use clearly outbalance the risk of severe side effects.

New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).

Abstract.  Eeg‐Olofsson K, Cederholm J, Nilsson PM, Zethelius B, Svensson A‐M, Gudbjörnsdóttir S, Eliasson B (Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg; Department of Public Health and Caring Sciences/Family Medicine and Clinical Epidemiology, Uppsala University, Uppsala; Department of Clinical Sciences, Lund University, University Hospital, Malmö; Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala; and Center of Registers in Region Västra Götaland, Gothenburg, Sweden) New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR). J Intern Med 2010; 268: 471–482.

Risk Prediction of Cardiovascular Disease in Type 2 Diabetes: A risk equation from the Swedish National Diabetes Register

OBJECTIVE—Risk prediction models obtained in samples from the general population do not perform well in type 2 diabetic patients. Recently, 5-year risk estimates were proposed as being more accurate than 10-year risk estimates. This study presents a diabetes-specific equation for estimation of the absolute 5-year risk of first incident fatal/nonfatal cardiovascular disease (CVD) in type 2 diabetic patients with use of A1C and clinical characteristics. RESEARCH DESIGN AND METHODS—The study was based on 11,646 female and male patients, aged 18–70 years, from the Swedish National Diabetes Register with 1,482 first incident CVD events based on 58,342 person-years with mean follow-up of 5.64 years. RESULTS—This risk equation incorporates A1C, as in the UK Prospective Diabetes Study risk engine, and several clinical characteristics: onset age of diabetes, diabetes duration, sex, BMI, smoking, systolic blood pressure, and antihypertensive and lipid-reducing drugs. All predictors included were associated with the outcome (P < 0.0001, except for BMI P = 0.0016) with Cox regression analysis. Calibration was excellent when assessed by comparing observed and predicted risk. Discrimination was sufficient, with a receiver operator curve statistic of 0.70. Mean 5-year risk of CVD in all patients was 12.0 ± 7.5%, whereas 54% of the patients had a 5-year risk ≥10%. CONCLUSIONS—This more simplified risk equation enables 5-year risk prediction of CVD based on easily available nonlaboratory predictors in clinical practice and A1C and was elaborated in a large observational study obtained from the normal patient population aged up to 70 years.

Exenatide Affects Circulating Cardiovascular Risk Biomarkers Independently of Changes in Body Composition

OBJECTIVE To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. RESEARCH DESIGN AND METHODS Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. RESULTS Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. CONCLUSIONS Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.