Reductions in FPG were apparent as early as week 1. Throughout the study, FPG reductions were more marked in 5 and 10 mg dapagliflozin arms and were statistically significant at week 24 Fig.
Mean body weight decreases were greater with all dapagliflozin doses than with placebo, although they did not reach statistical significance Fig.
Changes from baseline at week 24 in efficacy parameters, vital signs, and laboratory values. In the exploratory evening dose cohort, changes from baseline in A1C, FPG, and body weight at week 24 were similar to those seen in the main patient cohort Table 2.
In the exploratory high-A1C cohort Subgroup analyses of the main patient cohort by baseline A1C were consistent with the ability of dapagliflozin to cause greater A1C reductions in patients with high baseline A1C.
Treatment with dapagliflozin did not result in any clinically meaningful changes from baseline in serum electrolytes including serum sodium Table 2.
There were no clinically relevant changes in any renal function parameter including serum creatinine, blood urea nitrogen, or cystatin C.
In addition, there were no clinically relevant changes in mean serum albumin with dapagliflozin treatment. Small, dose-ordered mean increases in hematocrit up to 2.
A decrease in mean seated blood pressure with no notable increase in orthostatic hypotension was observed in the dapagliflozin arms Table 2.
Treatment with dapagliflozin did not alter the lipid profile of patients, although small numerical increases in HDL cholesterol were noted in all dapagliflozin arms placebo-subtracted adjusted mean change from baseline value [SE] ranged from 0.
Glucose-to-creatinine ratios were higher with dapagliflozin than with placebo Table 2. Higher values with the evening dose presumably reflect the pharmacokinetic half-life of dapagliflozin.
Adverse events are summarized in Table 3. There was one death due to a motor vehicle accident in the 10 mg dapagliflozin group.
There were no major episodes of hypoglycemia in this study, and none of the patients discontinued the study medication due to hypoglycemia. An increased incidence in signs and symptoms and other reports suggestive of UTIs and genital infections was noted with dapagliflozin treatment.
Safety data in the exploratory evening dose cohort were similar to those in the morning dose cohort. There were no other notable differences in the number or type of adverse events reported with the evening dose.
Administration of dapagliflozin as monotherapy to treatment-naive patients with type 2 diabetes resulted in clinically meaningful decreases in A1C and FPG, along with favorable effects on weight, blood pressure, and other metabolic parameters.
Although the decrease in body weight in our study did not reach statistical significance compared with placebo, dapagliflozin treatment did lead to increased renal glucose excretion.
It should also be noted that the progressive decrease in weight over time had not reached a plateau by the end of study; thus, long-term studies are needed to more precisely gauge the effect of dapagliflozin on weight in the monotherapy setting.
Furthermore, in exploratory analysis of pooled data greater increments in fractional renal glucose excretion were associated with greater decrements in body weight, suggesting a link between the mechanism of action of dapagliflozin and clinical outcome.
Data from the high-A1C cohort are of particular relevance given the mechanism of action of dapagliflozin as an SGLT2 inhibitor. Patients with high A1C at enrollment are likely already to present with glycosuria as their filtered glucose load may exceed the absorption capacity of the kidney.
However, dapagliflozin was able to elicit a considerable improvement in glycemia in the exploratory high-A1C cohort. There were no major episodes of hypoglycemia in this study.
After prospectively defined monitoring see research design and methods , signs and symptoms suggestive of UTIs and genital infections were more frequently reported in the dapagliflozin arms.
The decrease in mean systolic and diastolic blood pressure noted in this study is in keeping with the diuretic effect of dapagliflozin. Also consistent with this effect is the increase in hematocrit levels noted in the dapagliflozin arms.
In addition to blood pressure, favorable, albeit small, effects were also noted in several other clinical parameters including HDL cholesterol, uric acid, and high-sensitivity C-reactive protein.
Although effects on weight, blood pressure, and other metabolic risk factors were small, they may have a cumulative benefit in the long term.
Most notably, lowering of plasma glucose with dapagliflozin is accompanied by a urinary loss of calories, suggesting a shift toward negative net energy balance.
This effect of dapagliflozin is unlike that of other antidiabetic agents, which often cause weight gain as they lower plasma glucose concentrations.
Given its effect on net energy balance and its insulin-independent mechanism, dapagliflozin is likely to have beneficial effects in a wide spectrum of patients with diabetes 17 , No other potential conflicts of interest relevant to this article were reported.
We thank the investigators and contributors from each of the study sites. We also thank Sudha Vemuri, Ph.
The costs of publication of this article were defrayed in part by the payment of page charges. Section solely to indicate this fact.
National Center for Biotechnology Information , U. Journal List Diabetes Care v. Published online Jun Find articles by Weihua Tang.
Author information Article notes Copyright and License information Disclaimer. Received Mar 30; Accepted Jun Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
This article has been cited by other articles in PMC. Abstract OBJECTIVE Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner.
End points and assessments The primary efficacy end point was change from baseline in A1C at week 24 in the main patient cohort.
Open in a separate window. Table 1 Demographics and baseline characteristics. Table 2 Changes from baseline at week 24 in efficacy parameters, vital signs, and laboratory values.
Table 3 Adverse events. Footnotes Clinical trial reg. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes UKPDS N Engl J Med ; Oral antihyperglycemic therapy for type 2 diabetes: Weight gain and metabolic control in newly insulin-treated patients with type 2 diabetes with different insulin regimens.
Can J Diabetes ; Kidney Int ; In OCT, this interference is shortened to a distance of micrometers, owing to the use of broad-bandwidth light sources i.
Light with broad bandwidths can be generated by using superluminescent diodes or lasers with extremely short pulses femtosecond lasers.
White light is an example of a broadband source with lower power. Light in an OCT system is broken into two arms—a sample arm containing the item of interest and a reference arm usually a mirror.
The combination of reflected light from the sample arm and reference light from the reference arm gives rise to an interference pattern, but only if light from both arms have traveled the "same" optical distance "same" meaning a difference of less than a coherence length.
By scanning the mirror in the reference arm, a reflectivity profile of the sample can be obtained this is time domain OCT. Areas of the sample that reflect back a lot of light will create greater interference than areas that don't.
Any light that is outside the short coherence length will not interfere. A cross-sectional tomograph B-scan may be achieved by laterally combining a series of these axial depth scans A-scan.
A face imaging at an acquired depth is possible depending on the imaging engine used. OCT delivers high resolution because it is based on light, rather than sound or radio frequency.
An optical beam is directed at the tissue, and a small portion of this light that reflects from sub-surface features is collected.
Note that most light is not reflected but, rather, scatters off at large angles. In conventional imaging, this diffusely scattered light contributes background that obscures an image.
However, in OCT, a technique called interferometry is used to record the optical path length of received photons allowing rejection of most photons that scatter multiple times before detection.
Thus OCT can build up clear 3D images of thick samples by rejecting background signal while collecting light directly reflected from surfaces of interest.
Within the range of noninvasive three-dimensional imaging techniques that have been introduced to the medical research community, OCT as an echo technique is similar to ultrasound imaging.
Other medical imaging techniques such as computerized axial tomography, magnetic resonance imaging, or positron emission tomography do not use the echo-location principle.
It is also important to note that the laser output from the instruments is low — eye-safe near-infrared light is used — and no damage to the sample is therefore likely.
The principle of OCT is white light, or low coherence, interferometry. The optical setup typically consists of an interferometer Fig.
Light is split into and recombined from reference and sample arm, respectively. In time domain OCT the pathlength of the reference arm is varied in time the reference mirror is translated longitudinally.
A property of low coherence interferometry is that interference, i. This interference is called auto correlation in a symmetric interferometer both arms have the same reflectivity , or cross-correlation in the common case.
The envelope of this modulation changes as pathlength difference is varied, where the peak of the envelope corresponds to pathlength matching.
Due to the coherence gating effect of OCT the complex degree of coherence is represented as a Gaussian function expressed as .
In equation 2 , the Gaussian envelope is amplitude modulated by an optical carrier. The peak of this envelope represents the location of the microstructure of the sample under test, with an amplitude dependent on the reflectivity of the surface.
The optical carrier is due to the Doppler effect resulting from scanning one arm of the interferometer, and the frequency of this modulation is controlled by the speed of scanning.
Therefore, translating one arm of the interferometer has two functions; depth scanning and a Doppler-shifted optical carrier are accomplished by pathlength variation.
In OCT, the Doppler-shifted optical carrier has a frequency expressed as. The axial and lateral resolutions of OCT are decoupled from one another; the former being an equivalent to the coherence length of the light source and the latter being a function of the optics.
The axial resolution of OCT is defined as. In frequency domain OCT FD-OCT the broadband interference is acquired with spectrally separated detectors either by encoding the optical frequency in time with a spectrally scanning source or with a dispersive detector, like a grating and a linear detector array.
Due to the Fourier relation Wiener-Khintchine theorem between the auto correlation and the spectral power density the depth scan can be immediately calculated by a Fourier-transform from the acquired spectra, without movement of the reference arm.
The parallel detection at multiple wavelength ranges limits the scanning range, while the full spectral bandwidth sets the axial resolution.
Thereby the information of the full depth scan can be acquired within a single exposure. The drawbacks of this technology are found in a strong fall-off of the SNR, which is proportional to the distance from the zero delay and a sinc-type reduction of the depth dependent sensitivity because of limited detection linewidth.
One pixel detects a quasi-rectangular portion of an optical frequency range instead of a single frequency, the Fourier-transform leads to the sinc z behavior.
Additionally the dispersive elements in the spectroscopic detector usually do not distribute the light equally spaced in frequency on the detector, but mostly have an inverse dependence.
Therefore, the signal has to be resampled before processing, which can not take care of the difference in local pixelwise bandwidth, which results in further reduction of the signal quality.
However, the fall-off is not a serious problem with the development of new generation CCD or photodiode array with a larger number of pixels.
Synthetic array heterodyne detection offers another approach to this problem without the need for high dispersion. Here the spectral components are not encoded by spatial separation, but they are encoded in time.
The spectrum is either filtered or generated in single successive frequency steps and reconstructed before Fourier-transformation.
By accommodation of a frequency scanning light source i. Drawbacks are the nonlinearities in the wavelength especially at high scanning frequencies , the broadening of the linewidth at high frequencies and a high sensitivity to movements of the scanning geometry or the sample below the range of nanometers within successive frequency steps.
An imaging approach to temporal OCT was developed by Claude Boccara's team in ,  with an acquisition of the images without beam scanning.
More precisely, interferometric images are created by a Michelson interferometer where the path length difference is varied by a fast electric component usually a piezo mirror in the reference arm.
These images acquired by a CCD camera are combined in post-treatment or on-line by the phase shift interferometry method, where usually 2 or 4 images per modulation period are acquired, depending on the algorithm used.
The "en-face" tomographic images are thus produced by a wide-field illumination, ensured by the Linnik configuration of the Michelson interferometer where a microscope objective is used in both arms.
Furthermore, while the temporal coherence of the source must remain low as in classical OCT i. Focusing the light beam to a point on the surface of the sample under test, and recombining the reflected light with the reference will yield an interferogram with sample information corresponding to a single A-scan Z axis only.
Scanning of the sample can be accomplished by either scanning the light on the sample, or by moving the sample under test.
A linear scan will yield a two-dimensional data set corresponding to a cross-sectional image X-Z axes scan , whereas an area scan achieves a three-dimensional data set corresponding to a volumetric image X-Y-Z axes scan.
Systems based on single point, confocal, or flying-spot time domain OCT, must scan the sample in two lateral dimensions and reconstruct a three-dimensional image using depth information obtained by coherence-gating through an axially scanning reference arm Fig.
Two-dimensional lateral scanning has been electromechanically implemented by moving the sample  using a translation stage, and using a novel micro-electro-mechanical system scanner.
Parallel or full field OCT using a charge-coupled device CCD camera has been used in which the sample is full-field illuminated and en face imaged with the CCD, hence eliminating the electromechanical lateral scan.
By stepping the reference mirror and recording successive en face images a three-dimensional representation can be reconstructed.
Three-dimensional OCT using a CCD camera was demonstrated in a phase-stepped technique,  using geometric phase shifting with a Linnik interferometer ,  utilising a pair of CCDs and heterodyne detection,  and in a Linnik interferometer with an oscillating reference mirror and axial translation stage.
Optical coherence tomography is an established medical imaging technique and is used across several medical specialties including ophthalmology and cardiology, and is widely used in basic science research applications.
Ocular or ophthalmic OCT is used heavily by ophthalmologists and orthoptists to obtain high-resolution images of the retina and anterior segment.
Owing to OCT's capability to show cross-sections of tissue layers with micrometer resolution, OCT provides a straightforward method of assessing cellular organization , photoreceptor integrity ,     and axonal thickness in glaucoma ,  macular degeneration ,  diabetic macular edema ,  multiple sclerosis  and other eye diseases or systemic pathologies which have ocular signs .
More recently, ophthalmic OCT devices have been engineered to perform similar functions as fluorescein angiography , but without the need for injectable dye.
This new OCT angiography OCTA  technique is still in development, but has shown promise for assessing retinal microvasculature pathology.